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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq. Bras. Cardiol.</journal-id>
      <journal-title-group>
        <journal-title>Arquivos Brasileiros de Cardiologia</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Arq. Bras. Cardiol.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">0066-782X</issn>
      <issn pub-type="epub">1678-4170</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">kRb5YgS3HXrskbWXXzWSr4b</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2014000900001</article-id>
      <article-id pub-id-type="publisher-id">S0066-782X2014001300001</article-id>
      <article-id pub-id-type="doi">10.5935/abc.2014S002</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Diretrizes</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title xml:lang="pt">I Diretriz sobre Aspectos Espec&#237;ficos de Diabetes (tipo 2) Relacionados &#224; Cardiologia</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Soeiro</surname>
            <given-names>Alexandre de Matos</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Mansur</surname>
            <given-names>Antonio de P&#225;dua</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Schaan</surname>
            <given-names>Beatriz D.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Caramelli</surname>
            <given-names>Bruno</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rochitte</surname>
            <given-names>Carlos Eduardo</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Serrano</surname>
            <given-names>Carlos Vicente</given-names>
            <suffix>Jr.</suffix>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Garzillo</surname>
            <given-names>Cibele Larrosa</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Calderaro</surname>
            <given-names>Daniela</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Gualandro</surname>
            <given-names>Danielle M.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lima</surname>
            <given-names>Eduardo Gomes</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Marcondes-Braga</surname>
            <given-names>Fabiana G.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lima</surname>
            <given-names>Felipe Gallego</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Oliveira</surname>
            <given-names>Felipe Martins de</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Azevedo</surname>
            <given-names>Fernanda Reis</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Chauhan</surname>
            <given-names>Hiteshi</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Salles</surname>
            <given-names>Jo&#227;o Eduardo Nunes</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Soares</surname>
            <given-names>Jos&#233;</given-names>
            <suffix>Junior</suffix>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cardoso</surname>
            <given-names>Juliano Novaes</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pellanda</surname>
            <given-names>Lucia Campos</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Sacilotto</surname>
            <given-names>Luciana</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Baracioli</surname>
            <given-names>Luciano</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Bortolotto</surname>
            <given-names>Luiz A.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>C&#233;sar</surname>
            <given-names>Luiz Antonio Machado</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Ochiai</surname>
            <given-names>Marcelo Eidi</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Minami</surname>
            <given-names>Marcio H.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pinheiro</surname>
            <given-names>Martina Battistini</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Moretti</surname>
            <given-names>Miguel Antonio</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Oliveira</surname>
            <given-names>Mucio Tavares de</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rezende</surname>
            <given-names>Paulo Cury</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lemos</surname>
            <given-names>Pedro Alves</given-names>
            <suffix>Neto</suffix>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Admoni</surname>
            <given-names>Sharon Nina</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lottenberg</surname>
            <given-names>Sim&#227;o Augusto</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rocha</surname>
            <given-names>Viviane Z.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Hueb</surname>
            <given-names>Whady</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Mathias</surname>
            <given-names>Wilson</given-names>
            <suffix>Jr.</suffix>
          </name>
        </contrib>
      </contrib-group>
      <author-notes>
        <corresp><bold>Correspond&#234;ncia:</bold> Sociedade Brasileira de Cardiologia, Av. Marechal
               C&#226;mara, 160 - sala 330 - Centro - Rio de Janeiro-RJ - CEP 20020-907.</corresp>
      </author-notes>
      <pub-date pub-type="epub-ppub">
        <month>05</month>
        <year>2014</year>
      </pub-date>
      <volume>102</volume>
      <issue>5 Suppl 1</issue>
      <fpage>1</fpage>
      <lpage>41</lpage>
      <counts>
        <fig-count count="0"/>
        <table-count count="3"/>
        <equation-count count="0"/>
        <ref-count count="320"/>
        <page-count count="41"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <table-wrap>
      <caption>
        <title>Declara&#231;&#227;o de potencial conflito de Interesses dos autores/colaboradores da I
               Diretriz sobre Aspectos Espec&#237;ficos de Diabetes Melito (Tipo 2) Relacionados com a
               Cardiologia. Nos &#250;ltimos tr&#234;s anos, o autor/colaborador da diretriz:</title>
      </caption>
      <table frame="hsides" rules="rows">
        <thead>
          <tr>
            <th>Nomes Integrantes da Diretriz</th>
            <th>Participou de estudos cl&#237;nicos e/ ou experimentais subvencionados pela
                     ind&#250;stria farmac&#234;utica ou de equipamentos relacionados &#224; diretriz em
                     quest&#227;o</th>
            <th>Foi palestrante em eventos ou atividades patrocinadas pela ind&#250;stria
                     relacionados &#224; diretriz em quest&#227;o</th>
            <th>Foi (&#233;) membro do conselho consultivo ou diretivo da ind&#250;stria farmac&#234;utica ou
                     de equipamentos</th>
            <th>Participou de comit&#234;s normativos de estudos cient&#237;ficos patrocinados pela
                     ind&#250;stria</th>
            <th>Recebeu aux&#237;lio pessoal ou institucional da ind&#250;stria</th>
            <th>Elaborou textos cient&#237;ficos em peri&#243;dicos patrocinados pela ind&#250;stria</th>
            <th>Tem a&#231;&#245;es da ind&#250;stria</th>
          </tr>
        </thead>
        <tbody>
          <tr>
            <td>Alexandre de Matos Soeiro</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">GSK</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Antonio de P&#225;dua Mansur</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Beatriz D'Agord Schaan</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Bruno Caramelli</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Carlos Eduardo Rochitte</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Carlos Vicente Serrano Jr</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Cibele Larrosa Garzillo</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Daniela Calderaro</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Danielle Menosi Gualandro</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Eduardo Gomes Lima</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Fabiana G. Marcondes-Braga</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Felipe Gallego Lima</td>
            <td align="center">Astra Zeneca, Takeda, Roche, Sanofi-Aventis</td>
            <td align="center">Astra Zeneca</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Felipe Martins de Oliveira</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Fernanda Reis de Azevedo</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Hiteshi Chauan</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Jo&#227;o Eduardo Nunes Salles</td>
            <td align="center">SIM Ach&#233;, Boeringher-Ingelheim, Janssen- Cilag, Novartis, Novo
                     Nordisk, Sanofi</td>
            <td align="center">SIMAbbott Nutrition Astra Zeneca, Boeringher-Ingelheim,
                     Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Novartis, Novo Nordisk,
                     Sanoff</td>
            <td align="center">SIM Abbott, Nutrition, Astra Zeneca, Boeringher-Ingelheim,
                     Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Novartis, Novo Nordisk,
                     Sanoff</td>
            <td align="center">N&#227;o</td>
            <td align="center">SIM Abbott Nutrition, Astra Zeneca, Boeringher-Ingelheim,
                     Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Novartis, Novo Nordisk,
                     Sanofi</td>
            <td align="center">SIM Abbott Nutrition, Astra Zeneca, Boeringher-Ingelheim,
                     Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Novartis, Novo Nordisk,
                     Sanofi</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Jos&#233; Soares Junior</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Juliano Novaes Cardoso</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Lucia Campos Pellanda</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Luciana Sacilotto</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Luciano Moreira Baracioli</td>
            <td align="center">Daiichi-Sankyo, Lilly, Astra Zeneca</td>
            <td align="center">Astra Zeneca, Daiichi-Sankyo</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">Sanofi, Astra Zeneca</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Luiz Aparecido Bortolotto</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">Baldacci, Daichi-Sankyo</td>
            <td align="center">Baldacci, Daichi-Sankyo</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Luiz Antonio Machado Cesar</td>
            <td align="center">Astra Zeneca, Servier</td>
            <td align="center">Servier</td>
            <td align="center">Servier, Astra Zeneca</td>
            <td align="center">Servier, Astra Zeneca</td>
            <td align="center">Servier, Astra Zeneca</td>
            <td align="center">Servier, Astra Zeneca</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Marcelo Eidi Ochiai</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Marcio Hiroshi Miname</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Martina Battistini Pinheiro</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Miguel Antonio Moretti</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Mucio Tavares de Oliveira Junior</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">Sanofi, Merck Serono, Boehringer Ingelheim</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Paulo Cury Rezende</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Pedro A. Lemos</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Sharon Nina Admoni</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Sim&#227;o Augusto Lottenberg</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">Merck, Novo, Boehringer, Lily</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Viviane Zorzanelli Rocha</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Whady Hueb</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
          <tr>
            <td>Wilson Mathias Junior</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
            <td align="center">N&#227;o</td>
          </tr>
        </tbody>
      </table>
    </table-wrap>
    <sec>
      <title>1. Apresenta&#231;&#227;o e objetivos</title>
      <p>Aproximadamente dois ter&#231;os dos indiv&#237;duos com o diagn&#243;stico de diabetes
               <italic>mellitus</italic> (DM) acabam por falecer devido a doen&#231;a arterial
            coronariana (DAC) ou doen&#231;a cerebrovascular (DCV)<xref ref-type="bibr" rid="B01">1</xref>.</p>
      <p>O decl&#237;nio de mortalidade por DAC que tem sido observado na popula&#231;&#227;o geral nos EUA
            tamb&#233;m acontece entre os indiv&#237;duos com DM. De acordo com Gregg et al., a mortalidade
            por DAC entre os indiv&#237;duos adultos com DM diminuiu 40% e a mortalidade por todas as
            causas, 23% entre 1997 e 2006<xref ref-type="bibr" rid="B02">2</xref>. Estes dados
            indicam que a taxa de incremento de mortalidade por DAC e relacionada ao DM (quando em
            compara&#231;&#227;o com os adultos sem DM) diminuiu de 5,8 para 2,3 mortes por DAC em cada 1.000
            indiv&#237;duos, enquanto a taxa de incremento de mortalidade por todas as causas e
            relacionada ao DM diminuiu de 10,8 para 6,1 mortes por DAC em cada 1.000 indiv&#237;duos. Os
            autores concluem, entretanto, que estes resultados encorajadores podem provocar um
            aumento na preval&#234;ncia do DM no futuro pr&#243;ximo, se n&#227;o houver uma redu&#231;&#227;o importante na
            incid&#234;ncia desta doen&#231;a.</p>
      <p>Infelizmente a incid&#234;ncia do DM associado, na maioria das vezes, &#224; obesidade - o que
            levou &#224; cria&#231;&#227;o do termo <italic>diabesity</italic> - tem aumentado em diversos pa&#237;ses,
            inclusive no Brasil, tornando-se um grande problema de sa&#250;de p&#250;blica, o "calcanhar de
            Aquiles" da sociedade moderna<xref ref-type="bibr" rid="B03">3</xref>. A conflu&#234;ncia da
            maior incid&#234;ncia com a menor mortalidade tornar&#225; imprescind&#237;vel o esfor&#231;o conjunto de
            diversas especialidades m&#233;dicas para a preven&#231;&#227;o da doen&#231;a, tendo em vista o grande
            contingente de indiv&#237;duos que frequentar&#227;o ambulat&#243;rios de aten&#231;&#227;o prim&#225;ria, cl&#237;nicos
            gerais e especialistas.</p>
      <p>O cardiologista, portanto, deve estar familiarizado e atento a todos os aspectos
            relacionados ao DM, desde o diagn&#243;stico at&#233; o tratamento. O tratamento conjunto e
            complementar entre endocrinologistas e cardiologistas &#233; cada vez mais necess&#225;rio e o uso
            de uma linguagem e par&#226;metros &#250;nicos, indispens&#225;vel.</p>
      <p>Estas foram as raz&#245;es pelas quais a Sociedade Brasileira de Cardiologia (SBC) prop&#244;s a
            um seleto grupo de profissionais da sa&#250;de a elabora&#231;&#227;o de recomenda&#231;&#245;es relativas ao
            tratamento e &#224; preven&#231;&#227;o das complica&#231;&#245;es cardiovasculares do DM. O conte&#250;do deste
            documento, aprovado por todo o grupo participante, constitui a I Diretriz sobre Aspectos
            Espec&#237;ficos de Diabetes <italic>Mellitus</italic> (tipo 2) Relacionados &#224;
            Cardiologia.</p>
    </sec>
    <sec>
      <title>2. Epidemiologia</title>
      <p>Em 2010 o DM atingia 6,4% da popula&#231;&#227;o adulta mundial (20 a 79 anos), e para 2030 a
            estimativa &#233; de que a cifra atingir&#225; 7,7%<xref ref-type="bibr" rid="B04">4</xref>. A
            maior parte do aumento se dar&#225; em pa&#237;ses em desenvolvimento. No Brasil, dados da
            Vigil&#226;ncia de Fatores de Risco e Prote&#231;&#227;o para Doen&#231;as Cr&#244;nicas por Inqu&#233;rito Telef&#244;nico
            (VIGITEL) em pessoas com mais de 18 anos de idade residentes em capitais brasileiras
            mostram que a preval&#234;ncia de quem refere ter DM aumentou de 5,3% para 6,3% entre 2006 e
               2010<xref ref-type="bibr" rid="B05">5</xref>. No Brasil, em 2006, 6.317.621 de
            adultos referiam ter DM e 25.690.145, hipertens&#227;o arterial sist&#234;mica (HAS)<xref ref-type="bibr" rid="B06">6</xref>. Esse crescimento (20% em apenas quatro anos) pode
            ter sido resultado de maior n&#250;mero de diagn&#243;sticos. No entanto, padr&#245;es temporais
            desfavor&#225;veis de estilos de vida observados no pa&#237;s podem ter elevado a incid&#234;ncia de DM
            no per&#237;odo, contribuindo, dessa forma, tamb&#233;m para o aumento observado na
            preval&#234;ncia.</p>
      <p>As complica&#231;&#245;es agudas e cr&#244;nicas do DM causam elevada morbimortalidade, acarretando
            altos custos para os sistemas de sa&#250;de<xref ref-type="bibr" rid="B07">7</xref>. A
            mortalidade padronizada por causa espec&#237;fica (DCV e DM) em 2008 no Brasil foi de 248
            para cada 100.000 habitantes entre 30 e 70 anos de idade<xref ref-type="bibr" rid="B08">8</xref>. A hiperglicemia &#233; respons&#225;vel por 6% dos riscos de morte atribu&#237;veis na
            popula&#231;&#227;o em termos globais<xref ref-type="bibr" rid="B09">9</xref>. A presen&#231;a de DM &#233;
            um fator de risco independente para DAC, acidente vascular encef&#225;lico (AVE), doen&#231;a
            arterial perif&#233;rica (DAP) e insufici&#234;ncia card&#237;aca (IC), que s&#227;o as principais causas de
            morte nesses pacientes. Estudo transversal que incluiu 927 pacientes com DM tipo 2 (DM2)
            atendidos em n&#237;vel ambulatorial em tr&#234;s centros m&#233;dicos do Rio Grande do Sul observou
            36% de preval&#234;ncia de DAC, 33% de DAP e 73% de HAS<xref ref-type="bibr" rid="B10">10</xref>. Por outro lado, em um estudo realizado em Pernambuco com 323 pacientes
            com mais de 30 anos internados, sendo todos portadores de doen&#231;a card&#237;aca e, portanto,
            mais graves, a preval&#234;ncia de DM foi de 33,1%, sendo maior entre as mulheres (42,6%
            versus (vs.) 26,8%)<xref ref-type="bibr" rid="B11">11</xref>.</p>
      <p>O risco relativo para DCV aumenta de duas a quatro vezes nos pacientes com DM2 em
            compara&#231;&#227;o com a popula&#231;&#227;o em geral<xref ref-type="bibr" rid="B12">12</xref>. Estes
            pacientes apresentam frequentemente associa&#231;&#227;o de fatores de risco cardiovascular: HAS,
            n&#237;veis s&#233;ricos baixos de colesterol da lipoprote&#237;na de alta densidade (HDL-C),
            microalbumin&#250;ria e doen&#231;a renal, aumento do &#237;ndice de massa corporal (IMC) e da rela&#231;&#227;o
               cintura-quadril<xref ref-type="bibr" rid="B10">10</xref>
				<sup>,</sup>
				<xref ref-type="bibr" rid="B13">13</xref>. Considerando-se o conceito de risco
            cardiovascular global, pacientes com DM, mesmo sem doen&#231;a ateroscler&#243;tica estabelecida,
            apresentam maior risco de desenvolver eventos vasculares no futuro, embora este risco
            n&#227;o seja t&#227;o elevado quanto o daqueles que j&#225; tiveram evento isqu&#234;mico<xref ref-type="bibr" rid="B14">14</xref>.</p>
      <p>A DAC &#233; mais incidente e mais grave nos pacientes com DM em rela&#231;&#227;o &#224;queles sem DM<xref ref-type="bibr" rid="B13">13</xref>. As mulheres com DM s&#227;o particularmente afetadas
            pela DAC e seu risco de morte &#233; 50% maior do que o dos homens com DM. O DM, quando
            associado a fatores de risco cl&#225;ssicos para DAC, como hipercolesterolemia, fumo e HAS,
            aumenta o risco para DCV atribu&#237;do a cada um destes fatores de forma mais importante do
            que &#233; observado em indiv&#237;duos sem DM<xref ref-type="bibr" rid="B12">12</xref>. A
            frequ&#234;ncia de hipertens&#227;o mascarada pode ser maior no DM do que em indiv&#237;duos sem DM, e
            a incid&#234;ncia de desfechos cardiovasculares &#233; maior nesses pacientes, quando n&#227;o
               tratados<xref ref-type="bibr" rid="B15">15</xref>. A aus&#234;ncia de controle da HAS em
            pacientes com DM tamb&#233;m est&#225; associada a uma significativa carga de doen&#231;a nesses
            indiv&#237;duos, com uma fra&#231;&#227;o de risco atribu&#237;vel na popula&#231;&#227;o de cerca de 28%<xref ref-type="bibr" rid="B16">16</xref>.</p>
      <p>A apresenta&#231;&#227;o cl&#237;nica da DAC pode ser dor anginosa t&#237;pica ou at&#237;pica, mas a aus&#234;ncia de
            sintomas &#233; frequente (55% dos pacientes com DM)<xref ref-type="bibr" rid="B17">17</xref>. Al&#233;m disso, a DAC nesses pacientes tem pior progn&#243;stico, com menor sobrevida
            em curto prazo, maior risco de recorr&#234;ncia e pior resposta aos tratamentos
               propostos<xref ref-type="bibr" rid="B18">18</xref>. A letalidade do infarto agudo do
            mioc&#225;rdio (IAM) em pacientes com DM &#233; duas vezes maior do que naqueles sem DM, em raz&#227;o
            da maior frequ&#234;ncia de complica&#231;&#245;es como IC, reinfarto e morte s&#250;bita<xref ref-type="bibr" rid="B17">17</xref>. Por outro lado, a maior dura&#231;&#227;o do DM est&#225;
            associada &#224; ocorr&#234;ncia de IAM silencioso<xref ref-type="bibr" rid="B19">19</xref>.</p>
      <p>A doen&#231;a cerebrovascular tem tamb&#233;m maior incid&#234;ncia em pacientes com DM do que em
            indiv&#237;duos sem a doen&#231;a. Pacientes com DM tem um risco 1,5 a 3 vezes maior de apresentar
            AVE, e as doen&#231;as cerebrovasculares representam 20% das mortes dos pacientes com DM<xref ref-type="bibr" rid="B20">20</xref>. O AVE manifesta-se em pacientes com DM em idade
            inferior &#224; daqueles sem DM e, nos Estados Unidos, estima-se que 37% a 42% de todos os
            casos de AVE isqu&#234;mico sejam atribu&#237;veis ao DM, isoladamente ou em combina&#231;&#227;o com a
               HAS<xref ref-type="bibr" rid="B21">21</xref>.</p>
      <p>A DAP acomete duas a quatro vezes mais pacientes com DM, atingindo a preval&#234;ncia de 12%
            a 16% quando avaliada por meio da medida do &#237;ndice tornozelo-braquial (ITB). A presen&#231;a
            do DM aumenta o risco de desenvolver isquemia cr&#237;tica dos membros com DAP. A DAP
            associada ao DM &#233; a principal causa de amputa&#231;&#227;o n&#227;o traum&#225;tica de membros inferiores
            nos Estados Unidos. Cerca de 50% das amputa&#231;&#245;es de membros inferiores s&#227;o relacionadas
            ao DM e, embora tenha ocorrido uma diminui&#231;&#227;o importante do risco relativo de amputa&#231;&#245;es
            nos pacientes com DM quando em compara&#231;&#227;o com indiv&#237;duos sem DM, este risco continua
            bastante elevado - cerca de oito vezes<xref ref-type="bibr" rid="B22">22</xref>. A
            dura&#231;&#227;o do DM e a hiperglicemia se associam positivamente &#224; presen&#231;a e &#224; gravidade da
            DAP. Al&#233;m do aumento da frequ&#234;ncia de DAP, o DM afeta a distribui&#231;&#227;o da aterosclerose
            nos membros inferiores, atingindo tipicamente as art&#233;rias tibiais, peroneais, femorais e
            popl&#237;teas. Al&#233;m disso, as les&#245;es ateroscler&#243;ticas nos pacientes com DM apresentam
            calcifica&#231;&#245;es vasculares com maior frequ&#234;ncia do que nos pacientes sem DM<xref ref-type="bibr" rid="B23">23</xref>.</p>
    </sec>
    <sec>
      <title>3. Aterosclerose</title>
      <sec>
        <title>3a. Peculiaridades da estratifica&#231;&#227;o do risco cardiovascular no DM</title>
        <p>Como mencionado anteriormente, o DM aumenta significativamente o risco de doen&#231;a
               ateroscler&#243;tica, sendo que pacientes com DM apresentam aumento de at&#233; quatro vezes na
               incid&#234;ncia de DAC<xref ref-type="bibr" rid="B24">24</xref>, AVE<xref ref-type="bibr" rid="B25">25</xref> e DAP<xref ref-type="bibr" rid="B26">26</xref>. Al&#233;m do
               aumento na incid&#234;ncia de eventos cardiovasculares, o DM se associa a DCV de maior
                  morbidade<xref ref-type="bibr" rid="B27">27</xref>. Diante desses dados, diversas
               entidades cient&#237;ficas, como o National Heart, Lung and Blood Institute (NHLBI), o
               Adult Treatment Panel III (ATP III), a Associa&#231;&#227;o Americana de Diabetes ADA<xref ref-type="bibr" rid="B28">28</xref> e tamb&#233;m diretrizes brasileiras<xref ref-type="bibr" rid="B29">29</xref> reconhecem que o DM por se tratar de uma
               condi&#231;&#227;o de maior risco ateroscler&#243;tico, merece considera&#231;&#245;es especiais para a
               defini&#231;&#227;o de metas terap&#234;uticas de colesterol da lipoprote&#237;na de baixa densidade
               (LDL-C).</p>
        <p>A popula&#231;&#227;o de indiv&#237;duos com DM &#233; altamente heterog&#234;nea e com risco de doen&#231;a
               macrovascular muito vari&#225;vel, dependendo de fatores de risco associados como
               dislipidemia, HAS e presen&#231;a de tabagismo. Dessa forma, alguns pesquisadores sugerem
               a individualiza&#231;&#227;o da avalia&#231;&#227;o do risco cardiovascular em pacientes com DM por meio
               de escores de estratifica&#231;&#227;o de risco. O escore de risco de Framingham (<ext-link ext-link-type="uri" xlink:href="http://hp2010.nhlbihin.net/atpiii/calculator.asp">http://hp2010.nhlbihin.net/atpiii/calculator.asp</ext-link>), amplamente
               utilizado para estimar o risco de eventos coronarianos, resultou da avalia&#231;&#227;o do
               perfil de risco de 5.573 indiv&#237;duos sem DAC conhecida, dos quais 6% eram portadores
               de DM<xref ref-type="bibr" rid="B30">30</xref>. O <italic>UKPDS risk engine</italic>
               derivou da avalia&#231;&#227;o de participantes do United Kingdom Prospective Diabetes Study
               (UKPDS) e estima o risco de DAC e AVE fatal ou n&#227;o fatal utilizando tamb&#233;m vari&#225;veis
               mais espec&#237;ficas do DM, al&#233;m de vari&#225;veis tradicionais (sexo, idade, dura&#231;&#227;o do DM,
               hemoglobina glicada (HbA1c), etnia, tabagismo, fibrila&#231;&#227;o atrial, press&#227;o arterial
               sist&#243;lica [PAS], colesterol total [CT] e HDL-C)<xref ref-type="bibr" rid="B31">31</xref>. Este escore pode ser encontrado no endere&#231;o eletr&#244;nico: <ext-link ext-link-type="uri" xlink:href="http://www.dtu.ox.ac.uk/riskengine/index.php">http://www.dtu.ox.ac.uk/riskengine/index.php</ext-link>.</p>
        <p>Entretanto, em indiv&#237;duos recentemente diagnosticados com DM, essas ferramentas de
               estratifica&#231;&#227;o apresentam apenas modesto poder de discrimina&#231;&#227;o e baixa calibra&#231;&#227;o,
               nem sempre sendo capazes de prover estimativas de risco precisas nessa popula&#231;&#227;o<xref ref-type="bibr" rid="B32">32</xref>. O escore de risco global avaliou n&#227;o apenas o
               risco de eventos coronarianos, mas o de eventos cardiovasculares em geral (DAC, AVE,
               DAP ou IC), e incluiu tamb&#233;m o DM como uma vari&#225;vel categ&#243;rica (<ext-link ext-link-type="uri" xlink:href="http://www.framinghamheartstudy.org/risk/gencardio.html#">http://www.framinghamheartstudy.org/risk/gencardio.html#</ext-link>)<xref ref-type="bibr" rid="B33">33</xref>. O escore de risco global apresentou melhor
                  <italic>performance</italic> do que o escore de Framingham tradicional na
               estimativa de eventos cardiovasculares gerais, mas seu uso em pacientes com DM ainda
               requer mais estudos.</p>
        <p>Segundo as &#250;ltimas diretrizes sobre dislipidemia e preven&#231;&#227;o cardiovascular, o DM &#233;
               uma condi&#231;&#227;o associada a risco cardiovascular elevado para o qual est&#225; indicado o
               n&#237;vel mais rigoroso de metas lip&#237;dicas, independente dos demais fatores de risco
                  cardiovascular<xref ref-type="bibr" rid="B29">29</xref>. Por outro lado, a an&#225;lise
               de outras vari&#225;veis presentes no escore <italic>UKPDS risk engine</italic> e no
               escore de risco global pode ser &#250;til para defini&#231;&#227;o de estrat&#233;gias adicionais de
               preven&#231;&#227;o prim&#225;ria, como, por exemplo, a utiliza&#231;&#227;o do &#225;cido acetilsalic&#237;lico
               (AAS).</p>
        <p>
          <bold>Grau de recomenda&#231;&#227;o I</bold>
        </p>
        <list list-type="bullet">
          <list-item>
            <p>Estratifica&#231;&#227;o de risco cardiovascular em 10 anos utilizando o escore de risco
                        <italic>UKPDS risk engine</italic> e o escore de risco global.
                           <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
          </list-item>
        </list>
        <sec>
          <title>3a.1 Escore de c&#225;lcio</title>
          <p>A calcifica&#231;&#227;o nas art&#233;rias coron&#225;rias, quantificada pela tomografia utilizando o
                  m&#233;todo do escore de c&#225;lcio de Agatston (CAC), &#233; um marcador da presen&#231;a e extens&#227;o
                  da doen&#231;a ateroscler&#243;tica do indiv&#237;duo, como j&#225; demonstrado em estudo
                  anatomopatol&#243;gico pr&#233;vio, com forte associa&#231;&#227;o com a ocorr&#234;ncia de eventos
                  cardiovasculares futuros<xref ref-type="bibr" rid="B34">34</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B35">35</xref>. Sua presen&#231;a e intensidade est&#227;o
                  relacionadas com a carga total de placas ateroscler&#243;ticas. Os estudos The
                  Multi-Ethnic Study of Atherosclerosis (MESA)<xref ref-type="bibr" rid="B36">36</xref> e Heinz Nixdorff<xref ref-type="bibr" rid="B37">37</xref>
                  demonstraram que o CAC &#233; preditor de eventos coronarianos e seu emprego auxilia na
                  estratifica&#231;&#227;o de risco cardiovascular de pacientes em preven&#231;&#227;o prim&#225;ria,
                  agregando valor ao escore cl&#237;nico. Achados similares s&#227;o encontrados para
                  pacientes com DM. V&#225;rios estudos mostram maior preval&#234;ncia e intensidade de
                  calcifica&#231;&#245;es coronarianas entre os indiv&#237;duos com DM quando em compara&#231;&#227;o com a
                  popula&#231;&#227;o geral<xref ref-type="bibr" rid="B38">38</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B39">39</xref>, que &#233; relacionada com aumento na
                  mortalidade geral<xref ref-type="bibr" rid="B39">39</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B40">40</xref>.</p>
          <p>O estudo de Raggi et al. acompanhou por cinco anos 10.377 indiv&#237;duos
                  assintom&#225;ticos (903 com DM) que realizaram escore de c&#225;lcio. O escore de c&#225;lcio
                  m&#233;dio foi maior naqueles com DM do que nos sem DM (281 &#177; 567 vs. 119 &#177; 341,
                     <italic>p</italic> &lt; 0,0001). O estudo tamb&#233;m mostrou que, quanto maior o
                  escore de c&#225;lcio no pacientes com DM, maior a taxa de mortalidade, em propor&#231;&#227;o
                  at&#233; maior do que para o indiv&#237;duo sem DM. Outro dado interessante foi a elevada
                  sobrevida dos pacientes com DM e c&#225;lcio zero, similar &#224; dos indiv&#237;duos sem DM
                  (98,8% vs. 99,4%, <italic>p</italic> = 0,5)<xref ref-type="bibr" rid="B38">38</xref>.</p>
          <p>Uma metan&#225;lise de oito estudos com 6.521 indiv&#237;duos com DM (seguimento m&#233;dio de
                  5,18 anos) mostrou que a mortalidade por todas as causas ou evento cardiovascular,
                  comparando escore de c&#225;lcio &#8805; 10 com &lt; 10, foi de 5,47 (intervalo de confian&#231;a
                  [IC] 95% 2,59 a 11,53, <italic>p</italic> &lt; 0,001). O escore de c&#225;lcio &#8805; 10
                  apresentou sensibilidade de 94% e especificidade de 34% para o desfecho composto.
                  Para os indiv&#237;duos com escore de c&#225;lcio &lt; 10, a probabilidade p&#243;s-teste de
                  eventos para o desfecho composto foi de 1,8%, o que representa uma redu&#231;&#227;o de 6,8
                  vezes da probabilidade pr&#233;-teste. O estudo conclui que o escore de c&#225;lcio baixo
                  (&lt; 10) pode auxiliar a detectar, nesta popula&#231;&#227;o considerada de alto risco
                  cardiovascular, um subgrupo de indiv&#237;duos de menor risco<xref ref-type="bibr" rid="B41">41</xref>.</p>
          <p>O escore de c&#225;lcio tamb&#233;m pode agregar valor na estratifica&#231;&#227;o de risco dos
                  indiv&#237;duos com DM. O estudo Patients with Renal Impairment and Diabetes Undergoing
                  Computed Tomography (PREDICT) acompanhou 589 pacientes com DM sem DCV pr&#233;via por
                  cerca de quatro anos. O estudo tamb&#233;m mostrou que, quanto maior o escore de
                  c&#225;lcio, maior o risco de eventos cardiovasculares. A &#225;rea sob a <italic>receive
                     operator caracteristic curve</italic> (curva ROC) para discrimina&#231;&#227;o de risco
                  utilizando o escore cl&#237;nico do UKPDS foi de 0,63, que se elevou para 0,73 com o
                  escore de c&#225;lcio agregado (<italic>p</italic> = 0,03)<xref ref-type="bibr" rid="B42">42</xref>. De forma similar, o DM Heart Study tamb&#233;m mostrou melhor
                  discrimina&#231;&#227;o de risco com uso do escore de c&#225;lcio (melhora da &#225;rea sob a curva
                  ROC de 0,70 para 0,75), com melhora no &#237;ndice de reclassifica&#231;&#227;o (NRI = 0,13)<xref ref-type="bibr" rid="B43">43</xref>.</p>
          <p>O CAC est&#225; associado com altera&#231;&#227;o perfusional na cintilografia mioc&#225;rdica. Estudo
                  de Anand et al. mostra que 48,3% dos pacientes com DM com escore de c&#225;lcio entre
                  401 a 1.000 apresentavam defeito perfusional, e esse n&#250;mero subia para 71,4% para
                  aqueles com escore de c&#225;lcio acima de 1.000<xref ref-type="bibr" rid="B44">44</xref>.</p>
          <p>O escore de c&#225;lcio &#233; uma ferramenta &#250;til na avalia&#231;&#227;o de risco cardiovascular de
                  pacientes com DM assintom&#225;ticos, permitindo a identifica&#231;&#227;o de indiv&#237;duos de maior
                  risco que eventualmente se beneficiariam do rastreamento de isquemia silenciosa e
                  tratamento cl&#237;nico mais agressivo. A sua realiza&#231;&#227;o pode ser considerada em
                  pacientes com DM com mais de 40 anos de idade.</p>
          <p>Finalmente, cabe ressaltar que a tomografia para avalia&#231;&#227;o do escore de c&#225;lcio &#233;
                  um exame SEM contraste.</p>
          <p>Considerando a natureza desta diretriz, contendo orienta&#231;&#245;es para pacientes com
                  DM, recomendamos a solicita&#231;&#227;o de escore de c&#225;lcio:</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o IIa</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>Avalia&#231;&#227;o de risco cardiovascular em pacientes com idade superior a 40 anos.
                              <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
        <sec>
          <title>3a.2 Angiotomografia de coron&#225;rias</title>
          <p>A angiotomografia das art&#233;rias coron&#225;rias (angio-TC) &#233; um m&#233;todo cada vez mais
                  consistente e dispon&#237;vel para a avalia&#231;&#227;o n&#227;o invasiva da DAC. Dados consistentes
                  na literatura v&#234;m demonstrando alta acur&#225;cia diagn&#243;stica para a detec&#231;&#227;o de
                  estenose coronariana significativa em compara&#231;&#227;o com a angiografia invasiva<xref ref-type="bibr" rid="B45">45</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B47">47</xref>. Al&#233;m da acur&#225;cia diagn&#243;stica, a informa&#231;&#227;o da presen&#231;a de doen&#231;a
                  coronariana obstrutiva e n&#227;o obstrutiva pela angio-TC tem claro impacto
                     progn&#243;stico<xref ref-type="bibr" rid="B48">48</xref>. Previamente, Van
                  Werkhoven et al.<xref ref-type="bibr" rid="B49">49</xref>, em uma an&#225;lise
                  multivariada com 616 indiv&#237;duos com DM2 com seguimento m&#233;dio de 20 &#177; 5,4 meses,
                  demonstraram que a presen&#231;a de DAC obstrutiva identificada pela angio-TC foi um
                  preditor independente de desfecho combinado de morte por causas card&#237;acas, IAM n&#227;o
                  fatal e angina inst&#225;vel. Al&#233;m disso, este estudo tamb&#233;m demonstrou que todos os
                  pacientes com DM que n&#227;o apresentavam sinais de DAC pela angio-TC (59 casos no
                  total) n&#227;o apresentaram evento no seguimento. Este dado &#233; de extrema relev&#226;ncia,
                  pois permite identificar, entre os pacientes com DM, um subgrupo de baixo risco.
                  Assim, embora a &#226;ngio-TC de coron&#225;rias tamb&#233;m apresente papel na estratifica&#231;&#227;o de
                  risco, similar e possivelmente mais poderoso que o do escore de c&#225;lcio, o seu uso
                  com este objetivo deve considerar o uso de contraste iodado e a dose de radia&#231;&#227;o
                  adicional. No momento n&#227;o h&#225; dados que demonstrem benef&#237;cio definitivo do uso
                  deste exame em pacientes com DM assintom&#225;ticos. Em linhas gerais, as principais
                  indica&#231;&#245;es da angio-TC se reservam a pacientes com sintomas<xref ref-type="bibr" rid="B50">50</xref>.</p>
          <p>Portanto, na aus&#234;ncia de sintomas cl&#237;nicos, n&#227;o existem, na atualidade, estudos
                  que sustentem o uso de qualquer exame de rastreamento no diagn&#243;stico de DAC em
                  portadores de DM<xref ref-type="bibr" rid="B28">28</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B49">49</xref>.</p>
          <sec>
            <title>Recomenda&#231;&#227;o para solicita&#231;&#227;o de tomografia de art&#233;rias coron&#225;rias em
                     pacientes com DM</title>
            <p>
              <bold>Grau de recomenda&#231;&#227;o III</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Avalia&#231;&#227;o de risco cardiovascular em pacientes assintom&#225;ticos.
                                 <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
        </sec>
        <sec>
          <title>3a.3 Ultrassom Doppler de car&#243;tidas</title>
          <p>O ultrassom Doppler de car&#243;tidas &#233; um m&#233;todo n&#227;o invasivo, com baixo risco de
                  eventos adversos e de custo relativamente baixo, que permite a avalia&#231;&#227;o da
                  car&#243;tida em dois aspectos: aferi&#231;&#227;o da espessura &#237;ntima-m&#233;dia carot&#237;dea (EIMC) e
                  avalia&#231;&#227;o de estenose carot&#237;dea em caso de placa obstrutiva.</p>
          <p>A EIMC foi avaliada no estudo de Bernard et al., que incluiu 229 indiv&#237;duos com DM
                  sem DCV. A EIMC mostrou-se preditora independente de eventos cardiovasculares
                     (<italic>p</italic> = 0,045), e a combina&#231;&#227;o da EIMC com o escore de Framingham
                  melhorou o modelo de predi&#231;&#227;o de risco cardiovascular<xref ref-type="bibr" rid="B51">51</xref>. Outro estudo de Yoshida et al. tamb&#233;m avaliou a EIMC em
                  783 pacientes com DM, seguidos por 5,4 anos. A an&#225;lise multivariada mostrou que a
                  idade, o sexo e a EIMC foram preditores independentes de evento
                     cardiovascular<xref ref-type="bibr" rid="B52">52</xref>.</p>
          <p>O estudo de Lacroix avaliou estenose carot&#237;dea pelo ultrassom Doppler. Foram
                  inclu&#237;dos 300 indiv&#237;duos com DM assintom&#225;ticos, idade m&#233;dia de 62,5 anos, 55,3%
                  homens. A preval&#234;ncia de oclus&#227;o &gt; 60% foi de 4,7%, e a de aterosclerose
                  carot&#237;dea foi de 68,3%. A probabilidade de encontrar estenose carot&#237;dea
                  significativa foi maior em homens com DAC pr&#233;via e ITB &lt; 0,85<xref ref-type="bibr" rid="B53">53</xref>.</p>
          <p>Apesar de alguns estudos mostrarem a associa&#231;&#227;o da EIMC com eventos
                  cardiovasculares, ainda n&#227;o h&#225; evid&#234;ncias fortes para aferi&#231;&#227;o rotineira da EIMC
                  nos pacientes com DM. Por&#233;m, por se tratar de um m&#233;todo n&#227;o invasivo e de baixo
                  custo, pode ser considerada sua avalia&#231;&#227;o em indiv&#237;duos com DM assintom&#225;ticos
                  acima de 40 anos de idade. N&#227;o existe recomenda&#231;&#227;o para pesquisa de estenose
                  carot&#237;dea de forma indiscriminada em pacientes com DM assintom&#225;ticos e sem AVE
                  pr&#233;vio.</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o IIb</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>Avalia&#231;&#227;o de risco cardiovascular em assintom&#225;ticos com mais de 40 anos.
                              <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
        <sec>
          <title>3a.4 Microalbumin&#250;ria</title>
          <p>Estudos prospectivos e epidemiol&#243;gicos mostraram que a microalbumin&#250;ria &#233;
                  preditora independente de mortalidade por todas as causas e cardiovascular, al&#233;m
                  de predizer eventos cardiovasculares nos pacientes com DM, com HAS ou na popula&#231;&#227;o
                  geral.</p>
          <p>O estudo de revis&#227;o de Dinneen et al. analisou 11 estudos de coorte, representando
                  um total de 2.138 pacientes acompanhados por 6,4 anos. A preval&#234;ncia de
                  microalbumin&#250;ria variou de 20% a 36%. Todos os estudos mostraram tend&#234;ncia ou
                  associa&#231;&#227;o significativa entre microalbumin&#250;ria e mortalidade total ou mortalidade
                  ou morbidade cardiovascular<xref ref-type="bibr" rid="B54">54</xref>. O estudo de
                  Neil et al. tamb&#233;m demonstrou, em uma coorte de 236 pacientes com DM, que a
                  microalbumin&#250;ria foi preditora de mortalidade (risco relativo [RR] de 2,2;
                  intervalo de confian&#231;a [IC] 95% 1,3-3,7)<xref ref-type="bibr" rid="B55">55</xref>.</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o I</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>A dosagem de microalbumin&#250;ria deve ser feita anualmente em todo paciente com
                        DM2. <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
        <sec>
          <title>3a.5 &#205;ndice tornozelo-braquial (ITB)</title>
          <p>A doen&#231;a arterial perif&#233;rica &#233; caracterizada como doen&#231;a ateroscler&#243;tica oclusiva
                  de membros inferiores, sendo frequentemente acompanhada de doen&#231;as coronariana e
                  cerebrovascular. O DM e o tabagismo s&#227;o os principais fatores de risco para o
                  desenvolvimento de DAP. O ITB &#233; uma metodologia simples e de baixo custo que
                  envolve a aferi&#231;&#227;o da PAS no tornozelo (art&#233;rias pediosa e tibial posterior) e no
                  bra&#231;o (art&#233;ria braquial) com aux&#237;lio de um Doppler e a rela&#231;&#227;o entre os valores
                  obtidos. Ademais, apresenta sensibilidade em torno de 95% e quase 100% de
                  especificidade.</p>
          <p>Um ITB reduzido representa fator de risco para morbimortalidade cardiovascular. O
                  Fremantle DM Study<xref ref-type="bibr" rid="B56">56</xref> mostrou que um ITB &#8804;
                  0,9 em pacientes com DM aumentava o risco de morte card&#237;aca em 67%. Um estudo
                  sueco com pacientes idosos com DM mostrou que a taxa de eventos card&#237;acos foi de
                  102 por 1.000 pacientes/ano em indiv&#237;duos com ITB &lt; 0,9 vs. 28,4 naqueles com
                  ITB normal. Existem tamb&#233;m evid&#234;ncias de que um ITB acima de 1,4 est&#225; associado a
                  maior taxa de eventos cardiovasculares.</p>
          <p>A pesquisa de DAP deve ser feita em todo paciente com DM sintom&#225;tico.</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o IIa</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>Medida do ITB em pacientes com mais de 50 anos de idade. <bold><italic>N&#237;vel
                              de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
            <list-item>
              <p>Medida do ITB em pacientes com menos de 50 anos de idade que apresentem
                        outros fatores de risco para doen&#231;a arterial perif&#233;rica (como tabagismo,
                        hipertens&#227;o arterial, dislipidemia ou dura&#231;&#227;o do DM superior a 10 anos).
                              <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
            <list-item>
              <p>Pacientes com ITB normal, repetir a cada cinco anos.<bold><italic>N&#237;vel de
                              evid&#234;ncia C</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
      </sec>
      <sec>
        <title>3b. Preven&#231;&#227;o prim&#225;ria da aterosclerose no DM: mito ou realidade?</title>
        <p>A utiliza&#231;&#227;o de medica&#231;&#245;es para preven&#231;&#227;o prim&#225;ria &#233; sempre um t&#243;pico pol&#234;mico, uma
               vez que temos que pesar o risco dos efeitos colaterais das medica&#231;&#245;es utilizadas
               versus o benef&#237;cio da potencial redu&#231;&#227;o de eventos cardiovasculares. Pacientes com DM
               t&#234;m um risco de eventos cardiovasculares 2-4 vezes maior do que indiv&#237;duos sem DM da
               mesma faixa et&#225;ria e sexo<xref ref-type="bibr" rid="B57">57</xref>.</p>
        <sec>
          <title>3b.1 Dislipidemias e uso de hipolipemiantes</title>
          <p>Em pacientes com DM, &#233; comum a presen&#231;a de triglic&#233;rides (TGs) elevados e HDL-C
                  baixo. J&#225; as concentra&#231;&#245;es de LDL-C podem ser elevadas, mas tamb&#233;m normais ou
                  mesmo baixas. As part&#237;culas de LDL-C s&#227;o frequentemente pequenas e densas
                  (carreando menos colesterol por part&#237;cula), por&#233;m mais numerosas em indiv&#237;duos com
                  DM, o que parece representar um risco adicional. Essa tr&#237;ade constitu&#237;da de TG
                  altos, HDL-C baixo e LDL-C pequena e densa &#233; conhecida como dislipidemia
                  aterog&#234;nica do DM.</p>
          <p>Embora o LDL-C elevado n&#227;o seja a caracter&#237;stica mais marcante da dislipidemia
                  aterog&#234;nica do DM, a redu&#231;&#227;o do LDL-C associa-se a significativa diminui&#231;&#227;o de
                  eventos cardiovasculares em indiv&#237;duos com e sem DM. Segundo metan&#225;lise do
                  Cholesterol Treatment Trialists' (CTT) Collaboration, que incluiu dados
                  individuais de 170.000 indiv&#237;duos, o uso de estatina vs. placebo (ou de estatina
                  em dose maior vs. dose menor) reduziu eventos vasculares maiores em cerca de 20% a
                  cada redu&#231;&#227;o de 40 mg/dl no LDL-C. Esse resultado foi observado em indiv&#237;duos com
                  ou sem DM2<xref ref-type="bibr" rid="B58">58</xref>.</p>
          <p>Em 2010, uma metan&#225;lise demonstrou associa&#231;&#227;o entre o uso de estatina e o aumento
                  na incid&#234;ncia de DM<xref ref-type="bibr" rid="B59">59</xref>. Entretanto, em
                  suban&#225;lise do estudo Justification for the Use of Statins in Primary Prevention:
                  An Intervention Trial Evaluating Rosuvastatin (JUPITER), que incluiu 17.603 homens
                  e mulheres, demonstrou-se que, em compara&#231;&#227;o com placebo, as estatinas apenas
                  aceleraram o tempo m&#233;dio para diagn&#243;stico de DM em cerca de 5,4 semanas,
                  particularmente em indiv&#237;duos com um ou mais fatores de risco para o
                  desenvolvimento de DM<xref ref-type="bibr" rid="B60">60</xref>. Esses estudos
                  foram realizados em pacientes sem o diagn&#243;stico de DM. Em metan&#225;lise de estudos
                  randomizados com 3.232 pacientes com DM, os autores demonstraram que o uso de
                  estatinas n&#227;o alterou o controle glic&#234;mico destes pacientes<xref ref-type="bibr" rid="B61">61</xref>. Al&#233;m disso, em estudos de larga escala, como o CTT
                  mencionado anteriormente, o benef&#237;cio cardiovascular do uso de estatinas em
                  pacientes com DM2 n&#227;o apresentou qualquer diferen&#231;a em rela&#231;&#227;o ao benef&#237;cio
                  encontrado em indiv&#237;duos sem DM<xref ref-type="bibr" rid="B58">58</xref>. Portanto
                  os benef&#237;cios na redu&#231;&#227;o do risco cardiovascular do uso das estatinas excedem
                  qualquer potencial risco de piora glic&#234;mica em indiv&#237;duos com DM.</p>
          <p>Hipertrigliceridemia e HDL baixo s&#227;o as anormalidades lip&#237;dicas mais frequentes
                  entre pacientes com DM. Embora v&#225;rios estudos tenham demonstrado associa&#231;&#227;o entre
                  as concentra&#231;&#245;es de TG e HDL com risco vascular, as interven&#231;&#245;es que reduzem os
                  n&#237;veis de TG e/ou aumentam o HDL-C n&#227;o mostraram benef&#237;cio consistente. Os
                  fibratos s&#227;o efetivos principalmente na redu&#231;&#227;o de TG e no aumento do HDL-C. Os
                  estudos que avaliaram seus efeitos sobre o risco cardiovascular mostraram
                  resultados conflitantes. Metan&#225;lise recente com n&#250;mero muito grande de pacientes
                  (incluindo indiv&#237;duos com DM) mostrou redu&#231;&#227;o de cerca de 10% no risco relativo de
                  eventos cardiovasculares maiores e 13% no risco relativo de eventos coronarianos,
                  sem benef&#237;cio no risco de AVE<xref ref-type="bibr" rid="B62">62</xref>. No estudo
                  Action to Control Cardiovascular Risk in Diabetes (ACCORD), realizado em pacientes
                  com DM, a combina&#231;&#227;o de fenofibrato e sinvastatina n&#227;o reduziu o &#237;ndice de eventos
                  cardiovasculares em compara&#231;&#227;o com a monoterapia com estatina. An&#225;lise de subgrupo
                  indicou poss&#237;vel benef&#237;cio da combina&#231;&#227;o medicamentosa para pacientes com DM com
                  TGs mais altos e HDL-C mais baixo, mas essa constata&#231;&#227;o ainda requer estudos
                     adicionais<xref ref-type="bibr" rid="B63">63</xref>. Por outro lado, n&#237;veis de
                  triglic&#233;rides acima de 500 mg/dl est&#227;o associados ao maior risco de
                  pancreatite.</p>
          <p>Apesar da associa&#231;&#227;o inversa entre n&#237;vel de HDL-C e risco cardiovascular, ainda
                  n&#227;o se mostrou que a eleva&#231;&#227;o do HDL pelo uso de medica&#231;&#227;o seja de fato ben&#233;fica.
                  No estudo Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High
                  Triglycerides: Impact on Global Health Outcomes (AIM-HIGH), em que indiv&#237;duos com
                  DCV estabelecida apresentavam LDL-C &lt; 70 mg/dl sob o uso de estatina, o
                  acr&#233;scimo de niacina n&#227;o esteve associado a benef&#237;cio adicional, a despeito da
                  melhora nos n&#237;veis de HDL e TG. Portanto a combina&#231;&#227;o de estatina com fibrato ou
                  niacina para controle dos TG e/ou HDL n&#227;o mostrou benef&#237;cios cardiovasculares
                  superiores aos conferidos pela monoterapia com estatina quando o LDL-C se encontra
                     controlado<xref ref-type="bibr" rid="B64">64</xref>.</p>
          <p>As recomenda&#231;&#245;es gerais para o tratamento das dislipidemias podem ser encontradas
                  na Diretriz de Dislipidemias da Sociedade Brasileira de Cardiologia<xref ref-type="bibr" rid="B29">29</xref>. Para a maioria dos pacientes com DM, o
                  primeiro alvo no tratamento da dislipidemia &#233; a redu&#231;&#227;o do LDL-C com a prescri&#231;&#227;o
                  de estatinas. As interven&#231;&#245;es no estilo de vida, como dieta, atividade f&#237;sica e
                  controle de peso, podem auxiliar no controle lip&#237;dico e devem ser estimuladas.</p>
          <sec>
            <title>Recomenda&#231;&#245;es do tratamento com hipolipemiantes para indiv&#237;duos com DM,
                     al&#233;m das interven&#231;&#245;es no estilo de vida</title>
            <sec>
              <title>A. Para introdu&#231;&#227;o de hipolipemiantes</title>
              <p>
                <bold>Grau de recomenda&#231;&#227;o I</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Em indiv&#237;duos com TG &#8805; 500 mg, a redu&#231;&#227;o dos TGs deve ser a primeira
                              medida terap&#234;utica, sendo que fibrato e niacina s&#227;o op&#231;&#245;es de
                              tratamento. Ap&#243;s controle dos TGs, a redu&#231;&#227;o do LDL-C deve ser o alvo
                              seguinte. <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Estatinas devem ser administradas a pacientes com DCV conhecida OU com
                              idade &gt; 40 anos, independente dos n&#237;veis de colesterol.
                                    <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Para pacientes com idade &lt; 40 anos e sem DCV, o tratamento com
                              estatina deve ser considerado na presen&#231;a de m&#250;ltiplos fatores de
                              risco, independente dos n&#237;veis de colesterol. <bold><italic>N&#237;vel de
                                    evid&#234;ncia C</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Para pacientes com idade &lt; 40 anos, sem DCV e sem m&#250;ltiplos fatores
                              de risco, a estatina deve ser administrada quando LDL-C &gt; 100
                              mg/dl. <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
            <sec>
              <title>B. Monitoriza&#231;&#227;o do tratamento com estatinas em pacientes com DM</title>
              <p>
                <bold>Grau de recomenda&#231;&#227;o I</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Para pacientes com DM nos quais foi iniciado o tratamento com
                              estatinas segundo os crit&#233;rios citados anteriormente, o objetivo deve
                              ser a redu&#231;&#227;o de LDL-C para menos de 70 mg/dl OU de pelo menos 30%-50%
                              do valor inicial do LDL-C. <bold><italic>N&#237;vel de evid&#234;ncia
                                 C</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
          </sec>
        </sec>
        <sec>
          <title>3b.2 &#193;cido acetilsalic&#237;lico (AAS)</title>
          <p>Apesar do indiscut&#237;vel benef&#237;cio do uso do AAS para preven&#231;&#227;o secund&#225;ria de
                  eventos cardiovasculares, o seu uso em preven&#231;&#227;o prim&#225;ria sempre deve ser
                  questionado e bem avaliado, uma vez que ele est&#225; associado a maior risco de
                  sangramento gastrointestinal (mesmo as doses menores), sem redu&#231;&#227;o na
                     mortalidade<xref ref-type="bibr" rid="B65">65</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B67">67</xref>.</p>
          <p>As evid&#234;ncias atuais sobre o uso de AAS em preven&#231;&#227;o prim&#225;ria derivam de tr&#234;s
                  estudos randomizados que inclu&#237;ram apenas pacientes com DM<xref ref-type="bibr" rid="B68">68</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B70">70</xref> e de
                  an&#225;lise de subgrupo de pacientes com DM de seis estudos com popula&#231;&#245;es gerais<xref ref-type="bibr" rid="B71">71</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B76">76</xref>. Os resultados de dois principais estudos randomizados sobre o uso
                  do AAS em pacientes com DM levantaram d&#250;vidas sobre a efic&#225;cia do uso de AAS para
                  preven&#231;&#227;o prim&#225;ria<xref ref-type="bibr" rid="B70">70</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B69">69</xref>. No estudo Prevention of Progression of
                  Arterial Disease and Diabetes Trial (POPADAD), 1.276 pacientes com idade acima de
                  40 anos, DM (tipos 1 e 2) e ITB &#8804; 0,99 foram randomizados para receber AAS 100 mg
                  ou placebo, com seguimento m&#233;dio de 6,7 anos. N&#227;o houve diferen&#231;a entre os grupos
                  quanto &#224; mortalidade por DAC ou AVE, IAM, AVE n&#227;o fatal, ou amputa&#231;&#227;o por isquemia
                  cr&#237;tica de membros inferiores (18,2% no grupo AAS vs. 18,3% no grupo placebo;
                     <italic>harzard ratio</italic> [HR] 0,98; IC 95% 0,76-1,26; <italic>p</italic>
                  = 0,86). Por outro lado, tamb&#233;m n&#227;o houve diferen&#231;a nos sangramentos
                  gastrointestinais (4,4% no grupo AAS vs. 4,3% no grupo placebo; HR 0,9; IC 95%
                  0,53-1,52; <italic>p</italic> = 0,69)<xref ref-type="bibr" rid="B70">70</xref>. No
                  estudo Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes
                  (JPAD), 2.539 pacientes com idade entre 30 e 85 anos com DM2 foram randomizados
                  para receber AAS ou nenhuma medica&#231;&#227;o, com seguimento m&#233;dio de 4,37 anos. N&#227;o
                  houve diferen&#231;a entre os grupos na incid&#234;ncia do desfecho combinado (morte s&#250;bita,
                  morte de causa cardiovascular ou doen&#231;a a&#243;rtica, IAM n&#227;o fatal, angina est&#225;vel ou
                  inst&#225;vel, AVE isqu&#234;mico ou hemorr&#225;gico, acidente isqu&#234;mico transit&#243;rio e doen&#231;as
                  de aorta ou vasculares perif&#233;ricas): 5,4% de eventos no grupo AAS vs. 6,7% no
                  grupo controle (HR 0,8; IC 95% 0,58-1,1; <italic>p</italic> = 0,16). Entretanto,
                  no subgrupo de 1.363 pacientes com idade acima de 65 anos, esta incid&#234;ncia foi
                  menor no grupo AAS (6,3% vs. 9,2%; HR 0,68; IC 95% 0,46-0,99; <italic>p</italic> =
                  0,047). Al&#233;m disso, no geral, houve redu&#231;&#227;o na incid&#234;ncia de IAM e AVE fatais,
                  sendo que um paciente do grupo AAS apresentou AVE fatal e 10 do grupo controle
                  apresentaram IAM ou AVE fatais (HR 0,1; IC 95% 0,01-0,79; <italic>p</italic> =
                  0,0037). Apesar destes benef&#237;cios, a taxa geral de eventos foi baixa (17 em 1.000
                  pacientes japoneses com DM) em rela&#231;&#227;o a estudos anteriores, provavelmente pela
                  melhora no tratamento dos fatores de risco nestes pacientes<xref ref-type="bibr" rid="B69">69</xref>. Estudos anteriores sobre o uso de AAS em preven&#231;&#227;o
                  prim&#225;ria na popula&#231;&#227;o geral reportaram resultados conflitantes na an&#225;lise do
                  subgrupo de pacientes com DM, talvez porque os estudos come&#231;aram a ser realizados
                  na d&#233;cada de 1980, quando outras estrat&#233;gias de preven&#231;&#227;o, como o uso de
                  estatinas, n&#227;o eram realizadas, conferindo um maior papel ao AAS como fator
                     protetor<xref ref-type="bibr" rid="B68">68</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B72">72</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B74">74</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B76">76</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B77">77</xref>.</p>
          <p>Uma metan&#225;lise dos pacientes com DM destes estudos demonstrou que o uso de AAS
                  estava associado a uma redu&#231;&#227;o de 9% no risco de IAM fatal e n&#227;o fatal (RR 0,91;
                  IC 95% 0,79-1,05) e de 15% no risco de AVE (RR 0,85; IC 95% 0,66-1,11), por&#233;m sem
                  signific&#226;ncia estat&#237;stica<xref ref-type="bibr" rid="B57">57</xref>. Outras duas
                  metan&#225;lises de estudos randomizados tampouco demonstraram redu&#231;&#227;o significativa em
                  eventos CV maiores, IAM, AVE ou mortalidade CV ou geral com o uso de AAS<xref ref-type="bibr" rid="B78">78</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B79">79</xref>. Entretanto, na metan&#225;lise de Berardis et al. o uso de AAS reduziu
                  significativamente o risco de IAM em homens (RR 0,57; IC 95% 0,34-0,94), mas n&#227;o
                  em mulheres (RR 1,08; IC 95% 0,71-1,65)<xref ref-type="bibr" rid="B78">78</xref>.
                  Por outro lado, o estudo Women's Health Study (WHS), que randomizou 39.876
                  mulheres com mais de 45 anos para receber AAS ou placebo, demonstrou que o uso de
                  AAS reduziu em 24% o risco de AVE em mulheres (RR 0,76; IC 95% 0,69-0,99;
                     <italic>p</italic> =0,04), principalmente no grupo acima de 65 anos, inclusive
                  no subgrupo de pacientes com DM<xref ref-type="bibr" rid="B78">78</xref>. Dois
                  estudos randomizados avaliando o uso de AAS como preven&#231;&#227;o prim&#225;ria est&#227;o em
                  andamento: o estudo ingl&#234;s A Study of Cardiovascular Events iN Diabetes (ASCEND),
                  que j&#225; randomizou 15.480 pacientes com mais de 40 anos e tem o final do
                  acompanhamento previsto para 2017, e o estudo italiano Aspirin and Simvastatin
                  Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D), que
                  planeja randomizar 5.170 pacientes em uso de estatinas.</p>
          <p>O risco de efeitos colaterais do AAS tamb&#233;m deve ser considerado. Em um estudo
                  observacional com 186.425 pacientes em uso de AAS e 186.425 controles, os autores
                  demonstraram que o uso de AAS estava associado a maior risco de sangramentos
                  gastrointestinais e cerebrais. Entretanto, na an&#225;lise de subgrupo de indiv&#237;duos
                  com DM, o uso de AAS aumentou apenas marginalmente o risco de sangramentos
                  maiores, sem signific&#226;ncia estat&#237;stica (RR 1,09; IC 95% 0,97-1,22). Por outro
                  lado, independente de usar ou n&#227;o AAS, a presen&#231;a de DM foi associada a aumento do
                  risco de sangramentos maiores (RR 1,36; IC 95% 1,28-1,44). Outros fatores de risco
                  independentemente associados a sangramento foram idade, sexo masculino, HAS e
                  hist&#243;ria de DCV<xref ref-type="bibr" rid="B80">80</xref>.</p>
          <p>Portanto ainda s&#227;o conflitantes as evid&#234;ncias para realizarmos recomenda&#231;&#245;es
                  definitivas sobre o uso de AAS para preven&#231;&#227;o prim&#225;ria em pacientes com DM. Ao
                  considerarmos a prescri&#231;&#227;o de AAS como preven&#231;&#227;o prim&#225;ria, devemos levar em conta
                  a estimativa de risco de eventos cardiovasculares em 10 anos. Apesar de pacientes
                  com DM terem sido considerados automaticamente de alto risco cardiovascular
                  (equivalente &#224; doen&#231;a ateroscler&#243;tica manifesta) em algumas
                     diretrizes<sup>(</sup>
						<xref ref-type="bibr" rid="B81">81</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B29">29</xref>
						<sup>)</sup>
                  visando o tratamento agressivo de fatores de risco e meta de LDL-C, para a
                  prescri&#231;&#227;o de uma medica&#231;&#227;o que tem conhecido aumento no risco de sangramento
                  devemos fazer uma estratifica&#231;&#227;o do risco cardiovascular adicional e individual
                  para estes pacientes, uma vez que s&#243; ter&#227;o um perfil de risco/benef&#237;cio favor&#225;vel
                  &#224; prescri&#231;&#227;o de AAS os pacientes de maior risco cardiovascular. Entre os escores
                  de risco somente para pacientes com DM, uma ferramenta que pode ser usada para
                  estratifica&#231;&#227;o de risco CV &#233; o <italic>UKPDS Risk Engine</italic>
						<sup>(</sup>
						<xref ref-type="bibr" rid="B31">31</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B82">82</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B84">84</xref>.</p>
          <sec>
            <title>Recomenda&#231;&#245;es para o uso do AAS como preven&#231;&#227;o prim&#225;ria em pacientes com
                     DM</title>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIa</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Uso de AAS 81-100 mg/dia <italic>especificamente</italic> para pacientes
                           com risco estimado de eventos cardiovasculares em 10 anos &gt; 10%, como
                           homens acima de 50 anos e mulheres acima de 60 anos com um ou mais
                           fatores de risco (tabagismo, HAS, dislipidemia, hist&#243;ria familiar de DAC
                           precoce e microalbumin&#250;ria), desde que n&#227;o tenham risco aumentado de
                           sangramento (hist&#243;ria de &#250;lcera g&#225;strica/duodenal ou sangramento
                           gastrointestinal pr&#233;vio ou uso de medica&#231;&#245;es que aumentem o risco de
                           sangramento, como anticoagulantes ou anti-inflamat&#243;rios n&#227;o hormonais).
                                 <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
              </list-item>
            </list>
            <p>
              <bold>Grau de Recomenda&#231;&#227;o IIb</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Uso de AAS 81-100mg/dia para pacientes com risco de complica&#231;&#245;es
                           cardiovasculares em 10 anos entre 5-10%, como pacientes mais jovens com
                           fatores de risco ou mais idosos sem fatores de risco, desde que n&#227;o
                           tenham risco aumentado de sangramento. <bold><italic>N&#237;vel de evid&#234;ncia
                                 C</italic></bold>.</p>
              </list-item>
            </list>
            <p>
              <bold>Grau de recomenda&#231;&#227;o III</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Uso de AAS para pacientes com risco estimado de eventos cardiovasculares
                           em 10 anos &lt; 5%, como homens com idade inferior a 50 anos ou mulheres
                           abaixo de 60 anos sem os fatores de risco descritos anteriormente.
                                 <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>3.c Peculiaridades no diagn&#243;stico e tratamento da doen&#231;a coronariana cr&#244;nica em
               pacientes com DM</title>
        <sec>
          <title>3c.1 Diagn&#243;stico</title>
          <p>A rela&#231;&#227;o entre DCV e DM j&#225; &#233; bem estabelecida. Nos &#250;ltimos 10 anos avan&#231;os na
                  biologia vascular melhoraram o entendimento do processo da aterosclerose, da
                  forma&#231;&#227;o da placa e da trombog&#234;nese.</p>
          <p>Achados dos mais importantes estudos demonstram que a DCV ocorre numa frequ&#234;ncia
                  significativamente maior nos indiv&#237;duos com DM do que na popula&#231;&#227;o em geral<xref ref-type="bibr" rid="B85">85</xref>. Por serem de um grupo de maior risco, por
                  apresentarem formas mais graves de DAC e por se beneficiarem de um tratamento
                  precoce e mais agressivo, a detec&#231;&#227;o precoce da DAC &#233; muito importante. As
                  manifesta&#231;&#245;es cl&#237;nicas da DAC podem ser diferentes nos pacientes com DM<xref ref-type="bibr" rid="B86">86</xref>
						<sup>,</sup>
						<xref ref-type="bibr" rid="B87">87</xref> em rela&#231;&#227;o aos sem DM, por isso v&#225;rios estudos buscam pacientes
                  assintom&#225;ticos &#224; procura de isquemia silenciosa. Essa preval&#234;ncia de isquemia
                  silenciosa foi avaliada em muitos estudos, mas ainda existe controv&#233;rsia sobre o
                  benef&#237;cio da sua pesquisa rotineira<xref ref-type="bibr" rid="B88">88</xref>
						<sup>-</sup>
						<xref ref-type="bibr" rid="B90">90</xref>.</p>
          <p>Cerca de 20%-30% dos pacientes com DM apresentam isquemia silenciosa<xref ref-type="bibr" rid="B91">91</xref>. Essa consider&#225;vel parcela de pacientes com
                  DAC, particularmente aqueles com DM e HAS, n&#227;o apresentam angina, ou mant&#234;m-se
                  assintom&#225;ticos mesmo ap&#243;s um evento de DAC aguda ou, mais frequentemente,
                  apresentam epis&#243;dios de isquemia silenciosa junto com epis&#243;dios de angina<xref ref-type="bibr" rid="B92">92</xref>. Nesses eventos, principalmente nos casos
                  de infarto n&#227;o reconhecido ou silencioso, as apresenta&#231;&#245;es cl&#237;nicas mais
                  frequentes incluem a IC, isto &#233;: dispneia nova sem dor ou piora de IC j&#225;
                  estabelecida; angina de peito de menor intensidade e dura&#231;&#227;o; localiza&#231;&#227;o n&#227;o
                  usual da dor; outras manifesta&#231;&#245;es do sistema nervoso central (SNC) secund&#225;rias &#224;
                  redu&#231;&#227;o do d&#233;bito card&#237;aco em paciente com aterosclerose cerebral, assemelhando-se
                  &#224;s do AVE; s&#237;ncopes; sensa&#231;&#227;o de indigest&#227;o ou eventos emb&#243;licos<xref ref-type="bibr" rid="B93">93</xref>. Desta forma, pode ser importante
                  estratificar o risco desses pacientes por meio de um m&#233;todo confi&#225;vel, com o
                  objetivo de otimizar a terap&#234;utica.</p>
          <sec>
            <title>3c.1.a Teste ergom&#233;trico</title>
            <p>Embora o teste de esfor&#231;o f&#237;sico seja a modalidade mais comum para a avalia&#231;&#227;o
                     cardiovascular n&#227;o invasiva, tem valor limitado nesta popula&#231;&#227;o, que pode ter
                     uma capacidade f&#237;sica frequentemente prejudicada por doen&#231;a vascular ou
                     neuropatia perif&#233;rica<xref ref-type="bibr" rid="B94">94</xref>. Entretanto, em
                     pacientes que tenham sintomas que podem ser devidos &#224; isquemia mioc&#225;rdica, o
                     teste de esfor&#231;o pode ser, sim, um exame &#250;til em n&#227;o havendo limita&#231;&#227;o da
                     capacidade de caminhar r&#225;pido do paciente. As indica&#231;&#245;es respeitam as mesmas
                     dos pacientes sem DM<xref ref-type="bibr" rid="B95">95</xref>.</p>
            <p>Todavia, apesar de indiv&#237;duos assintom&#225;ticos com DM apresentarem maior risco
                     cardiovascular e maior preval&#234;ncia de isquemia nos exames funcionais<xref ref-type="bibr" rid="B96">96</xref>, at&#233; o momento n&#227;o h&#225; evid&#234;ncias de que
                     a pesquisa rotineira de isquemia silenciosa em pacientes assintom&#225;ticos reduza
                     a mortalidade nesse grupo de pacientes como um todo<xref ref-type="bibr" rid="B97">97</xref>.</p>
            <sec>
              <title>Recomenda&#231;&#227;o para realiza&#231;&#227;o do teste ergom&#233;trico em
                        assintom&#225;ticos:</title>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIa</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Avalia&#231;&#227;o antes do in&#237;cio de atividade f&#237;sica moderada a intensa em
                              pacientes com mais de 40 anos. <bold><italic>N&#237;vel de evid&#234;ncia
                                    C</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
          </sec>
          <sec>
            <title>3c.1.b Cintilografia de perfus&#227;o mioc&#225;rdica</title>
            <p>In&#250;meras publica&#231;&#245;es, algumas incluindo grande casu&#237;stica, atestam a
                     import&#226;ncia da cintilografia de perfus&#227;o mioc&#225;rdica na detec&#231;&#227;o de isquemia
                     induzida por estresse em pacientes com DM<xref ref-type="bibr" rid="B44">44</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B96">96</xref>
							<sup>-</sup>
							<xref ref-type="bibr" rid="B98">98</xref>.</p>
            <p>A cintilografia de perfus&#227;o mioc&#225;rdica com estresse e repouso tem uma boa
                     acur&#225;cia, sendo similar em indiv&#237;duos com e sem DM. Em estudo com 4.755
                     pacientes com sintomas, dos quais 929 apresentavam DM, os seguintes resultados
                     foram observados ap&#243;s 2,5 anos: pacientes com DM tiveram taxa de morte card&#237;aca
                     ou infarto do mioc&#225;rdio significativamente maior do que os sem DM (8,6 vs.
                     4,5%) e maior taxa de revasculariza&#231;&#227;o; pacientes com DM apresentaram maior
                     incid&#234;ncia de cintilografias anormais (48% vs. 42%)<xref ref-type="bibr" rid="B99">99</xref>. Outro estudo incluiu 1.271 pacientes com DM e 5.862 sem
                     DM com DAC conhecida ou suspeita, demonstrando que entre os pacientes com DM, a
                     taxa de eventos foi de 1% a 2% por ano naqueles com cintilografia normal e
                     maior que 7% ao ano em pacientes com exames moderada ou acentuadamente
                     anormais, com evolu&#231;&#245;es ainda piores naqueles de alto risco<xref ref-type="bibr" rid="B100">100</xref>. Naqueles que n&#227;o s&#227;o aptos a realizar
                     exerc&#237;cio f&#237;sico, defeitos perfusionais amplos s&#227;o associados &#224; alta
                     mortalidade anual (&gt; 22%)<xref ref-type="bibr" rid="B96">96</xref>, portanto
                     as indica&#231;&#245;es da cintilografia de perfus&#227;o mioc&#225;rdica para diagn&#243;stico de DAC
                     em pacientes com sintomas sugestivos de isquemia em pacientes com DM s&#227;o as
                     mesmas dos pacientes sem DM.</p>
            <p>A preval&#234;ncia de isquemia assintom&#225;tica detectada por imagens n&#227;o invasivas em
                     pacientes com DM varia de 16% a 59%. No estudo Detection of Ischemia in
                     Asymptomatic Diabetics (DIAD), pacientes com risco relativamente baixo foram
                     randomizados para avalia&#231;&#227;o de isquemia silenciosa usando cintilografia de
                     perfus&#227;o mioc&#225;rdica com adenosina como teste de inicial de avalia&#231;&#227;o. Os
                     resultados mostraram taxa anual de evento cardiovascular de 0,4% para aqueles
                     com cintilografia normal ou de baixo risco, em compara&#231;&#227;o com 2,4% para aqueles
                     com defeitos perfusionais moderados ou grandes (<italic>p</italic> =
                        0,001)<xref ref-type="bibr" rid="B97">97</xref>. Um estudo da Mayo Clinic
                     mostrou que 58,6% dos pacientes com DM assintom&#225;ticos tiveram cintilografia
                     anormal, enquanto 19,7%, de alto risco<xref ref-type="bibr" rid="B101">101</xref>. Em um estudo prospectivo, 48% dos pacientes com DM e escore de
                     c&#225;lcio &gt; 400 apresentaram isquemia na imagem cintilogr&#225;fica, e entre aqueles
                     com escore de c&#225;lcio &gt; 1.000, 71,4% tiveram isquemia<xref ref-type="bibr" rid="B44">44</xref>. Pacientes com DM com isquemia induzida por estresse
                     apresentam taxa anual de morte ou infarto n&#227;o fatal maior quando em com aqueles
                     sem DM com anormalidades perfusionais similares (10% vs. 6%)<xref ref-type="bibr" rid="B98">98</xref>. Portanto, em pacientes assintom&#225;ticos
                     com CAC &gt; 400, podemos considerar a realiza&#231;&#227;o de cintilografia de perfus&#227;o
                     mioc&#225;rdica.</p>
            <p>Novas t&#233;cnicas promissoras, como a cintilografia de perfus&#227;o mioc&#225;rdica
                     estresse/repouso realizada com rub&#237;dio-82 em equipamento de tomografia por
                     emiss&#227;o de p&#243;sitrons (PET), permitem a detec&#231;&#227;o precoce e n&#227;o invasiva de
                     doen&#231;a arterial coronariana, incluindo a possibilidade de avalia&#231;&#227;o mais
                     precisa e quantitativa de doen&#231;a de microcircula&#231;&#227;o, uma caracter&#237;stica do
                        DM<xref ref-type="bibr" rid="B102">102</xref>. Todavia ainda n&#227;o h&#225; estudos
                     suficientes para indicar essa t&#233;cnica a pacientes com DM.</p>
            <sec>
              <title>Recomenda&#231;&#245;es de cintilografia de perfus&#227;o mioc&#225;rdica para pacientes com
                        DM assintom&#225;ticos</title>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIb</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Avalia&#231;&#227;o de risco cardiovascular em assintom&#225;ticos com escore de
                              c&#225;lcio &#8805; 400. <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
          </sec>
          <sec>
            <title>3c.1.c Ecocardiograma com estresse</title>
            <p>A ecocardiografia de estresse &#233; um importante m&#233;todo de diagn&#243;stico, n&#227;o
                     invasivo, seguro, fact&#237;vel, com boa acur&#225;cia, valor diagn&#243;stico e progn&#243;stico,
                     e com resultado bem estabelecido na literatura m&#233;dica<xref ref-type="bibr" rid="B94">94</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B103">103</xref>.
                     Sua aplicabilidade nas avalia&#231;&#245;es diagn&#243;stica e progn&#243;stica em pacientes com DM
                     e doen&#231;a coronariana conhecida ou suspeita tem sido repetidamente confirmada em
                     muitos estudos. A taxa de mortalidade cumulativa em pacientes com
                     ecocardiograma de estresse anormal foi 9%, em compara&#231;&#227;o com 3% em um ano; 29%,
                     em compara&#231;&#227;o com 11% em tr&#234;s anos; e 31%, em compara&#231;&#227;o com 24% em cinco
                        anos<xref ref-type="bibr" rid="B104">104</xref>.</p>
            <p>Em outro importante estudo, Cortigiani et al. estudaram 5.456 pacientes (749
                     diab&#233;ticos) por ecocardiografia sob estresse por dipiridamol
                        (<italic>n</italic> = 3.306) ou dobutamina (<italic>n</italic> = 2.150) que
                     foram acompanhados prospectivamente para a ocorr&#234;ncia de eventos card&#237;acos
                     maiores (morte e/ou infarto do mioc&#225;rdio n&#227;o fatal). Durante um tempo m&#233;dio de
                     31 meses ocorreram 411 mortes e 236 infartos. Houve 132 eventos em pacientes
                     diab&#233;ticos e 515 em n&#227;o diab&#233;ticos (18% vs. 11%, respectivamente,
                        <italic>p</italic> &lt; 0,0001). Isquemia detectada pela ecocardiografia sob
                     estresse, &#237;ndice de escore de motilidade de parede e idade foram preditores
                     independentes de morte e eventos de ambos os pacientes, diab&#233;ticos e n&#227;o
                     diab&#233;ticos. Contudo, um ecocardiograma sob estresse normal foi associado a uma
                     taxa de eventos anual superior a duas vezes em diab&#233;ticos em compara&#231;&#227;o com n&#227;o
                     diab&#233;ticos que eram mais jovens (2,6% vs. 1%) ou tinham mais de 65 anos de
                     idade (5,5% vs. 2,2%)<xref ref-type="bibr" rid="B105">105</xref>.</p>
            <p>As orienta&#231;&#245;es gerais sobre indica&#231;&#245;es s&#227;o id&#234;nticas &#224;quelas para os indiv&#237;duos
                     sem DM e podem ser verificadas nas diretrizes sobre ecocardiografia da SBC<xref ref-type="bibr" rid="B106">106</xref>, &#224;s p&#225;ginas e284-5.</p>
          </sec>
          <sec>
            <title>3c.1.d Angiotomografia de coron&#225;rias</title>
            <p>N&#227;o h&#225; estudos em pacientes com DM que sustentem a indica&#231;&#227;o deste exame no
                     diagn&#243;stico de pacientes sintom&#225;ticos. Assim, conforme a diretriz brasileira de
                     imagem em cardiologia, n&#227;o deve ser indicado com este fim para pacientes
                        ambulatoriais<xref ref-type="bibr" rid="B35">35</xref>.</p>
          </sec>
          <sec>
            <title>3c.1.e Hemodin&#226;mica</title>
            <p>O preparo e a interpreta&#231;&#227;o da cineangiocoronariografia e m&#233;todos invasivos
                     adjuntos n&#227;o diferem fundamentalmente entre pacientes com e sem DM. No entanto
                     a associa&#231;&#227;o entre doen&#231;a coronariana e DM determina algumas peculiaridades de
                     relev&#226;ncia cl&#237;nica.</p>
            <p>Pacientes com DM e indica&#231;&#227;o de cineangiocoronariografia, particularmente
                     aqueles com disfun&#231;&#227;o renal, apresentam-se mais predispostos a desenvolver
                     nefropatia induzida por contraste (NIC). Diversos estudos t&#234;m avaliado o
                     impacto de estrat&#233;gias de nefroprote&#231;&#227;o com o intuito de reduzir o risco de
                     insufici&#234;ncia renal ap&#243;s contraste iodinado. Na popula&#231;&#227;o geral, o risco de NIC
                     &#233; inversamente proporcional &#224; fun&#231;&#227;o renal basal, tornando-se clinicamente
                     relevante quando o <italic>clearance</italic> de creatinina &#233; &lt; 60
                     ml/min/1,73 m<sup>2</sup>
							<xref ref-type="bibr" rid="B107">107</xref>.
                     Desidrata&#231;&#227;o, volume de contraste e utiliza&#231;&#227;o concomitante de medica&#231;&#245;es
                     nefrot&#243;xicas (p. ex., anti-inflamat&#243;rios n&#227;o esteroidais) s&#227;o outros fatores de
                     risco para a piora da fun&#231;&#227;o renal p&#243;s-contraste. &#201; importante salientar, no
                     entanto, que a presen&#231;a de DM configura-se um fator de risco adicional e
                     independente para a ocorr&#234;ncia de NIC. O risco para o desenvolvimento de NIC
                     pode ser estimado por diferentes algoritmos, como demonstrado na <xref ref-type="table" rid="t01">Tabela 1</xref>
							<xref ref-type="bibr" rid="B108">108</xref>, de acordo com a qual o risco de NIC aumenta em pacientes com
                     escores &#8805; 6 e &#233; substancial naqueles com escores &#8805; 8. Pacientes sem risco
                     elevado podem realizar procedimentos com contraste iodado sem a utiliza&#231;&#227;o de
                     estrat&#233;gias preventivas.</p>
            <table-wrap id="t01">
              <label>Tabela 1</label>
              <caption>
                <title>Escore de risco para desenvolvimento de NIC</title>
              </caption>
              <table frame="hsides" rules="rows">
                <thead>
                  <tr>
                    <th align="left">Caracter&#237;stica</th>
                    <th>Escore</th>
                  </tr>
                </thead>
                <tbody>
                  <tr>
                    <td>Idade &gt; 80 anos</td>
                    <td align="center">2</td>
                  </tr>
                  <tr>
                    <td>Sexo feminino</td>
                    <td align="center">1,5</td>
                  </tr>
                  <tr>
                    <td>DM</td>
                    <td align="center">3</td>
                  </tr>
                  <tr>
                    <td>Procedimento de urg&#234;ncia*</td>
                    <td align="center">2,5</td>
                  </tr>
                  <tr>
                    <td>Procedimento de emerg&#234;ncia**</td>
                    <td align="center">3,5</td>
                  </tr>
                  <tr>
                    <td>Insufici&#234;ncia card&#237;aca</td>
                    <td align="center">4,5</td>
                  </tr>
                  <tr>
                    <td>Creatinina 1,3-1,9 mg/dl</td>
                    <td align="center">5</td>
                  </tr>
                  <tr>
                    <td>Creatinina &#8805; 2 mg/dl</td>
                    <td align="center">10</td>
                  </tr>
                  <tr>
                    <td>Bal&#227;o intra-a&#243;rtico pr&#233;-angioplastia</td>
                    <td align="center">13</td>
                  </tr>
                </tbody>
              </table>
              <table-wrap-foot>
                <fn id="tfn01t01">
                  <label>*</label>
                  <p>Urg&#234;ncia: circunst&#226;ncias cl&#237;nicas que indicam necessidade de
                              perman&#234;ncia no hospital at&#233; que a angioplastia seja realizada; sem
                              risco de mortalidade ou morbidade imediata;</p>
                </fn>
                <fn id="tfn02t01">
                  <label>**</label>
                  <p>Emerg&#234;ncia: circunst&#226;ncias cl&#237;nicas que indicam angioplastia de
                              imediato, a fim de evitar morbidade ou mortalidade<xref ref-type="bibr" rid="B108">108</xref>.</p>
                </fn>
              </table-wrap-foot>
            </table-wrap>
            <sec>
              <title>Recomenda&#231;&#245;es para a preven&#231;&#227;o de NIC em pacientes com alto risco<xref ref-type="bibr" rid="B109">109</xref>-<xref ref-type="bibr" rid="B112">112</xref>
							</title>
              <p>
                <bold>Grau de recomenda&#231;&#227;o I</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Expans&#227;o vol&#234;mica com solu&#231;&#227;o salina isot&#244;nica ou de bicarbonato.
                                    <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
              </list>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIb</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Administra&#231;&#227;o de N-acetilciste&#237;na. <bold><italic>N&#237;vel de evid&#234;ncia
                                    A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Administra&#231;&#227;o de estatina. <bold><italic>N&#237;vel de Evid&#234;ncia
                                 A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Administra&#231;&#227;o de teofilina. <bold><italic>N&#237;vel de evid&#234;ncia
                                    A</italic></bold>.</p>
                </list-item>
              </list>
              <p>A interpreta&#231;&#227;o da cineangiocoronariografia n&#227;o difere entre pacientes com e
                        sem DM. No entanto, os com DM possuem tipicamente maior propens&#227;o a
                        apresentar condi&#231;&#245;es que dificultam a avalia&#231;&#227;o cl&#237;nica da
                        cineangiocoronariografia e maior tend&#234;ncia &#224; doen&#231;a coronariana
                        oligossintom&#225;tica, com acometimento difuso e polifocal. Neste contexto, a
                        associa&#231;&#227;o entre os achados coronariogr&#225;ficos e a repercuss&#227;o funcional
                        sobre a perfus&#227;o mioc&#225;rdica pode ser reduzida, especialmente em indiv&#237;duos
                        com provas isqu&#234;micas n&#227;o invasivas inconclusivas ou contradit&#243;rias.
                        Particularmente em pacientes com les&#245;es de obstru&#231;&#227;o intermedi&#225;ria (i.e.,
                        entre 40% e 70% de estenose em di&#226;metro), les&#245;es longas, les&#245;es em s&#233;rie ou
                        em vasos difusamente acometidos, a interpreta&#231;&#227;o da cineangiocoronariografia
                        pode ser especialmente dif&#237;cil. A utiliza&#231;&#227;o, na sala de cateterismo, de
                        m&#233;todos adjuntos como ultrassom intravascular e reserva fracionada de fluxo
                        tem se mostrado ferramenta valiosa para aumentar a acur&#225;cia diagn&#243;stica da
                        cineangiocoronariografia e guiar a estrat&#233;gia terap&#234;utica subsequente. As
                        recomenda&#231;&#245;es para a utiliza&#231;&#227;o dos m&#233;todos diagn&#243;sticos invasivos adjuntos
                        &#224; cineangiocoronariografia s&#227;o as mesmas que para os pacientes sem DM<xref ref-type="bibr" rid="B113">113</xref>
								<sup>-</sup>
								<xref ref-type="bibr" rid="B115">115</xref>.</p>
            </sec>
          </sec>
        </sec>
        <sec>
          <title>3c.2 Tratamento</title>
          <sec>
            <title>3c.2.a Tratamento cl&#237;nico</title>
            <p>O tratamento cl&#237;nico &#233; fundamental no manejo do paciente com DM portador de DAC
                     cr&#244;nica. Essa conduta n&#227;o deve ser entendida como simples op&#231;&#227;o terap&#234;utica
                     para o tratamento da DAC, uma vez que ambas as enfermidades s&#227;o de car&#225;ter
                     progressivo e todos os indiv&#237;duos nessa condi&#231;&#227;o devem receb&#234;-lo, mesmo aqueles
                     submetidos a terapias intervencionistas.</p>
            <p>O que entendemos por tratamento cl&#237;nico &#233; um conjunto de medidas que v&#227;o desde
                     mudan&#231;as no estilo de vida ao uso de tratamento farmacol&#243;gico apropriado. Na
                     terap&#234;utica n&#227;o farmacol&#243;gica, as medidas recomendadas s&#227;o semelhantes &#224;s
                     indicadas aos demais pacientes portadores de DAC<xref ref-type="bibr" rid="B28">28</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B116">116</xref>.</p>
            <sec>
              <title>Tratamento medicamentoso do DM no contexto da DAC</title>
              <p>Em rela&#231;&#227;o ao controle do DM nessa popula&#231;&#227;o, algumas considera&#231;&#245;es devem
                        ser feitas (<xref ref-type="table" rid="t02">Tabela 2</xref>). Existem
                        evid&#234;ncias da redu&#231;&#227;o de complica&#231;&#245;es microvasculares com controle glic&#234;mico
                           intensivo<xref ref-type="bibr" rid="B117">117</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B118">118</xref>, o qual pode se refletir em redu&#231;&#227;o
                        de eventos cardiovasculares ap&#243;s longo prazo de seguimento<xref ref-type="bibr" rid="B119">119</xref> ou quando se associam
                        intensivamente outras medidas de mudan&#231;a de estilo de vida e farmacol&#243;gicas
                        sabidamente relacionadas com a redu&#231;&#227;o de desfechos cardiovasculares<xref ref-type="bibr" rid="B120">120</xref>. Com base na evid&#234;ncia vigente,
                        parece razo&#225;vel manter o alvo de HbA1c em torno de 7%<xref ref-type="bibr" rid="B28">28</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B116">116</xref>, devendo haver individualiza&#231;&#227;o desse alvo, com aten&#231;&#227;o
                        especial quanto ao risco de hipoglicemia, a qual deve ser evitada, uma vez
                        que est&#225; relacionada com piora da isquemia mioc&#225;rdica e surgimento de
                        arritmias card&#237;acas<xref ref-type="bibr" rid="B121">121</xref>.</p>
              <table-wrap id="t02">
                <label>Tabela 2</label>
                <caption>
                  <title>Tratamento farmacol&#243;gico do DM2</title>
                </caption>
                <table frame="hsides" rules="rows">
                  <thead>
                    <tr>
                      <th align="left">Efeito</th>
                      <th>Classe da droga</th>
                      <th>Medica&#231;&#245;es</th>
                      <th>Hipoglicemia</th>
                      <th>Observa&#231;&#245;es</th>
                    </tr>
                  </thead>
                  <tbody>
                    <tr>
                      <td rowspan="2">Aumenta a sensibilidade &#224; insulina</td>
                      <td align="center">Metformina</td>
                      <td align="center">Metformina</td>
                      <td align="center">N&#227;o</td>
                      <td align="center">EC gastrointestinais, acidose l&#225;tica,
                                    defici&#234;ncia de B12, CI: IRC, hip&#243;xia e desidrata&#231;&#227;o</td>
                    </tr>
                    <tr>
                      <td align="center">Tiazolinedionas</td>
                      <td align="center">Pioglitazona</td>
                      <td align="center">N&#227;o</td>
                      <td align="center">Insufici&#234;ncia card&#237;aca, edema, fraturas, c&#226;ncer
                                    de bexiga</td>
                    </tr>
                    <tr>
                      <td rowspan="14">Estimula a secre&#231;&#227;o de insulina</td>
                      <td rowspan="5" align="center">Sulfonilureias</td>
                      <td style="border-bottom:hidden" align="center">Clorpropamida</td>
                      <td rowspan="5" align="center">Sim</td>
                      <td rowspan="5" align="center">Alergia, risco de hipoglicemia e
                                    ganho de peso</td>
                    </tr>
                    <tr>
                      <td align="center" style="border-bottom:hidden">Glibenclamida</td>
                    </tr>
                    <tr>
                      <td align="center" style="border-bottom:hidden">Gliclazida</td>
                    </tr>
                    <tr>
                      <td align="center" style="border-bottom:hidden">Glimepirida</td>
                    </tr>
                    <tr>
                      <td align="center">Glipizida</td>
                    </tr>
                    <tr>
                      <td rowspan="2" align="center">Meglitinidas</td>
                      <td style="border-bottom:hidden" align="center">Repaglinida</td>
                      <td rowspan="2" align="center">Sim</td>
                      <td rowspan="2" align="center">Dosagens frequentes, risco de
                                    hipoglicemia</td>
                    </tr>
                    <tr>
                      <td align="center">Nateglinida</td>
                    </tr>
                    <tr>
                      <td rowspan="2" align="center">Agonistas de GLP-1</td>
                      <td style="border-bottom:hidden" align="center">Exenatida</td>
                      <td rowspan="2" align="center">N&#227;o</td>
                      <td rowspan="2" align="center">EC gastrointestinais, pancreatite,
                                    injet&#225;vel</td>
                    </tr>
                    <tr>
                      <td align="center">Liraglutida</td>
                    </tr>
                    <tr>
                      <td rowspan="5" align="center">Inibidores de DPP-4</td>
                      <td style="border-bottom:hidden" align="center">Sitagliptina</td>
                      <td rowspan="5" align="center">N&#227;o</td>
                      <td rowspan="5" align="center">Pancreatite</td>
                    </tr>
                    <tr>
                      <td style="border-bottom:hidden" align="center">Vidagliptina</td>
                    </tr>
                    <tr>
                      <td style="border-bottom:hidden" align="center">Saxagliptina</td>
                    </tr>
                    <tr>
                      <td style="border-bottom:hidden" align="center">Linagliptina</td>
                    </tr>
                    <tr>
                      <td align="center">Alogliptina</td>
                    </tr>
                    <tr>
                      <td>Insulina</td>
                      <td align="center">Insulina</td>
                      <td align="center">&#160;</td>
                      <td align="center">Sim</td>
                      <td align="center">Injet&#225;vel, risco de hipoglicemia e ganho de
                                    peso</td>
                    </tr>
                    <tr>
                      <td>Inibe a absor&#231;&#227;o de glicose</td>
                      <td align="center">Inibidores de alfa-glicosidase</td>
                      <td align="center">Acarbose</td>
                      <td align="center">N&#227;o</td>
                      <td align="center">EC gastrointestinal, dosagens frequentes</td>
                    </tr>
                  </tbody>
                </table>
                <table-wrap-foot>
                  <fn>
                    <p>EC: efeitos colaterais; CI: contraindica&#231;&#227;o; GLP-1: pept&#237;deo
                                 semelhante ao glucagon. Adaptado de: Ryd&#233;n et al.<xref ref-type="bibr" rid="B154">154</xref>.</p>
                  </fn>
                </table-wrap-foot>
              </table-wrap>
              <p>A metformina deve ser recomendada como primeira escolha a pacientes com DM
                        portadores de DAC<xref ref-type="bibr" rid="B122">122</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B123">123</xref>.
                        Estudos recentes t&#234;m alertado para um efeito cardioprotetor da droga<xref ref-type="bibr" rid="B124">124</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B125">125</xref>, com preserva&#231;&#227;o do mecanismo de
                        pr&#233;-condicionamento isqu&#234;mico<xref ref-type="bibr" rid="B126">126</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B127">127</xref>, a
                        qual n&#227;o &#233; uniforme entre as drogas antidiab&#233;ticas. Drogas como
                           glibenclamida<xref ref-type="bibr" rid="B128">128</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B129">129</xref> e repaglinida<xref ref-type="bibr" rid="B130">130</xref> parecem bloque&#225;-lo, enquanto a vildagliptina, um
                        inibidor da dipeptidil-peptidase 4 (DPP-4), preservou o pr&#233;-condicionamento
                        isqu&#234;mico em popula&#231;&#227;o com DM portadora de DAC multiarterial em estudo
                           recente<xref ref-type="bibr" rid="B131">131</xref>. No entanto, uma vez
                        que os estudos cl&#237;nicos n&#227;o mostraram preju&#237;zo do uso de sulfonilureias em
                        pacientes com diabetes, com ou sem cardiopatia pr&#233;via, n&#227;o h&#225; evid&#234;ncia para
                        contraindicar seu uso. Embora os inibidores da alfa-glicosidase (acarbose,
                        principalmente) sejam op&#231;&#227;o como segunda droga no tratamento do DM, seu uso
                        &#233; limitado pela efic&#225;cia moderada e alta incid&#234;ncia de efeitos adversos. N&#227;o
                        parece haver benef&#237;cio na redu&#231;&#227;o de eventos cardiovasculares<xref ref-type="bibr" rid="B132">132</xref>.</p>
              <p>Apesar de estudos iniciais sugerirem a exist&#234;ncia de um efeito
                        cardioprotetor das novas classes de antidiab&#233;ticos, como inibidores da DPP-4
                        e an&#225;logos do pept&#237;deo semelhante ao glucagon 1 (GLP-1), na popula&#231;&#227;o
                        portadora de insufici&#234;ncia coronariana<xref ref-type="bibr" rid="B131">131</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B133">133</xref>, dois
                        estudos recentes randomizados n&#227;o demonstraram redu&#231;&#227;o de eventos CVs com
                        estas medica&#231;&#245;es. Em pacientes com DM e s&#237;ndrome coronariana aguda recente
                        (Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2
                        Diabetes and Acute Coronary Syndrome [EXAMINE]) ou com doen&#231;a cardiovascular
                        pr&#233;via (SAVOR-TIMI), nem a alogliptina (EXAMINE) nem a saxagliptina
                        (Saxagliptin Assessment of Vascular. Outcomes Recorded in Patients with.
                        Diabetes Mellitus - Thrombolysis In Myocardial Infarction [SAVOR-TIMI])
                        foram superiores ao uso de placebo como segunda droga adicionada &#224;
                        metformina em reduzir eventos cardiovasculares num seguimento de at&#233; dois
                           anos<xref ref-type="bibr" rid="B134">134</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B135">135</xref>. Uma vez que esses agentes t&#234;m
                        pouca pot&#234;ncia quanto &#224; melhora do controle glic&#234;mico<xref ref-type="bibr" rid="B134">134</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B135">135</xref>, alto custo e n&#227;o apresentam seguran&#231;a comprovada em longo
                        prazo, estes resultados apontam para que n&#227;o sejam priorizados neste
                        contexto, exceto quando os pacientes exibirem efeitos adversos inaceit&#225;veis
                        com o uso de sulfonilureias.</p>
              <p>Quanto ao uso das glitazonas, embora a rosiglitazona tenha sido retirada do
                        mercado por se associar a maior risco de infarto do mioc&#225;rdio<xref ref-type="bibr" rid="B136">136</xref> e eventos cardiovasculares<xref ref-type="bibr" rid="B137">137</xref>, a pioglitazona n&#227;o mostrou este
                        tipo de efeito adverso quando<xref ref-type="bibr" rid="B138">138</xref>
                        testada em popula&#231;&#227;o de pacientes com DM e doen&#231;a cardiovascular pr&#233;via.
                        Cabe ressaltar que ambas se associam a aumento no risco de interna&#231;&#245;es por
                        insufici&#234;ncia card&#237;aca<xref ref-type="bibr" rid="B139">139</xref>.</p>
              <p>Quando necess&#225;rio, deve-se usar associa&#231;&#227;o de grupos de drogas
                        antidiab&#233;ticas para se conseguir melhor controle glic&#234;mico. O uso de
                        insulina deve sempre ser ponderado devido ao car&#225;ter progressivo do DM2,
                        principalmente entre aqueles com DAC avan&#231;ada e dif&#237;cil controle glic&#234;mico
                        j&#225; em uso de terapia antidiab&#233;tica oral<xref ref-type="bibr" rid="B140">140</xref>. Sua utiliza&#231;&#227;o n&#227;o se associa a piores desfechos
                           cardiovasculares<xref ref-type="bibr" rid="B119">119</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B120">120</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B141">141</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B142">142</xref>.</p>
            </sec>
            <sec>
              <title>Tratamento medicamentoso da insufici&#234;ncia coron&#225;ria em pacientes com
                        DM</title>
              <p>Nessa popula&#231;&#227;o, o uso da chamada terapia medicamentosa otimizada (TMO) com
                        benef&#237;cios na preven&#231;&#227;o secund&#225;ria segue diretrizes espec&#237;ficas<xref ref-type="bibr" rid="B116">116</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B143">143</xref>.</p>
              <p>Vale ressaltar, no entanto, que o uso de inibidor da enzima conversora da
                        angiotensina (IECA), por exemplo, deve ser recomendado fortemente a essa
                        popula&#231;&#227;o, considerando seu comprovado benef&#237;cio na preven&#231;&#227;o de eventos
                        macro e microvasculares<xref ref-type="bibr" rid="B144">144</xref>. Esse
                        benef&#237;cio tem se estendido aos bloqueadores de receptor de angiotensina
                           (BRA)<xref ref-type="bibr" rid="B145">145</xref>, devendo estes
                        substituir aqueles em caso de contraindica&#231;&#227;o. Entre os benef&#237;cios do
                        bloqueio do sistema renina-angiotensina-aldosterona est&#227;o a redu&#231;&#227;o da
                        albumin&#250;ria com preven&#231;&#227;o da progress&#227;o da nefropatia diab&#233;tica<xref ref-type="bibr" rid="B146">146</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B147">147</xref> e a preven&#231;&#227;o de morte entre os pacientes com
                        disfun&#231;&#227;o ventricular<xref ref-type="bibr" rid="B148">148</xref> e
                           p&#243;s-IAM<xref ref-type="bibr" rid="B149">149</xref>. Estudos recentes
                        observaram, ainda, benef&#237;cio na redu&#231;&#227;o de mortes em popula&#231;&#227;o com DAC e
                        fun&#231;&#227;o ventricular preservada<xref ref-type="bibr" rid="B150">150</xref>.</p>
              <p>Em rela&#231;&#227;o aos betabloqueadores, h&#225; car&#234;ncia de estudos desenhados
                        especificamente para avaliar seus benef&#237;cios entre pacientes com DM.
                        Contudo, alguma cautela deve haver no uso de betabloqueadores entre
                        indiv&#237;duos com DM. Seu efeito vasoconstritor pode levar ao aumento da
                        resist&#234;ncia insul&#237;nica por redu&#231;&#227;o da &#225;rea microvascular muscular destinada
                        &#224; capta&#231;&#227;o de glicose insulinomediada<xref ref-type="bibr" rid="B151">151</xref>. Por&#233;m &#233; claro seu benef&#237;cio na redu&#231;&#227;o de mortalidade entre
                        os portadores de disfun&#231;&#227;o ventricular esquerda<xref ref-type="bibr" rid="B152">152</xref> e IAM<xref ref-type="bibr" rid="B153">153</xref>.</p>
              <p>
                <bold>Grau de recomenda&#231;&#227;o I</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Medidas n&#227;o farmacol&#243;gicas como cessa&#231;&#227;o do tabagismo, perda de peso,
                              atividade f&#237;sica regular, controle diet&#233;tico e de fatores de risco
                              est&#227;o indicadas para todos os pacientes com DM portadores de DAC.
                                    <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>A preven&#231;&#227;o secund&#225;ria com uso de AAS e estatinas (com alvo de LDL-C
                              &lt; 70 mg/dl) est&#225; indicada para todos, salvo contraindica&#231;&#245;es.
                                    <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>O uso de IECAs est&#225; recomendado (salvo contraindica&#231;&#245;es) para
                              pacientes portadores de DAC e DM para redu&#231;&#227;o de risco cardiovascular.
                                    <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>BRAs devem substituir IECAs quando o paciente apresentar tosse
                              relacionada com o IECA. <bold><italic>N&#237;vel de evid&#234;ncia
                                 B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Betabloqueadores est&#227;o indicados para pacientes portadores de DAC e DM
                              com disfun&#231;&#227;o ventricular esquerda, observando-se as indica&#231;&#245;es da
                              diretriz de IC. <bold><italic>N&#237;vel de evid&#234;ncia
                              A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Betabloqueadores ap&#243;s IAM por at&#233; tr&#234;s anos, sujeito a reavalia&#231;&#227;o.
                                    <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Betabloqueadores para tratar angina e/ou isquemia silenciosa.
                                    <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
              </list>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIa</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>A metformina est&#225; indicada como droga de primeira escolha para
                              pacientes portadores de DM2 e DAC. <bold><italic>N&#237;vel de evid&#234;ncia
                                    B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Sulfonilureias, acarbose ou insulina est&#227;o indicadas como segunda
                              droga para pacientes portadores de DM2 e DAC, escolhendo-se a mais
                              adequada caso a caso. <bold><italic>N&#237;vel de evid&#234;ncia
                                 B</italic></bold>.</p>
                </list-item>
              </list>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIb</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Deve-se considerar in&#237;cio precoce de terapia com insulina nessa
                              popula&#231;&#227;o para redu&#231;&#227;o de eventos cardiovasculares.
                                    <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>&#201; razo&#225;vel o uso de inibidores de DPP-4 e/ou an&#225;logos de GLP-1 em
                              associa&#231;&#227;o a metformina para melhor controle glic&#234;mico.
                                    <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
            <sec>
              <title>3c.2.b Tratamento intervencionista</title>
              <p>As indica&#231;&#245;es de terapia intervencionista para revasculariza&#231;&#227;o em pacientes
                        portadores de DAC est&#225;vel s&#227;o normatizadas por diretrizes espec&#237;ficas<xref ref-type="bibr" rid="B155">155</xref>
								<sup>-</sup>
								<xref ref-type="bibr" rid="B157">157</xref>.</p>
              <p>Entre os pacientes com DM s&#227;o v&#225;lidas algumas considera&#231;&#245;es. Em primeiro
                        lugar, v&#225;rios estudos t&#234;m demonstrado que a presen&#231;a de DM &#233; fator de pior
                        progn&#243;stico entre pacientes portadores de DAC, mesmo aqueles que se submetem
                        a procedimentos de revasculariza&#231;&#227;o<xref ref-type="bibr" rid="B130">130</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B158">158</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B159">159</xref>. O
                        estudo Bypass Angioplasty Revascularization Investigation (BARI)<xref ref-type="bibr" rid="B160">160</xref> demonstrou, em uma an&#225;lise de
                        subgrupo, maior sobrevida em pacientes com DM quando submetidos a cirurgia
                        de revasculariza&#231;&#227;o em compara&#231;&#227;o com aqueles submetidos a angioplastia com
                        bal&#227;o (76,4% vs. 55,7%; <italic>p</italic> = 0,001). Esse achado suscitou o
                        surgimento de v&#225;rios estudos comparando os diversos tratamentos para DAC na
                        popula&#231;&#227;o diab&#233;tica.</p>
              <p>O estudo Bypass Angioplasty Revascularization Investigation 2 in Diabetes
                        (BARI 2D)<xref ref-type="bibr" rid="B142">142</xref>, avaliando 2.368
                        pacientes com DM e DAC multiarterial, demonstrou n&#227;o haver diferen&#231;a na
                        incid&#234;ncia de IAM, AVE ou morte quando comparados pacientes submetidos a
                        interven&#231;&#227;o (revasculariza&#231;&#227;o mioc&#225;rdica cir&#250;rgica ou angioplastia com
                           <italic>stent</italic> convencional) vs. TMO exclusivo em seguimento de
                        longo prazo. Houve, por&#233;m, menor incid&#234;ncia do desfecho prim&#225;rio combinado
                        de IAM, AVE e morte no subgrupo submetido a cirurgia em compara&#231;&#227;o com o
                        grupo TMO (22,4% vs. 30,5%; <italic>p</italic> = 0,01).</p>
              <p>Em nosso meio, uma suban&#225;lise do estudo Medicine, Angioplasty or Surgery
                        Study (MASS) comparando tr&#234;s modalidades terap&#234;uticas (cirurgia,
                        angioplastia e TMO) em 190 pacientes com DM portadores de DAC est&#225;vel
                        multiarterial dos 611 inclu&#237;dos no estudo original observou, ap&#243;s o primeiro
                        ano de seguimento, menor mortalidade entre aqueles submetidos aos
                        procedimentos intervencionistas (cirurgia e angioplastia) quando em
                        compara&#231;&#227;o com o grupo TMO (<italic>p</italic> = 0,039)<xref ref-type="bibr" rid="B161">161</xref>.</p>
              <p>An&#225;lise colaborativa com dados de 10 estudos da era pr&#233;-The SYNergy between
                        Percutaneous Coronary Intervention and Cardiac Surgery (SYNTAX) comparando o
                        tratamento cir&#250;rgico e a angioplastia (com <italic>stent</italic>
                        convencional e bal&#227;o) encontrou uma mortalidade significativamente menor no
                        grupo cir&#250;rgico entre a popula&#231;&#227;o com DM (HR 0,70; 0,56-0,87)<xref ref-type="bibr" rid="B162">162</xref>.</p>
              <p>No que concerne ao tipo de <italic>stent</italic> utilizado, estudos t&#234;m
                        demonstrado superioridade dos <italic>stents</italic> farmacol&#243;gicos sobre
                        os <italic>stents</italic> convencionais, com menor necessidade de
                        revasculariza&#231;&#227;o adicional de vaso alvo para os primeiros<xref ref-type="bibr" rid="B163">163</xref>. Ainda assim, alguns estudos mais
                        recentes, utilizando <italic>stents</italic> farmacol&#243;gicos, t&#234;m revelado
                        resultados inferiores aos da cirurgia na popula&#231;&#227;o diab&#233;tica portadora de
                        DAC multiarterial<xref ref-type="bibr" rid="B164">164</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B165">165</xref>.</p>
              <p>Uma suban&#225;lise do estudo SYNTAX comparando os tratamentos cir&#250;rgico e
                        angioplastia com <italic>stent</italic> farmacol&#243;gico revestido com
                        paclitaxel em 452 dos 1.800 pacientes inclu&#237;dos no estudo principal n&#227;o
                        encontrou diferen&#231;a na incid&#234;ncia de eventos cardiovasculares adversos entre
                        os grupos em um seguimento de um ano<xref ref-type="bibr" rid="B159">159</xref>. Em an&#225;lise de cinco anos de seguimento<xref ref-type="bibr" rid="B166">166</xref> do mesmo estudo foi observada maior incid&#234;ncia de
                        eventos cardiovasculares adversos no grupo submetido a angioplastia em
                        compara&#231;&#227;o com o grupo cir&#250;rgico (46,5% vs. 29%, respectivamente;
                           <italic>p</italic> &lt; 0,001).</p>
              <p>Mais recentemente, o estudo The Future REvascularization Evaluation in
                        patients with Diabetes mellitus: optimal management of Multivessel disease
                           (FREEDOM)<xref ref-type="bibr" rid="B167">167</xref>, comparando os
                        tratamentos cir&#250;rgico e angioplastia com <italic>stent</italic>
                        farmacol&#243;gico em 1.900 pacientes com DM portadores de DAC multiarterial
                        seguidos por um tempo m&#233;dio de 3,8 anos, mostrou que a cirurgia &#233; superior &#224;
                        angioplastia, com menor mortalidade (10,9% vs. 16,3% respectivamente;
                           <italic>p</italic> = 0,049), menor incid&#234;ncia de IAM (6% vs. 13,9%;
                           <italic>p</italic> &lt; 0,001), por&#233;m com maior incid&#234;ncia de AVE (5,2%
                        vs. 2,4%; <italic>p</italic> = 0,03).</p>
              <p>
                <bold>Grau de recomenda&#231;&#227;o I</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Para pacientes portadores de DAC extensa est&#225; indicado procedimento de
                              revasculariza&#231;&#227;o para preven&#231;&#227;o de eventos cardiovasculares maiores.
                                    <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Na popula&#231;&#227;o de pacientes multiarteriais com indica&#231;&#227;o de interven&#231;&#227;o,
                              a cirurgia deve ser preferida sobre a angioplastia para redu&#231;&#227;o de
                              eventos cardiovasculares maiores. <bold><italic>N&#237;vel de evid&#234;ncia
                                    B</italic></bold>.</p>
                </list-item>
                <list-item>
                  <p>Quando definido por tratamento intervencionista percut&#226;neo, deve-se
                              preferir o uso de <italic>stents</italic> farmacol&#243;gicos para redu&#231;&#227;o
                              da incid&#234;ncia de reestenose e de revasculariza&#231;&#227;o adicional.
                                    <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
              </list>
              <p>
                <bold>Grau de recomenda&#231;&#227;o IIa</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Em pacientes portadores de DAC com sintomas bem controlados e fun&#231;&#227;o
                              ventricular preservada &#233; razo&#225;vel a manuten&#231;&#227;o do tratamento
                              medicamentoso exclusivo com controle de fatores de risco e terapia de
                              metas. <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                </list-item>
              </list>
            </sec>
          </sec>
          <sec>
            <title>3d. Peculiaridades no diagn&#243;stico e tratamento da doen&#231;a coronariana aguda
                     no paciente com DM</title>
            <sec>
              <title>3d.1 Diagn&#243;stico</title>
              <sec>
                <title>3d.1.a Apresenta&#231;&#227;o cl&#237;nica</title>
                <p>No mundo, estima-se que haja mais de 170 milh&#245;es de pacientes com DM e
                           que esse n&#250;mero possa aumentar at&#233; 165% nos pr&#243;ximos 12 anos.
                           Aproximadamente 20% a 37% dos pacientes com SCAs t&#234;m DM, e muitos, apesar
                           de o possu&#237;rem, ainda n&#227;o sabem do diagn&#243;stico at&#233; a apresenta&#231;&#227;o da
                           doen&#231;a coronariana. Geralmente o paciente com DM &#233; mais idoso e tem
                           comorbidades agregadas, como hipertens&#227;o, obesidade, insufici&#234;ncia renal
                           cr&#244;nica e dislipidemia<xref ref-type="bibr" rid="B168">168</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B169">169</xref>.</p>
                <p>A maioria dos pacientes com DM tem a mesma apresenta&#231;&#227;o cl&#237;nica de
                           s&#237;ndrome coronariana aguda (SCA) que os sem DM. No entanto o paciente com
                           DM entra no grupo de doentes que com mais frequ&#234;ncia apresenta sintomas
                           at&#237;picos de DAC, como dor epig&#225;strica, dores em pontada, empachamento,
                           dor pleur&#237;tica, s&#237;ncope e dispneia<xref ref-type="bibr" rid="B155">155</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B170">170</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B173">173</xref>.
                           Dessa forma, a aus&#234;ncia dos sintomas cl&#225;ssicos pode comprometer o
                           diagn&#243;stico de SCA no paciente com DM, principalmente quando o
                           eletrocardiograma (ECG) for normal ou apresentar alguma altera&#231;&#227;o pr&#233;via
                           que atrapalhe a sua interpreta&#231;&#227;o.</p>
              </sec>
              <sec>
                <title>3d.1.b Eletrocardiograma</title>
                <p>N&#227;o existe diferen&#231;a em rela&#231;&#227;o a solicita&#231;&#227;o e avalia&#231;&#227;o do ECG no
                           paciente com ou sem DM. O mesmo deve ser solicitado em at&#233; 10 minutos
                           ap&#243;s a chegada do paciente ao setor de emerg&#234;ncia e repetido pelo menos
                           uma vez em 6 a 9 horas<xref ref-type="bibr" rid="B174">174</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B175">175</xref>.</p>
              </sec>
              <sec>
                <title>3d.1.c Marcadores de necrose mioc&#225;rdica</title>
                <p>Da mesma forma que o ECG, a dosagem de troponina (T ou I) deve ser
                           realizada segundo as mesmas orienta&#231;&#245;es para atendimento de pacientes sem
                           DM. A coleta deve ser solicitada na chegada, podendo ser repetida 6 a 9
                           horas ap&#243;s, caso o resultado inicial n&#227;o seja conclusivo ou quando n&#227;o
                           houver tempo h&#225;bil em rela&#231;&#227;o ao in&#237;cio da dor<xref ref-type="bibr" rid="B176">176</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B184">184</xref>. A interpreta&#231;&#227;o do resultado depende do kit utilizado,
                           devendo-se prestar aten&#231;&#227;o em pacientes com DM e doen&#231;a renal cr&#244;nica
                           concomitante. Pacientes com <italic>clearance</italic> de creatinina &lt;
                           25 ml/min podem apresentar eleva&#231;&#227;o da troponina sem necessariamente
                           estar relacionada com SCA, devendo ser repetida a dosagem ap&#243;s 6 a 9
                           horas. Altera&#231;&#227;o significativa entre as duas dosagens de troponina sugere
                           fortemente o diagn&#243;stico de IAM<xref ref-type="bibr" rid="B182">182</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B185">185</xref>.</p>
              </sec>
              <sec>
                <title>3d.1.d.Diagn&#243;stico diferencial</title>
                <p>A possibilidade diagn&#243;stica de SCA sempre deve ser considerada para
                           pacientes com DM com dor tor&#225;cica devido &#224; elevada incid&#234;ncia da doen&#231;a
                           nessa popula&#231;&#227;o. No entanto surgem como diagn&#243;stico diferencial todas as
                           outras situa&#231;&#245;es (dissec&#231;&#227;o de aorta, tromboembolismo pulmonar,
                           pneumot&#243;rax, espasmo esof&#225;gico etc.) consideradas na popula&#231;&#227;o em geral
                              <xref ref-type="bibr" rid="B170">170</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B172">172</xref>.</p>
                <p>Aproximadamente 15% dos pacientes com SCA n&#227;o apresentam les&#245;es
                           coronarianas obstrutivas compat&#237;veis com a apresenta&#231;&#227;o cl&#237;nica.
                           Especificamente no paciente com DM &#233; comum o diagn&#243;stico de angina
                           variante ou s&#237;ndrome X, caracterizada por altera&#231;&#245;es endoteliais em
                           microvasculatura coronariana, no entanto tal diagn&#243;stico s&#243; &#233; poss&#237;vel
                           ap&#243;s estratifica&#231;&#227;o coronariana invasiva<xref ref-type="bibr" rid="B170">170</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B172">172</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B176">176</xref>.</p>
              </sec>
              <sec>
                <title>3d.1.e. Estratifica&#231;&#227;o de risco</title>
                <p>Os mesmos escores de risco para SCA sem supradesn&#237;vel de ST aplicados a
                           pacientes sem DM, como o Thrombolysis in Myocardial Infarction Risk
                           (TIMI) e o Global Registry of Acute Coronary Events (GRACE), podem ser
                           utilizados em indiv&#237;duos com DM<xref ref-type="bibr" rid="B186">186</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B188">188</xref>. No
                           entanto, o DM &#233;, por si s&#243;, um preditor de risco de morte independente em
                           pacientes com SCA, acarretando risco duas a tr&#234;s vezes maior em rela&#231;&#227;o &#224;
                           popula&#231;&#227;o geral<xref ref-type="bibr" rid="B168">168</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B189">189</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B193">193</xref>.
                           Dessa forma, o paciente com DM pode ser considerado de alto risco
                           independente do escore utilizado, necessitando de terap&#234;utica otimizada,
                           incluindo, preferencialmente, estrat&#233;gia invasiva precoce<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B190">190</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B192">192</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B194">194</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B196">196</xref>.</p>
                <p>Apesar de reconhecidamente apresentarem maior risco de morte e eventos em
                           curto e longo prazos, pacientes com DM e SCA s&#227;o usualmente medicados de
                           maneira n&#227;o otimizada. Em registros europeus, observa-se que estrat&#233;gias
                           invasivas e terapias de reperfus&#227;o, bem como a administra&#231;&#227;o de
                           tienopirid&#237;nicos e inibidores das glicoprote&#237;na IIb/IIIa, s&#227;o menos
                           aplicadas aos pacientes com DM quando em compara&#231;&#227;o com o tratamento dos
                           pacientes sem DM, com reflexo claro na morbimortalidade<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B189">189</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B197">197</xref>.</p>
                <sec>
                  <title>Recomenda&#231;&#245;es para o manejo da s&#237;ndrome coronariana aguda em
                              pacientes com DM</title>
                  <p>
                    <bold>Grau de recomenda&#231;&#227;o I</bold>
                  </p>
                  <list list-type="bullet">
                    <list-item>
                      <p>Pacientes com DM e SCA com ou sem supradesn&#237;vel de ST devem ser
                                    considerados de alto risco para morte e eventos
                                    cardiovasculares. <bold><italic>N&#237;vel de evid&#234;ncia
                                       A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>A dosagem de troponina deve ser solicitada na chegada, podendo
                                    ser repetida 6 a 9 horas ap&#243;s, caso o resultado inicial n&#227;o seja
                                    conclusivo ou se n&#227;o houver tempo h&#225;bil em rela&#231;&#227;o ao in&#237;cio da
                                    dor. <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>A apresenta&#231;&#227;o cl&#237;nica at&#237;pica de dor tor&#225;cica deve ser
                                    considerada possibilidade de SCA. <bold><italic>N&#237;vel de
                                          evid&#234;ncia B</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>O ECG deve ser solicitado em at&#233; 10 minutos depois da chegada do
                                    paciente ao setor de emerg&#234;ncia e repetido pelo menos uma vez em
                                    6 a 9 horas. <bold><italic>N&#237;vel de evid&#234;ncia
                                    B</italic></bold>.</p>
                    </list-item>
                  </list>
                </sec>
              </sec>
            </sec>
            <sec>
              <title>3d.2 Tratamento</title>
              <p>Em ambas as apresenta&#231;&#245;es (SCA sem eleva&#231;&#227;o de ST e IAM com eleva&#231;&#227;o do
                        segmento ST), o DM se relaciona com pior progn&#243;stico a curto e longo prazos,
                        inclusive mortalidade<xref ref-type="bibr" rid="B168">168</xref>
								<sup>,</sup>
								<xref ref-type="bibr" rid="B198">198</xref>.</p>
              <p>O manejo dos pacientes com coronariopatia aguda com ou sem DM deve ser muito
                        semelhante, seguindo as diretrizes espec&#237;ficas de SCA<xref ref-type="bibr" rid="B173">173</xref>, IAM<xref ref-type="bibr" rid="B199">199</xref> e a
                        mais recente sobre antiplaquet&#225;rios e anticoagulantes<xref ref-type="bibr" rid="B200">200</xref>. Por&#233;m, devido &#224; influ&#234;ncia do DM no desfecho
                        cl&#237;nico dos pacientes com coronariopatia aguda, algumas observa&#231;&#245;es ser&#227;o
                        aqui expostas, assim como ser&#225; ressaltado o controle da hiperglicemia.</p>
              <sec>
                <title>3d.2.a Estrat&#233;gia invasiva vs. conservadora na SCA sem supradesn&#237;vel
                           de ST</title>
                <p>Embora nenhum grande estudo tenha sido desenhado para avaliar a melhor
                           estrat&#233;gia em pacientes diab&#233;ticos com SCA sem supradesn&#237;vel de ST, a
                           realiza&#231;&#227;o de estrat&#233;gia invasiva precoce deve preferencialmente ser
                           adotada, uma vez que pacientes com DM s&#227;o considerados de alto risco<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B195">195</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B196">196</xref>.</p>
                <p>No estudo Fast Revascularization during Instability in Coronary Artery
                           Disease II (FRISC-II) foi demonstrado que o benef&#237;cio da estrat&#233;gia
                           invasiva em pacientes com DM (raz&#227;o de chance [RC] = 0,72; IC 95%:
                           0,54-0,95) &#233; semelhante ao benef&#237;cio em pacientes sem DM de alto risco
                           tamb&#233;m submetidos &#224; estrat&#233;gia invasiva (OR = 0,61; IC 95%: 0,36-1,04),
                           com redu&#231;&#227;o do n&#250;mero de IAM e da mortalidade em um ano de
                              seguimento<xref ref-type="bibr" rid="B195">195</xref>.</p>
                <p>No estudo Treat Angina with Aggrastat and Determine the Cost of Therapy
                           With Invasive or Conservative Strategy - Thrombolysis In Myocardial
                           Infarction 18 (TACTICS-TIMI-18), os pacientes com DM apresentaram maior
                           benef&#237;cio que os sem DM com a ado&#231;&#227;o de estrat&#233;gia invasiva precoce, com
                           redu&#231;&#227;o do risco relativo de 27% vs. 13%, respectivamente<xref ref-type="bibr" rid="B169">169</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B190">190</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B201">201</xref>.</p>
              </sec>
              <sec>
                <title>3d.2.b Terapia de reperfus&#227;o na SCA com supradesn&#237;vel de ST</title>
                <p>Metan&#225;lise envolvendo todos os grandes estudos em SCA com supradesn&#237;vel
                           de ST que compararam tromb&#243;lise vs. placebo mostrou maior sobrevida ap&#243;s
                           35 dias de evolu&#231;&#227;o em pacientes com DM (<italic>n</italic> = 2.236)
                           submetidos &#224; administra&#231;&#227;o do fibrinol&#237;tico (3,7 vs. 1,5 vidas salvas por
                           100 pacientes tratados, respectivamente)<xref ref-type="bibr" rid="B202">202</xref>. Apesar de nenhum estudo ter especificamente comparado
                           tromb&#243;lise com angioplastia prim&#225;ria em pacientes com DM, uma suban&#225;lise
                           de 11 estudos randomizados demonstrou redu&#231;&#227;o de morte e reinfarto em 30
                           dias com realiza&#231;&#227;o de angioplastia prim&#225;ria em compara&#231;&#227;o com tromb&#243;lise
                           (9,2% vs. 19,3%, <italic>p</italic> &lt; 0,05). Al&#233;m disso, o benef&#237;cio
                           da angioplastia prim&#225;ria foi maior no grupo com DM vs. sem DM (n&#250;mero
                           necess&#225;rio para tratar [NNT]: 10 vs. 16, respectivamente)<xref ref-type="bibr" rid="B203">203</xref>. Dessa forma, a realiza&#231;&#227;o de
                           angioplastia prim&#225;ria, quando dispon&#237;vel, deve ser preferencialmente
                           adotada.</p>
              </sec>
              <sec>
                <title>3d.2.c Bloqueadores do sistema
                           renina-angiotensina-aldosterona</title>
                <p>Uma revis&#227;o sistem&#225;tica, incluindo cerca de 100.000 pacientes em uso dos
                           IECAs p&#243;s-IAM demonstrou seguran&#231;a e efic&#225;cia (redu&#231;&#227;o de mortalidade)
                           desta classe medicamentosa<xref ref-type="bibr" rid="B204">204</xref>.
                           Opini&#245;es diferem a respeito do uso dos IECAs em todos os pacientes ou
                           somente nos de alto risco. Devem ser considerados em todos pacientes com
                           aterosclerose, mas, devido aos seus efeitos modestos, o uso a longo prazo
                           deve ser mandat&#243;rio nos pacientes p&#243;s-IAM hipertensos, com IC, com
                           disfun&#231;&#227;o ventricular esquerda ou DM. O uso do bloqueador da aldosterona
                           passou a ser recomendado no p&#243;s-IAM, pois o estudo Eplerenone Post-Acute
                           Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
                           demonstrou diminui&#231;&#245;es significativas a favor do grupo tratado, entre
                           outras, na mortalidade por qualquer causa (diminui&#231;&#227;o de 15%,
                              <italic>p</italic> = 0,008), morte s&#250;bita (-21%, <italic>p</italic> =
                           0,03) e &#243;bito cardiovascular (-17%, <italic>p</italic> = 0,005)<xref ref-type="bibr" rid="B205">205</xref>.</p>
              </sec>
              <sec>
                <title>3d.2.d Antiplaquet&#225;rios</title>
                <p>O clopidogrel, cujas indica&#231;&#245;es foram bem estabelecidas nas
                              diretrizes<xref ref-type="bibr" rid="B173">173</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B199">199</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B200">200</xref>, pode apresentar varia&#231;&#245;es em seu efeito
                           antiplaquet&#225;rio devido ao fen&#243;tipo do paciente (obesidade e DM), a
                           polimorfismos ent&#233;rico (ABCB 1) e hep&#225;tico (enzima CYP450) e a medica&#231;&#245;es
                           que interferem na sua biotransforma&#231;&#227;o. Novos antiplaquet&#225;rios -
                           prasugrel e ticagrelor - surgiram no cen&#225;rio de coronariopatia aguda como
                           mais eficazes que o clopidogrel e passaram a ter indica&#231;&#245;es bem
                              estabelecidas<xref ref-type="bibr" rid="B200">200</xref>. Um subestudo
                           do Optimizing Platelet Inhibition with Prasugrel Thrombolysis in
                           Miocardial Infarction - Thrombolysis In Myocardial Infarction 38
                           (TRITON-TIMI 38)<xref ref-type="bibr" rid="B206">206</xref>, no qual
                           foram inclu&#237;dos cerca de 3.000 pacientes com DM e SCA com anatomia
                           favor&#225;vel para interven&#231;&#227;o coronariana percut&#226;nea ou IAM com indica&#231;&#227;o de
                           angioplastia prim&#225;ria, demonstrou que aos 450 dias de seguimento houve
                           redu&#231;&#227;o de 30% na mortalidade cardiovascular, IAM e AVE a favor do
                           prasugrel (12,2% vs. 17%, <italic>p</italic> &lt; 0,001). Para cada 21
                           pacientes com DM tratados com prasugrel em vez de clopidogrel, um evento
                           isqu&#234;mico maior foi prevenido. N&#227;o houve diferen&#231;a no sangramento TIMI
                           maior n&#227;o relacionado com a cirurgia nesta popula&#231;&#227;o de pacientes com DM.
                           Um subestudo do Platelet Inhibition and Patient Outcomes (PLATO)<xref ref-type="bibr" rid="B207">207</xref>, que incluiu cerca de 4.600
                           pacientes com DM e coronariopatia aguda (SCA ou IAM independente de
                           tratamento invasivo ou n&#227;o), demonstrou redu&#231;&#227;o do desfecho composto por
                           &#243;bito, IAM e AVE (HR: 0,88, IC 95%: 0,76-1,03), da mortalidade global
                           (HR: 0,82, IC95%: 0,66-1,01) e do IAM (HR: 0,92, IC 95%: 0,75-1,13) a
                           favor do ticagrelor vs. o clopidogrel; esses benef&#237;cios foram
                           consistentes com o estudo principal, mas n&#227;o alcan&#231;aram signific&#226;ncia
                           estat&#237;stica nominal (<italic>p</italic> de intera&#231;&#227;o em rela&#231;&#227;o ao
                              <italic>status</italic> de DM = n&#227;o significativo). A ocorr&#234;ncia de
                           sangramento foi similar em ambos os grupos, independentemente do DM.</p>
                <p>Quanto ao uso dos inibidores da glicoprote&#237;na IIb/IIIa, a maioria das
                           evid&#234;ncias favor&#225;veis ao seu uso foi antes da utiliza&#231;&#227;o de dupla
                           antiagrega&#231;&#227;o plaquet&#225;ria. N&#227;o se t&#234;m evid&#234;ncias na literatura de que
                           exista benef&#237;cio da adi&#231;&#227;o rotineira destas medica&#231;&#245;es em pacientes com
                           DM com o uso de dupla antiagrega&#231;&#227;o plaquet&#225;ria, principalmente em doses
                              elevadas<xref ref-type="bibr" rid="B208">208</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B210">210</xref>.</p>
              </sec>
              <sec>
                <title>3d.2.e Terapia anticoagulante</title>
                <p>N&#227;o existem diferen&#231;as em rela&#231;&#227;o ao uso de medica&#231;&#245;es anticoagulantes no
                           contexto de SCA em pacientes com ou sem DM. A princ&#237;pio, todas as
                           medica&#231;&#245;es indicadas rotineiramente (enoxaparina, heparina n&#227;o
                           fracionada, fondaparinux e bivalirudina) podem e devem ser utilizadas
                           caso haja indica&#231;&#227;o precisa. Especificamente em SCA sem supradesn&#237;vel de
                           ST, nos estudos Superior Yield of the New Strategy of Enoxaparin,
                           Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) e
                           Atkins, Traditional, Ornish, Zone (A TO Z), que testaram o uso de
                           heparina n&#227;o fracionada vs. enoxaparina, os grupos de pacientes com e sem
                           DM mostraram o mesmo n&#237;vel de benef&#237;cio em rela&#231;&#227;o &#224; redu&#231;&#227;o de desfechos
                           combinados, sem diferen&#231;a significativa entre as duas medica&#231;&#245;es<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B210">210</xref>
									<sup>-</sup>
									<xref ref-type="bibr" rid="B213">213</xref>.</p>
              </sec>
              <sec>
                <title>3d.2.f Revasculariza&#231;&#227;o na SCA sem supradesn&#237;vel de ST</title>
                <p>N&#227;o h&#225; estudos randomizados comparando interven&#231;&#227;o coronariana percut&#226;nea
                           (ICP) e revasculariza&#231;&#227;o mioc&#225;rdica cir&#250;rgica (RMC) no contexto de SCA.
                           Quando estabilizados os pacientes, a escolha da modalidade de
                           revasculariza&#231;&#227;o mioc&#225;rdica deve ter os mesmos crit&#233;rios usados para
                           aqueles com doen&#231;a coronariana est&#225;vel, sempre ressaltando o
                              <italic>heart team</italic>
									<sup>(</sup>
									<xref ref-type="bibr" rid="B167">167</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B176">176</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B214">214</xref>.</p>
                <p>No que diz respeito &#224; angioplastia coronariana, a escolha do tipo de
                              <italic>stent</italic> para pacientes com DM &#233; fundamental, e
                           novamente n&#227;o h&#225; dados espec&#237;ficos para o contexto de SCA e as evid&#234;ncias
                           dispon&#237;veis para o tratamento da doen&#231;a coronariana est&#225;vel s&#227;o a
                              refer&#234;ncia<xref ref-type="bibr" rid="B155">155</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B163">163</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B176">176</xref>.</p>
              </sec>
              <sec>
                <title>3d.2.g Hiperglicemia</title>
                <p>A hiperglicemia, durante a fase precoce do IAM vem sendo considerada uma
                           resposta ao estresse agudo, mas com clara correla&#231;&#227;o com DM sem
                           diagn&#243;stico pr&#233;vio. Tanto no paciente com quanto no sem DM , a
                           hiperglicemia se correlaciona com pior progn&#243;stico intra-hospitalar,
                           incluindo mortalidade. Al&#233;m disso, existem evid&#234;ncias de que a
                           hipoglicemia deve ser evitada<xref ref-type="bibr" rid="B215">215</xref>
									<sup>,</sup>
									<xref ref-type="bibr" rid="B216">216</xref>.
                           Tr&#234;s ensaios cl&#237;nicos randomizados avaliaram o papel do controle
                           glic&#234;mico sobre a incid&#234;ncia de desfechos cardiovasculares ap&#243;s IAM em
                           pacientes com DM. O estudo Diabetes and Insulin-Glucose Infusion in Acute
                           Myocardial Infarction (DIGAMI) incluiu 620 pacientes com DM e IAM<xref ref-type="bibr" rid="B217">217</xref> para uma de duas estrat&#233;gias de
                           tratamento: infus&#227;o intravenosa de insulina e glicose nas primeiras 24
                           horas, alvo glic&#234;mico de 126-196 mg/dl, seguida de administra&#231;&#227;o
                           subcut&#226;nea de insulina quatro vezes por dia por pelo menos tr&#234;s meses, ou
                           tratamento com insulina somente quando clinicamente indicado. O grupo que
                           utilizou insulina desde a fase aguda apresentou melhor controle glic&#234;mico
                           durante a interna&#231;&#227;o e depois de tr&#234;s meses e um ano, al&#233;m de menor taxa
                           de mortalidade com um ano e 3,4 anos de seguimento (19% vs. 26% e 33% vs.
                           44%, respectivamente). O DIGAMI-2 foi desenhado para diferenciar o papel
                           do tratamento com insulina durante a interna&#231;&#227;o do tratamento em n&#237;vel
                           ambulatorial, uma vez que no DIGAMI o grupo que utilizou insulina recebia
                           essas duas interven&#231;&#245;es<xref ref-type="bibr" rid="B218">218</xref>. Os
                           pacientes foram randomizados para tr&#234;s grupos: 1. uso de insulina durante
                           a interna&#231;&#227;o e em n&#237;vel ambulatorial; 2. uso de insulina somente durante
                           a interna&#231;&#227;o; 3. tratamento habitual durante todo o per&#237;odo. O controle
                           glic&#234;mico foi semelhante entre os grupos, assim como os desfechos
                           cardiovasculares, o que pode ter ocorrido pela baixa taxa de eventos e
                           por o estudo ter sido terminado antes do planejado (com apenas 50% da
                           amostra inclu&#237;da). O <italic>HI-5 trial</italic> incluiu 240 pacientes
                           com hist&#243;ria de DM ou glicemia &#8805; 140 mg/dl na admiss&#227;o hospitalar por IAM
                           que foram randomizados para controle glic&#234;mico estrito (alvo 72-180
                           mg/dl) com insulina e glicose intravenosas por pelo menos 24 horas ou
                           terapia convencional<xref ref-type="bibr" rid="B219">219</xref>. Depois
                           disso, eram manejados de acordo com o seu m&#233;dico assistente, com
                           recomenda&#231;&#227;o de manter HbA1c &lt; 7%. As taxas de mortalidade
                           intra-hospitalar em tr&#234;s e seis meses n&#227;o foram diferentes entre os
                           grupos, por&#233;m o estudo foi limitado pelo fato de n&#227;o ter havido diferen&#231;a
                           na glicose m&#233;dia entre os dois grupos e pela falta de cegamento.</p>
                <sec>
                  <title>Recomenda&#231;&#245;es para pacientes com DM</title>
                  <p>
                    <bold>Grau de recomenda&#231;&#227;o I</bold>
                  </p>
                  <list list-type="bullet">
                    <list-item>
                      <p>A realiza&#231;&#227;o de estrat&#233;gia invasiva precoce &#233; recomendada.
                                          <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Em pacientes com SCA com supradesn&#237;vel de ST, a angioplastia
                                    prim&#225;ria, quando dispon&#237;vel, deve ser preferencialmente adotada.
                                          <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Em pacientes SCA com supradesn&#237;vel de ST a realiza&#231;&#227;o de
                                    tromb&#243;lise deve ser adotada quando o tempo porta-bal&#227;o for
                                    superior a 90 minutos, principalmente nas primeiras 12 horas do
                                    quadro, desde que exclu&#237;das as contraindica&#231;&#245;es &#224; mesma.
                                          <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Uso de IECA p&#243;s SCA. <bold><italic>N&#237;vel de evid&#234;ncia
                                       A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Uso de bloqueador da aldosterona em pacientes no p&#243;s-IAM com
                                    fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo (FEVE) &#8804; 40%, mesmo na
                                    aus&#234;ncia de sinais de IC, em homens com creatinina &lt; 2,5
                                    mg/dl, em mulheres com creatinina &lt; 2 mg/dl e em ambos os
                                    sexos com K &lt; 5 mEq/L. <bold><italic>N&#237;vel de evid&#234;ncia
                                          B</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>O tratamento antitromb&#243;tico nos pacientes com DM e SCA &#233; o mesmo
                                    indicado para aqueles sem DM. <bold><italic>N&#237;vel de evid&#234;ncia
                                          C</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Ticagrelor (180 mg de ataque seguidos por 90 mg duas vezes ao
                                    dia) em pacientes com SCA ou IAM, independente da estrat&#233;gia de
                                    tratamento posterior (cl&#237;nico, cir&#250;rgico ou percut&#226;neo), por 12
                                    meses. <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Prasugrel (60 mg de ataque seguidos por 10 mg ao dia) em
                                    pacientes portadores SCA com anatomia coronariana conhecida (que
                                    ser&#225; submetido &#224; ICP) ou naqueles com IAM submetidos &#224; ICP
                                    prim&#225;ria e sem fatores de risco para sangramento por 12 meses
                                    (fatores de risco para sangramento: &#8805; 75 anos de idade; menos de
                                    60 kg; AVE ou ataque isqu&#234;mico transit&#243;rio [AIT] pr&#233;vios).
                                          <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Em pacientes que n&#227;o receberam dupla antiagrega&#231;&#227;o plaquet&#225;ria
                                    oral, o uso do tirofiban antes da estratifica&#231;&#227;o invasiva deve
                                    ser considerado em situa&#231;&#245;es de alto risco. <bold><italic>N&#237;vel
                                          de evid&#234;ncia A</italic></bold>
											</p>
                    </list-item>
                    <list-item>
                      <p>Quando indicado tratamento percut&#226;neo, devem-se utilizar
                                       <italic>stents</italic> farmacol&#243;gicos. <bold><italic>N&#237;vel
                                          de evid&#234;ncia A</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Dosar glicemia na chegada em todos pacientes com SCA.
                                          <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
                    </list-item>
                    <list-item>
                      <p>Manter a manter a glicemia abaixo de 180mg/dL nos pacientes com
                                    DM tipo 2 que internam por IAM, evitando ocorr&#234;ncia de
                                    hipoglicemias. <bold><italic>N&#237;vel de evid&#234;ncia
                                       C</italic></bold>
											</p>
                    </list-item>
                  </list>
                  <p>
                    <bold>Grau de recomenda&#231;&#227;o IIa</bold>
                  </p>
                  <list list-type="bullet">
                    <list-item>
                      <p>Em pacientes com SCA, em vig&#234;ncia de dupla antiagrega&#231;&#227;o
                                    plaquet&#225;ria oral, a adi&#231;&#227;o de inibidor da glicoprote&#237;na IIbIIIa
                                    pode ser considerada, caso o paciente apresente alta carga
                                    tromb&#243;tica durante a cineangiocoronariografia.
                                          <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>
											</p>
                    </list-item>
                  </list>
                </sec>
              </sec>
            </sec>
          </sec>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>4. Miocardiopatias</title>
      <sec>
        <title>4.a Fisiopatologia</title>
        <p>A etiologia mais frequente das miocardiopatias &#233; a isqu&#234;mica, podendo chegar a 70%
               segundo os registros e ensaios cl&#237;nicos. A presen&#231;a de DM &#233; importante fator de risco
               para doen&#231;a coronariana ateroscler&#243;tica. Assim, a rela&#231;&#227;o entre miocardiopatia e DM
               pode ser constatada em estudos epidemiol&#243;gicos e em grandes ensaios cl&#237;nicos. Esses
               estudos revelam alta preval&#234;ncia de pacientes com DM entre os portadores de IC (26% a
                  47%)<xref ref-type="bibr" rid="B220">220</xref>
					<sup>-</sup>
					<xref ref-type="bibr" rid="B225">225</xref>. Al&#233;m disso, a IC no paciente com DM &#233; mais intensa e
               apresenta pior progn&#243;stico quando em compara&#231;&#227;o com o paciente sem DM<xref ref-type="bibr" rid="B226">226</xref>. O DM acelera o desenvolvimento da
               aterosclerose, do infarto do mioc&#225;rdio e da doen&#231;a coronariana<xref ref-type="bibr" rid="B26">26</xref>
					<sup>,</sup>
					<xref ref-type="bibr" rid="B225">225</xref>. Outros
               fatores que contribuem para o aumento da preval&#234;ncia da IC entre os indiv&#237;duos com DM
               s&#227;o maior frequ&#234;ncia de hipertens&#227;o arterial, hiperlipidemia e hipertrofia card&#237;aca,
               que est&#227;o presentes em pacientes com DM e que s&#227;o fatores predisponentes para o
               desenvolvimento da IC<xref ref-type="bibr" rid="B223">223</xref>
					<sup>,</sup>
					<xref ref-type="bibr" rid="B225">225</xref>. O DM e a IC, ao lado dos fatores de risco
               comuns, possuem processos fisiopatol&#243;gicos semelhantes, como a ativa&#231;&#227;o do sistema
               neuro-hormonal, a disfun&#231;&#227;o endotelial e o aumento do estresse oxidativo<xref ref-type="bibr" rid="B26">26</xref>
					<sup>,</sup>
					<xref ref-type="bibr" rid="B220">220</xref>
					<sup>-</sup>
					<xref ref-type="bibr" rid="B225">225</xref>. Al&#233;m disso, o
               DM pode afetar a estrutura card&#237;aca e as fun&#231;&#245;es sist&#243;lica e diast&#243;lica de maneira
               independente dos fatores de risco. A hiperglicemia pode levar a piora da fun&#231;&#227;o
               diast&#243;lica, principalmente quando associada a aumento de triglic&#233;rides s&#233;ricos<xref ref-type="bibr" rid="B227">227</xref>. Estudos experimentais e cl&#237;nicos sugerem a
               exist&#234;ncia da cardiomiopatia diab&#233;tica relacionada com microangiopatia, fatores
               metab&#243;licos e fibrose mioc&#225;rdica, que contribuem para o aumento da incid&#234;ncia e da
               gravidade da IC entre os pacientes com DM<xref ref-type="bibr" rid="B26">26</xref>.
               Adicionalmente, a hiperglicemia pode reduzir os efeitos vasodilatadores das
               medica&#231;&#245;es utilizadas para o tratamento da IC<xref ref-type="bibr" rid="B228">228</xref>.</p>
        <p>O sistema renina-angiotensina-aldosterona (SRAA) desempenha um papel importante na
               fisiopatologia da IC, e essa ativa&#231;&#227;o piora o remodelamento. A inibi&#231;&#227;o desse sistema
               leva &#224; melhora da evolu&#231;&#227;o dos pacientes com IC tanto em remodelamento como em
               mortalidade. Por sua vez, o DM causa ativa&#231;&#227;o do SRAA, com aumento de renina,
               angiotensina II e aldosterona<xref ref-type="bibr" rid="B229">229</xref>.</p>
        <p>A import&#226;ncia do sistema adren&#233;rgico na IC &#233; conhecida e sua ativa&#231;&#227;o piora o
               progn&#243;stico dos pacientes. A resist&#234;ncia &#224; insulina promove aumento da estimula&#231;&#227;o
               simp&#225;tica e dos n&#237;veis do fator de necrose tumoral alfa (TNF-&#945;) e dos &#225;cidos graxos
               livres, fatores relacionados com menor efici&#234;ncia card&#237;aca<xref ref-type="bibr" rid="B26">26</xref>
					<sup>,</sup>
					<xref ref-type="bibr" rid="B225">225</xref>. O DM,
               principalmente nos est&#225;gios mais avan&#231;ados, pode causar uma neuropatia auton&#244;mica
                  cardiovascular<xref ref-type="bibr" rid="B230">230</xref>.</p>
        <p>A hiperglicemia est&#225; diretamente ligada &#224; progress&#227;o do dano card&#237;aco, quer por
               acentuar os fatores de risco cardiovascular, quer por aumentar o dep&#243;sito de col&#225;geno
               intersticial, resultando em disfun&#231;&#227;o diast&#243;lica e sist&#243;lica. A hiperglicemia aumenta
               o estresse oxidativo, estimula a atividade do sistema renina-angiotensina e da via
               proteinoquinase C, causando disfun&#231;&#227;o card&#237;aca<xref ref-type="bibr" rid="B26">26</xref>. A les&#227;o de pequenos vasos &#233; outro fator de acentua&#231;&#227;o do dano
               mioc&#225;rdico. A doen&#231;a de pequenos vasos foi evidente em 72% dos pacientes normotensos
               com DM, enquanto entre pessoas sem DM foi de somente 12%<xref ref-type="bibr" rid="B231">231</xref>. As altera&#231;&#245;es de pequenos vasos do cora&#231;&#227;o foram
               semelhantes &#224;s observadas em outros &#243;rg&#227;os, compreendendo espessamento da membrana
               basal do capilar mioc&#225;rdico e microaneurismas. Estas altera&#231;&#245;es parecem ser mais
               intensas nos pacientes com formas mais sintom&#225;ticas de DM (insulinodependentes). As
               altera&#231;&#245;es de pequenos vasos provocam isquemia mioc&#225;rdica e dano mioc&#225;rdico<xref ref-type="bibr" rid="B225">225</xref>
					<sup>,</sup>
					<xref ref-type="bibr" rid="B231">231</xref>.</p>
      </sec>
      <sec>
        <title>4.b Diagn&#243;stico</title>
        <p>Pacientes com DM apresentam risco aumentado de desenvolver doen&#231;as cardiovasculares
               como hipertens&#227;o, doen&#231;a coronariana e cardiomiopatia, sendo 4-5 vezes maior o risco
               de desenvolver IC.</p>
        <p>Hiperglicemia, hiperinsulinemia e aumento da resist&#234;ncia &#224; a&#231;&#227;o da insulina geram
               ativa&#231;&#227;o de citocinas que induzem deposi&#231;&#227;o de col&#225;geno e fibrose, o que leva a
               aumento do espessamento e da rigidez mioc&#225;rdica e, consequentemente, disfun&#231;&#227;o
               mioc&#225;rdica.</p>
        <p>A cardiomiopatia diab&#233;tica &#233; uma desordem estrutural e funcional do mioc&#225;rdio
               definida como disfun&#231;&#227;o ventricular sist&#243;lica e/ou diast&#243;lica em pacientes com DM sem
               outra causa definida para a cardiomiopatia. A fisiopatologia da cardiomiopatia
               diab&#233;tica &#233; complexa e multifatorial, por&#233;m envolve primariamente altera&#231;&#245;es
               estruturais e funcionais do mioc&#225;rdio. Diferentes m&#233;todos podem nos auxiliar no
               diagn&#243;stico da cardiomiopatia diab&#233;tica.</p>
        <sec>
          <title>4b.1 Ecodopplercardiograma</title>
          <p>A presen&#231;a de hipertrofia ventricular em pacientes com DM &#233; forte preditor do
                  desenvolvimento de IC e, associada ao remodelamento hipertr&#243;fico, gera altera&#231;&#227;o
                  do relaxamento do ventr&#237;culo esquerdo e consequente disfun&#231;&#227;o diast&#243;lica, que &#233;
                  uma das altera&#231;&#245;es funcionais mais precoces da cardiomiopatia diab&#233;tica. Estima-se
                  que aproximadamente 40%-75% dos pacientes com DM t&#234;m disfun&#231;&#227;o diast&#243;lica<xref ref-type="bibr" rid="B232">232</xref> e 30%-50% daqueles que evoluem com
                  sintomas de IC t&#234;m FE preservada<xref ref-type="bibr" rid="B233">233</xref>. A IC
                  de fra&#231;&#227;o de eje&#231;&#227;o preservada (ICFEP) ou IC diast&#243;lica<xref ref-type="bibr" rid="B234">234</xref> &#233; definida pela presen&#231;a de sintomas de IC associados a
                  disfun&#231;&#227;o diast&#243;lica com fra&#231;&#227;o de eje&#231;&#227;o normal (FE &#8805; 50%). A disfun&#231;&#227;o sist&#243;lica
                  ocorre apenas mais tardiamente na cardiomiopatia diab&#233;tica e confere pior
                     progn&#243;stico<xref ref-type="bibr" rid="B235">235</xref>.</p>
          <p>Neste contexto, altera&#231;&#245;es ecocardiogr&#225;ficas s&#227;o fundamentais para o diagn&#243;stico
                  da cardiomiopatia diab&#233;tica. Altera&#231;&#245;es sugestivas de disfun&#231;&#227;o diast&#243;lica como
                  aumento do &#225;trio esquerdo, raz&#227;o E/A &lt; 1 pelo Doppler, velocidade de propaga&#231;&#227;o
                  do fluxo (Vp) &lt; 45 cm/s, rela&#231;&#227;o E/E' &gt; 15 pelo Doppler tecidual ou rela&#231;&#227;o
                  E/E' entre 8 e 15 associada a outro marcador de disfun&#231;&#227;o ventricular, como
                  eleva&#231;&#227;o do pept&#237;deo natriur&#233;tico do tipo B (BNP &gt; 200 pg/ml), quando
                  associados a sintomas de IC, conferem o diagn&#243;stico de ICFEP<xref ref-type="bibr" rid="B236">236</xref>; e, quando em pacientes com DM, definem o diagn&#243;stico de
                  cardiomiopatia diab&#233;tica<xref ref-type="bibr" rid="B235">235</xref>.</p>
        </sec>
        <sec>
          <title>4b.2 Resson&#226;ncia magn&#233;tica card&#237;aca</title>
          <p>A resson&#226;ncia card&#237;aca permite a avalia&#231;&#227;o da massa e da fun&#231;&#227;o ventricular
                  esquerda e direita. Trata-se de m&#233;todo interessante para definir a etiologia da
                     cardiomiopatia<xref ref-type="bibr" rid="B236">236</xref>. Utilizando a t&#233;cnica
                  de realce tardio, &#233; capaz de detectar fibrose mioc&#225;rdica, que pode
                  correlacionar-se com disfun&#231;&#227;o diast&#243;lica e, em pacientes com DM sem outras causas
                  aparentes para a disfun&#231;&#227;o, contribuir para o diagn&#243;stico de cardiomiopatia
                     diab&#233;tica<xref ref-type="bibr" rid="B233">233</xref>.</p>
        </sec>
        <sec>
          <title>4b.3 Medicina nuclear</title>
          <p>A medicina nuclear pode ser utilizada para avalia&#231;&#227;o da fun&#231;&#227;o ventricular por
                  meio da t&#233;cnica de tomografia computadorizada por emiss&#227;o de f&#243;ton &#250;nico (SPECT)
                  sincronizada com o eletrocardiograma (Gated-SPECT) e pela ventriculografia
                  radioisot&#243;pica, que permitem a avalia&#231;&#227;o da fun&#231;&#227;o dos ventr&#237;culos esquerdo e
                  direito. Especificamente em pacientes com DM, poucos s&#227;o os estudos que avaliam o
                  Gated-SPECT como m&#233;todo diagn&#243;stico da cardiomiopatia. Recentemente, estudo
                  japon&#234;s envolvendo 563 pacientes com DM sugeriu que o m&#233;todo de perfus&#227;o
                  mioc&#225;rdica Gated-SPECT pode acrescentar informa&#231;&#227;o progn&#243;stica, sendo poss&#237;vel
                  predizer eventos card&#237;acos futuros (IAM n&#227;o fatal, morte card&#237;aca e IC grave com
                  necessidade de interna&#231;&#227;o) nesta popula&#231;&#227;o<xref ref-type="bibr" rid="B237">237</xref>.</p>
        </sec>
        <sec>
          <title>4b.4 Biomarcadores: BNP/NTproBNP</title>
          <p>Os pept&#237;deos natriur&#233;ticos como BNP e NTproBNP (fra&#231;&#227;o N-terminal do proBNP) s&#227;o
                  biomarcadores bem conhecidos e amplamente utilizados em pacientes com IC. Eles t&#234;m
                  papel importante tanto no diagn&#243;stico de IC entre pacientes com dispneia aguda na
                  sala de emerg&#234;ncia<xref ref-type="bibr" rid="B238">238</xref> quanto na avalia&#231;&#227;o
                  progn&#243;stica destes pacientes<xref ref-type="bibr" rid="B239">239</xref>.</p>
          <p>Alguns estudos t&#234;m avaliado o papel do BNP entre pacientes com DM. Kroon et al.
                  estudaram 300 pacientes sem IC (32% com DM) e demonstraram que n&#237;veis elevados de
                  BNP est&#227;o associados a aumento da massa de ventr&#237;culo esquerdo e progress&#227;o para
                  disfun&#231;&#227;o diast&#243;lica em oito anos em pacientes com DM<xref ref-type="bibr" rid="B240">240</xref>. Em outro estudo, Onodera et al. demonstraram que n&#237;veis
                  elevados de BNP s&#227;o preditores de eventos cardiovasculares dentro de cinco anos
                  numa coorte de pacientes com DM (<italic>n</italic> = 1.059)<xref ref-type="bibr" rid="B241">241</xref>. Mais recentemente, Peng et al. avaliaram os n&#237;veis de
                  BNP em pacientes com IC cr&#244;nica (<italic>n</italic> = 559) com e sem DM e
                  estabeleceram um escore de IC levando em considera&#231;&#227;o idade, classe funcional
                  segundo a New York Heart Association (NYHA), FE, espessura do septo e grau de
                  hipertens&#227;o arterial. Os autores observaram que os n&#237;veis de BNP aumentaram de
                  acordo com a maior pontua&#231;&#227;o obtida pelo escore, sendo esta correla&#231;&#227;o mais
                  intensa entre pacientes com DM. Observaram ainda que, para um mesmo valor do
                  escore de IC, os n&#237;veis de BNP foram significativamente mais elevados entre
                  pacientes com DM (<italic>p</italic> &lt; 0,05)<xref ref-type="bibr" rid="B242">242</xref>.</p>
          <p>Os pept&#237;deos natriur&#233;ticos podem ainda ser &#250;teis para predizer disfun&#231;&#227;o
                  diast&#243;lica pr&#233;-cl&#237;nica em pacientes com maior tend&#234;ncia a desenvolver eventos
                  cardiovasculares, como aqueles com DM descompensado, conforme demonstrado por
                  Romano et al. ao estudarem 127 pacientes com DM (42% evolu&#237;ram com disfun&#231;&#227;o
                  diast&#243;lica). O valor de 34 pg/ml foi o melhor ponto de corte de BNP para predizer
                  disfun&#231;&#227;o diast&#243;lica em pacientes com DM que apresentavam HbA1c &gt; 8%<xref ref-type="bibr" rid="B243">243</xref>.</p>
        </sec>
        <sec>
          <title>4b.5 Outros biomarcadores: acetona exalada</title>
          <p>Altera&#231;&#245;es do metabolismo de l&#237;pides geram aumento da produ&#231;&#227;o de corpos cet&#244;nicos
                  (acetoacetato, &#946;-hidroxibutirato e acetona). Entre estas tr&#234;s mol&#233;culas somente
                  acetoacetato e &#946;-hidroxibutirato s&#227;o metabolicamente ativos, mas a volatilidade da
                  acetona permite a detec&#231;&#227;o de cetose por meio do ar exalado. Considerando que
                  pacientes com DM, quando descompensados, aumentam a produ&#231;&#227;o de corpos cet&#244;nicos,
                  sensores capazes de detectar concentra&#231;&#245;es muito baixas de acetona no ar exalado
                  t&#234;m sido desenvolvidos e usados para o diagn&#243;stico de DM com sucesso<xref ref-type="bibr" rid="B244">244</xref>.</p>
          <p>Recentemente, um estudo brasileiro mostrou que a acetona no ar exalado eleva-se
                  tamb&#233;m em pacientes com IC sem DM quando em compara&#231;&#227;o com indiv&#237;duos saud&#225;veis,
                  sendo ainda mais elevada em pacientes descompensados que s&#227;o admitidos na
                  emerg&#234;ncia cl&#237;nica quando em compara&#231;&#227;o com os compensados. A acetona exalada
                  aumenta de acordo com a classe funcional segundo a NYHA e apresenta correla&#231;&#227;o
                  positiva com BNP<xref ref-type="bibr" rid="B245">245</xref>. Como a acetona
                  exalada pode ser um marcador n&#227;o invasivo tanto em pacientes com DM quanto
                  naqueles com IC, tamb&#233;m pode ser um biomarcador n&#227;o invasivo promissor na
                  avalia&#231;&#227;o de pacientes com DM que evoluem com cardiomiopatia. Estudos prospectivos
                  ainda s&#227;o necess&#225;rios para confirmar seu papel neste grupo de pacientes.</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o I</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>Ecodopplercardiograma na avalia&#231;&#227;o de pacientes com suspeita de IC.
                              <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
            <list-item>
              <p>BNP/NTproBNP na avalia&#231;&#227;o de pacientes com suspeita de IC.
                              <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
            </list-item>
          </list>
          <p>
            <bold>Grau de recomenda&#231;&#227;o IIa</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>Avalia&#231;&#227;o da rela&#231;&#227;o E/E' por ecodopplercardiograma para definir disfun&#231;&#227;o
                        diast&#243;lica em pacientes assintom&#225;ticos. <bold><italic>N&#237;vel de evid&#234;ncia
                              C</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
      </sec>
      <sec>
        <title>4.c Tratamento</title>
        <p>Al&#233;m do reconhecido aumento de eventos coronarianos nos pacientes portadores de DM,
               esta doen&#231;a eleva em 10% a 15% o risco de IC a cada aumento de 1% da HbA1c. E, sob
               outra &#243;tica, 25% a 40% dos pacientes com IC t&#234;m DM<xref ref-type="bibr" rid="B246">246</xref>.</p>
        <p>Sendo assim, &#233; importante o conhecimento da influ&#234;ncia do tratamento de uma condi&#231;&#227;o
               no da outra, isto &#233; do tratamento do DM na IC e vice-versa<xref ref-type="bibr" rid="B247">247</xref>.</p>
        <p>As recomenda&#231;&#245;es presentes nesta diretriz relacionam-se com quest&#245;es espec&#237;ficas de
               pacientes com DM. Quando as recomenda&#231;&#245;es para pacientes com DM forem as mesmas para
               a popula&#231;&#227;o geral, esta Diretriz inclui apenas a cita&#231;&#227;o da respectivas
                  publica&#231;&#245;es<xref ref-type="bibr" rid="B220">220</xref>
					<sup>-</sup>
					<xref ref-type="bibr" rid="B221">221</xref>.</p>
        <sec>
          <title>4c.1 Influ&#234;ncia de medicamentos utilizados no tratamento da IC no DM</title>
          <sec>
            <title>4c.1.a Betabloqueadores</title>
            <p>Apesar do receio inicial de que drogas antiadren&#233;rgicas pudessem piorar o
                     controle glic&#234;mico e mascarar os sintomas de hipoglicemia, diversos estudos j&#225;
                     demonstraram que o uso de betabloqueadores est&#225; associado a aumento de
                     sobrevida em pacientes com DM e IC<xref ref-type="bibr" rid="B152">152</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B248">248</xref>.</p>
            <p>Um subestudo do Carvedilol or Metoprolol European Trial (COMET) avaliou o
                     desenvolvimento de DM ou eventos relacionados com o DM (hiperglicemia, p&#233;
                     diab&#233;tico, intoler&#226;ncia &#224; glicose, coma diab&#233;tico) em uma coorte de pacientes
                     com IC (<italic>n</italic> = 2.298) tratados com carvedilol e tartarato de
                     metoprolol. Houve menor incid&#234;ncia de DM (10% &#215; 12%, <italic>p</italic> =
                     0,048) e menor taxa de eventos relacionados com o DM (10% &#215; 13%,
                        <italic>p</italic> = 0,039) com o uso de carvedilol (hiperglicemia, p&#233;
                     diab&#233;tico, intoler&#226;ncia &#224; glicose, coma diab&#233;tico) quando em compara&#231;&#227;o com o
                        metoprolol<xref ref-type="bibr" rid="B249">249</xref>. Embora este estudo
                     sugira certa prefer&#234;ncia pelo carvedilol para uso em pacientes com IC e DM,
                     devemos lembrar que o grande estudo (Metoprolol CR/XL Randomized Intervention
                     Trial [MERIT]) que revelou o metoprolol como um dos betabloqueadores capazes de
                     aumentar sobrevida de pacientes com IC utilizou o succinato de metoprolol, e
                     n&#227;o o tartarato de metoprolol. At&#233; o presente n&#227;o temos evid&#234;ncia suficiente
                     para definir o melhor betabloqueador para pacientes com DM e IC, portanto
                     recomendamos o uso dos tr&#234;s betabloqueadores liberados para tratamento de IC
                     sist&#243;lica: bisoprolol, succinato de metoprolol e carvedilol<xref ref-type="bibr" rid="B250">250</xref>.</p>
          </sec>
          <sec>
            <title>4c.1.b Inibidores da enzima de convers&#227;o de angiotensina/bloqueadores do
                     receptor de angiontensina (BRAs)</title>
            <p>Estudos randomizados j&#225; estabeleceram que o uso de IECAs melhora a sobrevida de
                     pacientes com DM e IC<xref ref-type="bibr" rid="B251">251</xref>.</p>
            <p>Al&#233;m disso, a utiliza&#231;&#227;o de IECA e BRAs mostrou-se eficaz em reduzir a
                     incid&#234;ncia de DM em pacientes com IC ou hipertens&#227;o. Esta diminui&#231;&#227;o de
                     incid&#234;ncia deve-se &#224; prov&#225;vel melhora da sensibilidade perif&#233;rica &#224; insulina
                     por aumento do fluxo muscular<xref ref-type="bibr" rid="B252">252</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B253">253</xref>.</p>
          </sec>
          <sec>
            <title>4c.1.c Antagonistas de aldosterona</title>
            <p>Assim como em pacientes sem DM, o uso de antagonistas de aldosterona, quando em
                     compara&#231;&#227;o com o placebo, mostrou-se eficaz na diminui&#231;&#227;o do risco de morte e
                     de hospitaliza&#231;&#227;o em pacientes com IC e sintomas leves<xref ref-type="bibr" rid="B254">254</xref>.</p>
            <p>No entanto, alguns estudos t&#234;m demonstrado efeitos da espironolactona em
                     aumentar a HbA1c em pacientes com DM<xref ref-type="bibr" rid="B255">255</xref>. Especificamente em pacientes com IC cr&#244;nica, a espironolactona
                     aumenta a HbA1c e os n&#237;veis de cortisol e reduz a adiponectina, achados que
                     podem aumentar o risco de desenvolver DM. Em contraste, o uso de eplerenona n&#227;o
                     parece influenciar o controle glic&#234;mico. Tal fato sugere a possibilidade de
                     efeitos distintos dependendo da seletividade do mineralocorticoide<xref ref-type="bibr" rid="B256">256</xref>. Al&#233;m disso, dados do Eplerenone in
                     Mild Patients Hospitalization and Survival Study (EMPHASIS) demonstram que o
                     uso de eplerenona n&#227;o influencia o desenvolvimento de DM em pacientes com
                        IC<xref ref-type="bibr" rid="B257">257</xref>.</p>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIa</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Pacientes em uso de espironolactona devem receber controle glic&#234;mico
                           otimizado. <bold><italic>N&#237;vel de evid&#234;ncia B</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
        </sec>
        <sec>
          <title>4c.2 Influ&#234;ncia de medicamentos utilizados no tratamento do DM na IC</title>
          <sec>
            <title>4c.2.a Metformina</title>
            <p>O uso da metformina em pacientes com IC era contraindicado at&#233; pouco tempo
                     atr&#225;s devido ao potencial risco de acidose l&#225;tica, apesar do ind&#237;cio crescente
                     sobre seu potencial benef&#237;cio neste grupo de pacientes<xref ref-type="bibr" rid="B258">258</xref>, Evid&#234;ncias recentes sugerem que o uso de metformina
                     em pacientes com IC &#233; seguro e pode colaborar para reduzir a morbimortalidade
                     quando em compara&#231;&#227;o com a utiliza&#231;&#227;o de sulfonilureia isoladamente<xref ref-type="bibr" rid="B259">259</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B260">260</xref>.</p>
            <p>Al&#233;m de n&#227;o aumentar o risco de acidose l&#225;tica, estudos observacionais
                     demonstraram que o uso da metformina foi eficaz na melhora da sobrevida dos
                     pacientes com DM e IC, bem como na diminui&#231;&#227;o de readmiss&#245;es relacionadas com a
                        IC<xref ref-type="bibr" rid="B246">246</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B260">260</xref>
							<sup>-</sup>
							<xref ref-type="bibr" rid="B263">263</xref>. O uso da metformina em pacientes com DM e IC,
                     portanto, n&#227;o est&#225; contraindicado, contudo deve ser evitado na descompensa&#231;&#227;o
                     aguda da IC em pacientes com risco de m&#225; perfus&#227;o tecidual e piora da fun&#231;&#227;o
                        renal<xref ref-type="bibr" rid="B261">261</xref>.</p>
            <p>
              <bold>Grau de recomenda&#231;&#227;o I</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>O uso de metformina para tratamento de DM &#233; seguro em pacientes com IC e
                           pode diminuir a morbimortalidade. <bold><italic>N&#237;vel de evid&#234;ncia
                                 B</italic></bold>.</p>
              </list-item>
            </list>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIa</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>O uso de metformina deve ser evitado na IC aguda descompensada em
                           pacientes com risco de m&#225; perfus&#227;o tecidual e piora da fun&#231;&#227;o renal.
                                 <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
          <sec>
            <title>4c.2.b Secretagogos de insulina</title>
            <p>No estudo em que se avaliou o uso da sulfonilureia como tratamento isolado de
                     pacientes com DM e IC, n&#227;o se observou aumento de mortalidade entre os
                     pacientes tratados, independente da classe (glipizida, glibenclamida ou
                        gliclazida)<xref ref-type="bibr" rid="B264">264</xref>.</p>
            <p>Tendo em vista, no entanto, a potencial piora do pr&#233;-condicionamento isqu&#234;mico
                     com o uso da glibenclamida quando em compara&#231;&#227;o com a glimepirida<xref ref-type="bibr" rid="B265">265</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B266">266</xref>, o maior risco de hipoglicemia com a
                        glibenclamida<xref ref-type="bibr" rid="B267">267</xref> e o risco
                     arritmog&#234;nico de epis&#243;dios hipoglic&#234;micos<xref ref-type="bibr" rid="B268">268</xref> deve-se considerar individualmente a n&#227;o utiliza&#231;&#227;o da
                     glibenclamida como primeira escolha de classe das sulfonilureias<xref ref-type="bibr" rid="B269">269</xref>.</p>
            <p>Em rela&#231;&#227;o &#224;s glinidas (meglitinidas), a outra classe de drogas secretagogas,
                     n&#227;o h&#225; estudos no contexto de IC<xref ref-type="bibr" rid="B270">270</xref>.</p>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIa</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>As sulfonilureias podem ser usadas em pacientes com IC.
                                 <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
          <sec>
            <title>4c.2.c Tiazolinedionas</title>
            <p>As tiazolinedionas (TZD), agentes que melhoram a sensibilidade da insulina, s&#227;o
                     associadas a aumento de edema e do risco de desenvolver IC<xref ref-type="bibr" rid="B247">247</xref>. Para uso mais seguro desta classe de medica&#231;&#227;o no
                     tratamento de DM &#233; importante avaliar os sinais e sintomas de IC congestiva
                     (ICC). Para pacientes com IC o uso de TZD est&#225; contraindicado<xref ref-type="bibr" rid="B138">138</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B271">271</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B272">272</xref>.</p>
            <p>
              <bold>Grau de recomenda&#231;&#227;o III</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>O uso de TZD no tratamento de DM em pacientes com IC classe funcional III
                           ou IV &#233; contraindicado. <bold><italic>N&#237;vel de evid&#234;ncia
                              A</italic></bold>.</p>
              </list-item>
              <list-item>
                <p>O uso de TZD no tratamento de DM em pacientes com IC classes funcionais I
                           e II &#233; contraindicado. <bold><italic>N&#237;vel de evid&#234;ncia
                           B</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
          <sec>
            <title>4c.2.d Incretinas</title>
            <p>A classe de medicamentos conhecida como incretinas &#233; composta por agentes
                     agonistas do GLP-1 (exenatida e liraglutida) e inibidores da enzima dipeptidil
                     peptidase 4 (DPP4) (sitagliptina, saxagliptina, linagliptina, vildagliptina e
                     alogliptina). O principal benef&#237;cio desta classe &#233; a melhora do controle
                     glic&#234;mico, minimizando riscos de hipoglicemia, quando usada em monoterapia, e,
                     no caso dos agonistas de GLP-1, levar a uma perda de peso; no entanto ocasionam
                     n&#225;usea em at&#233; 50% dos pacientes<xref ref-type="bibr" rid="B273">273</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B274">274</xref>. Pode
                     haver risco aumentado de pancreatite, c&#226;ncer de p&#226;ncreas e de tireoide com o
                     uso de exenatida<xref ref-type="bibr" rid="B275">275</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B276">276</xref>.</p>
            <p>Estudos em modelos animais de IC demonstraram um potencial efeito ben&#233;fico do
                     uso de agonistas de GLP-1 na fun&#231;&#227;o ventricular<xref ref-type="bibr" rid="B277">277</xref>. Em humanos, h&#225; poucos estudos com tratamento de incretinas cujo
                     foco seja a fun&#231;&#227;o card&#237;aca. Os estudos s&#227;o pequenos e os resultados, ainda
                     controversos: alguns estudos mostram melhora da fun&#231;&#227;o card&#237;aca com o uso
                     endovenoso de agonistas de GLP-1<xref ref-type="bibr" rid="B278">278</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B279">279</xref> e outros
                     deixam de demonstrar tal resultado<xref ref-type="bibr" rid="B280">280</xref>.
                     Duas revis&#245;es sistem&#225;ticas com metan&#225;lise avaliando ensaios cl&#237;nicos
                     randomizados que utilizaram exenatida vs. comparador ativo em pacientes com DM
                     falharam em mostrar seu efeito ben&#233;fico quando avaliados os desfechos
                        cardiovasculares<xref ref-type="bibr" rid="B281">281</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B282">282</xref>.</p>
            <p>N&#227;o h&#225; estudos de longo prazo avaliando preven&#231;&#227;o de complica&#231;&#245;es cr&#244;nicas ou
                     mortalidade. As incretinas s&#227;o contraindicadas em caso de hipersensibilidade &#224;
                     medica&#231;&#227;o, cetoacidose, doen&#231;as gastrointestinais sintom&#225;ticas e filtra&#231;&#227;o
                     glomerular &lt; 30 ml/min. A exenatida deve ser aplicada 15-60 min antes das
                     refei&#231;&#245;es.</p>
          </sec>
          <sec>
            <title>4c.2.e Inibidores da alfa-glicosidase</title>
            <p>Os inibidores da alfa-glicosidase, sendo a acarbose o principal representante
                     desta classe, agem inibindo a digest&#227;o de carboidratos complexos e, com isso,
                     diminuindo a incurs&#227;o glic&#234;mica p&#243;s-prandial - sabidamente um risco
                     cardiovascular.</p>
            <p>O uso desta classe de medicamentos em pacientes com pr&#233;-DM diminui o risco de
                     hipertens&#227;o e de doen&#231;a cardiovascular, todavia n&#227;o tem a&#231;&#227;o aparente no
                     desenvolvimento de IC<xref ref-type="bibr" rid="B283">283</xref>. N&#227;o h&#225;
                     estudos randomizados cujo objetivo seja avaliar a a&#231;&#227;o do uso da acarbose em
                     pacientes com IC. Em estudo em ratos, observou-se que o uso de inibidores de
                     alfa-glicosidase (voglibose) levou &#224; diminui&#231;&#227;o do remodelamento card&#237;aco e da
                     progress&#227;o para IC<xref ref-type="bibr" rid="B284">284</xref>. Para os
                     pacientes que fazem uso de digoxina, &#233; importante atentar para a poss&#237;vel
                     intera&#231;&#227;o medicamentosa entre estes dois medicamentos<xref ref-type="bibr" rid="B285">285</xref>.</p>
          </sec>
          <sec>
            <title>4c.2.f Insulina</title>
            <p>Nos estudos em que foi avaliada a rela&#231;&#227;o entre o uso de insulina e IC,
                     verificou-se um impacto nulo ou de aumento de mortalidade. Nenhum estudo foi
                     realizado, entretanto, com o objetivo de comparar objetivamente o impacto do
                     tratamento com e sem insulina. &#201; prov&#225;vel que a insulina represente apenas um
                     confundidor, tendo em vista que muitas vezes a sua indica&#231;&#227;o de tratamento
                     representa um DM avan&#231;ado ou a presen&#231;a de contraindica&#231;&#227;o para o uso de
                     medica&#231;&#227;o oral (como insufici&#234;ncia renal avan&#231;ada), o que por si j&#225; demonstra
                        <italic>status</italic> cl&#237;nico mais grave<xref ref-type="bibr" rid="B246">246</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B286">286</xref>
							<sup>,</sup>
							<xref ref-type="bibr" rid="B287">287</xref>.</p>
          </sec>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>5. Disautonomia</title>
      <p>A neuropatia auton&#244;mica diab&#233;tica (NAD) &#233; uma complica&#231;&#227;o pouco reconhecida, apesar da
            sua grande import&#226;ncia cl&#237;nica e do impacto negativo na morbimortalidade de pacientes
            com DM<xref ref-type="bibr" rid="B288">288</xref>. Quando detectada NAD sintom&#225;tica,
            estima-se mortalidade cardiovascular de 50% em cinco anos.</p>
      <p>A preval&#234;ncia &#233; cerca de 25% dos pacientes com DM1 e 34% daqueles com DM2<xref ref-type="bibr" rid="B289">289</xref>, mas, devido &#224; falta de defini&#231;&#227;o consensual,
            esta taxa &#233; muito vari&#225;vel. O sistema nervoso aut&#244;nomo (SNA) &#233; acometido de forma ampla,
            tanto o setor simp&#225;tico quanto o parassimp&#225;tico. Por um tempo, a doen&#231;a pode ser
            assintom&#225;tica, diagnosticada apenas em exames complementares. A manifesta&#231;&#227;o cl&#237;nica &#233;
            resultante da disfun&#231;&#227;o de um ou mais &#243;rg&#227;os (cardiovascular, gastrointestinal,
            genitourin&#225;rio, sudomotor e ocular). Os sinais e sintomas cl&#225;ssicos da disautonomia
            cardiovascular s&#227;o: taquicardia em repouso, hipotens&#227;o ortost&#225;tica, pr&#233;-s&#237;ncope,
            s&#237;ncope, labilidade hemodin&#226;mica durante cirurgias, isquemia mioc&#225;rdica silenciosa e
            baixa toler&#226;ncia ao exerc&#237;cio f&#237;sico. Outros sintomas correlatos s&#227;o resultantes da
            gastroparesia, da hipomotilidade dos c&#243;lons e da bexiga neurog&#234;nica.</p>
      <p>Os fatores de risco para NAD s&#227;o tempo de doen&#231;a e controle glic&#234;mico<xref ref-type="bibr" rid="B290">290</xref>. A neuropatia mais comumente relacionada com a
            NAD &#233; a polineuropatia perif&#233;rica (PNP) cl&#225;ssica (sim&#233;trica, distal e com predom&#237;nio
            sensitivo). Trata-se de uma polineuropatia de fibras finas, cujo mecanismo &#233;
            multifatorial - estresse oxidativo, disfun&#231;&#227;o de microcircula&#231;&#227;o por perda de &#243;xido
            n&#237;trico e les&#227;o da c&#233;lula de Schwann por ac&#250;mulo de radicais livres<xref ref-type="bibr" rid="B291">291</xref>.</p>
      <p>A diretriz norte-americana de endocrinologia recomenta investiga&#231;&#227;o da NAD em todos os
            pacientes com diagn&#243;stico na DM2 e ap&#243;s cinco anos no DM1. No seguimento, os exames
            devem ser feitos anualmente. Os pacientes que apresentam sintomas ou sinais sugestivos
            de disautonomia devem ser avaliados com exames complementares. A neuropatia diab&#233;tica
            pode acarretar deteriora&#231;&#227;o do controle glic&#234;mico por gastroparesia e m&#225; absor&#231;&#227;o.</p>
      <sec>
        <title>5a. Testes auton&#244;micos cardiovasculares</title>
        <p>O diagn&#243;stico pode ser corroborado com exames complementares. O teste mais amplamente
               usado para avaliar o SNA &#233; a variabilidade da frequ&#234;ncia card&#237;aca (FC) avaliada no
               Holter de 24 horas ou nos testes de Ewing. O diagn&#243;stico de NAD com os testes de
               Ewing (descritos a seguir) tem sensibilidade semelhante &#224; do diagn&#243;stico feito por
               meio do Holter de 24 horas<xref ref-type="bibr" rid="B292">292</xref>.</p>
        <sec>
          <title>5a.1. Avalia&#231;&#227;o da variabilidade da FC com Holter de 24 horas</title>
          <p>A variabilidade da FC no dom&#237;nio do tempo e a turbul&#234;ncia da FC podem ser
                  avaliadas durante o Holter de 24 horas. Os par&#226;metros utilizados para o
                  diagn&#243;stico precoce de NAD s&#227;o<xref ref-type="bibr" rid="B293">293</xref>: tr&#234;s
                  bandas de an&#225;lise espectral (tecnologia que utiliza algoritmo matem&#225;tico) que
                  classificam as intensidades em "muito baixa frequ&#234;ncia" (0,01 a 0,04 Hz, ligada a
                  termorregula&#231;&#227;o e sudorese - controle simp&#225;tico), "baixa frequ&#234;ncia" (0,04 a 0,15
                  Hz), "reflexo barorreceptor" (controle simp&#225;tico com modula&#231;&#227;o vagal) e, por fim,
                  "frequ&#234;ncia alta", relacionada com arritmia sinusal (controle parassimp&#225;tico).</p>
        </sec>
        <sec>
          <title>5a.2. Avalia&#231;&#227;o da variabilidade da FC com os testes de Ewing</title>
          <p>S&#227;o quatro os testes de Ewing: resposta da FC em rela&#231;&#227;o &#224; inspira&#231;&#227;o profunda,
                  manobra de Valsalva, teste ortost&#225;tico e teste de inclina&#231;&#227;o.</p>
          <p>&#201; considerada NAD a presen&#231;a de tr&#234;s ou mais par&#226;metros anormais, e NAD incipiente
                  quando s&#227;o dois, segundo a Associa&#231;&#227;o Americana de DM<xref ref-type="bibr" rid="B293">293</xref>.</p>
          <sec>
            <title>Resposta da FC durante inspira&#231;&#227;o profunda</title>
            <p>A variabilidade da FC batimento a batimento depende da inerva&#231;&#227;o vagal. A
                     metodologia mais aceita para a aferi&#231;&#227;o &#233; a inspira&#231;&#227;o profunda, seis vezes em
                     1 minuto, enquanto um monitor card&#237;aco quantifica a diferen&#231;a entre a FC m&#225;xima
                     e m&#237;nima. &#201; esperada diferen&#231;a m&#237;nima de 15 bpm e, se inferior a 10 bpm, &#233;
                     considerada alterada.</p>
          </sec>
          <sec>
            <title>Manobra de Valsalva</title>
            <p>Monitoriza&#231;&#227;o eletrocardiogr&#225;fica durante expira&#231;&#227;o for&#231;ada em man&#244;metro (40
                     mmHg) por 15 segundos. A resposta normal &#233; taquicardia e vasoconstri&#231;&#227;o seguida
                     de bradicardia e queda da PA. A rela&#231;&#227;o entre o RR mais longo e o RR mais curto
                     deve ser &gt; 1,2. Embora seja o teste de maior especificidade (80%)<xref ref-type="bibr" rid="B294">294</xref>, a manobra de Valsalva n&#227;o deve ser
                     realizada em pacientes com retinopatia proliferativa<xref ref-type="bibr" rid="B295">295</xref>.</p>
          </sec>
          <sec>
            <title>Hipotens&#227;o postural</title>
            <p>Definida como queda da PA superior a 20 mmHg na PAS e/ou 10mmHg na PA
                     diast&#243;lica (PAD) at&#233; 3 minutos ap&#243;s exposi&#231;&#227;o ortost&#225;tica.</p>
          </sec>
          <sec>
            <title>Teste de Inclina&#231;&#227;o (TI)</title>
            <p>A movimenta&#231;&#227;o postural passiva &#233; um m&#233;todo de avalia&#231;&#227;o da fun&#231;&#227;o auton&#244;mica
                     por meio do est&#237;mulo ortost&#225;tico a 70&#186;. O TI deve ser realizado em ambiente
                     tranquilo, com pouca ilumina&#231;&#227;o e temperatura agrad&#225;vel. Durante todo o exame,
                     o paciente &#233; monitorizado pelo eletrocardiograma e medidas de PA. A resposta
                     disauton&#244;mica &#233; caracterizada por queda lenta e progressiva da PA para n&#237;veis
                     inferiores a 80 mmHg, sem queda da FC, associada a sintomas de hipotens&#227;o
                     arterial como sudorese, tonturas e escurecimento visual<xref ref-type="bibr" rid="B296">296</xref>. A resposta cronotr&#243;pica ao estresse postural pode
                     estar deprimida ou ausente (aumento &lt; 10% em rela&#231;&#227;o &#224; frequ&#234;ncia card&#237;aca
                     basal).</p>
            <p>
              <bold>Grau de recomenda&#231;&#227;o I</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Pesquisar sintomas disauton&#244;micos e hipotens&#227;o ortost&#225;tica (anamnese e
                           exame f&#237;sico) em todos os pacientes com DM. <bold><italic>N&#237;vel de
                                 evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIa</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Solicitar testes auton&#244;micos a pacientes sintom&#225;ticos.
                                 <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
            <p>
              <bold>Grau de recomenda&#231;&#227;o IIb</bold>
            </p>
            <list list-type="bullet">
              <list-item>
                <p>Solicitar testes auton&#244;micos a pacientes assintom&#225;ticos ao diagn&#243;stico do
                           DM. <bold><italic>N&#237;vel de evid&#234;ncia C</italic></bold>.</p>
              </list-item>
            </list>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>5b Tratamento</title>
        <sec>
          <title>5b.1 Medidas comportamentais</title>
          <p>As medidas n&#227;o farmacol&#243;gicas incluem controles glic&#234;mico e lip&#234;mico, dieta e
                  exerc&#237;cio f&#237;sico, que s&#227;o importantes para reduzir o desenvolvimento da
                  neuropatia. A ingest&#227;o h&#237;drica de 2 litros de liquido por dia e o uso de meias
                  el&#225;sticas de m&#233;dia compress&#227;o s&#227;o recomend&#225;veis para pacientes sintom&#225;ticos.</p>
        </sec>
        <sec>
          <title>5b.2 Terapia medicamentosa</title>
          <p>N&#227;o h&#225; estudos com n&#250;mero de pacientes e seguimento suficientes para analisar o
                  impacto cl&#237;nico da interven&#231;&#227;o sobre o balan&#231;o auton&#244;mico em pacientes com DM e
                  disautonomias. Em pequenos estudos, foi demonstrado que a utiliza&#231;&#227;o de
                  antioxidantes, como o &#225;cido ti&#243;ctico, tem aparente benef&#237;cio.</p>
          <p>Os betabloqueadores adren&#233;rgicos parecem melhorar o balan&#231;o auton&#244;mico. O uso de
                  IECAs demonstrou resultados conflitantes, assim como o de bloqueadores do receptor
                  de angiotensina.</p>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>6. Hipertens&#227;o arterial sist&#234;mica</title>
      <sec>
        <title>6.a. Defini&#231;&#227;o e epidemiologia</title>
        <p>Hipertens&#227;o arterial sist&#234;mica (HAS) &#233; definida quando os valores da PA s&#227;o &#8805; 140
               mmHg e/ou 90 mmHg em pelo menos duas ocasi&#245;es distintas, na presen&#231;a ou n&#227;o de
                  DM<xref ref-type="bibr" rid="B297">297</xref>. HAS e DM frequentemente coexistem
               na pr&#225;tica cl&#237;nica, com um aumento atual na preval&#234;ncia das duas condi&#231;&#245;es,
               provavelmente pela eleva&#231;&#227;o das taxas de sobrepeso e obesidade e da popula&#231;&#227;o de
                  idosos<xref ref-type="bibr" rid="B298">298</xref>. Ao redor de 70% dos pacientes
               com DM s&#227;o hipertensos<xref ref-type="bibr" rid="B298">298</xref>, e a preval&#234;ncia de
               HAS &#233; duas a tr&#234;s vezes maior em indiv&#237;duos com DM do que na popula&#231;&#227;o geral<xref ref-type="bibr" rid="B299">299</xref>. A associa&#231;&#227;o das duas condi&#231;&#245;es aumenta o
               risco de IAM, AVE e mortalidade por todas as causas, assim como o risco de IC,
               insufici&#234;ncia renal e outras complica&#231;&#245;es microvasculares<xref ref-type="bibr" rid="B300">300</xref>. Os principais mecanismos envolvidos na HAS em pacientes com
               DM incluem aumento de atividade do sistema nervoso simp&#225;tico e do estresse oxidativo,
               decorrente da hiperatividade de metaloproteinases, e maior resist&#234;ncia ao sal<xref ref-type="bibr" rid="B301">301</xref>. Estes mecanismos integrados, em um ambiente
               hostil de maior risco, contribuem n&#227;o somente para g&#234;nese de HAS, mas tamb&#233;m para o
               desenvolvimento de doen&#231;as cardiovasculares<xref ref-type="bibr" rid="B301">301</xref>.</p>
      </sec>
      <sec>
        <title>6.b Avalia&#231;&#227;o cl&#237;nica e laboratorial</title>
        <p>A estratifica&#231;&#227;o de risco cardiovascular do paciente com DM com base na PA considera
               o indiv&#237;duo com moderado risco adicional se os valores est&#227;o abaixo de 130/85; alto
               risco adicional se valores entre 130/85 e 180/110; e muito alto se acima de
                  180/110<xref ref-type="bibr" rid="B297">297</xref>. A avalia&#231;&#227;o cl&#237;nica e
               laboratorial do paciente com DM hipertenso &#233; feita da mesma maneira que a recomendada
               para todos os hipertensos em geral<xref ref-type="bibr" rid="B302">302</xref>.
               Algumas considera&#231;&#245;es especiais devem ser levadas em conta no paciente com DM. Como a
               hipotens&#227;o postural &#233; mais comum em pacientes com DM, a PA deve ser medida sempre nas
               posi&#231;&#245;es supina e ortost&#225;tica<xref ref-type="bibr" rid="B297">297</xref>. Al&#233;m disso,
               o exame de fundo de olho pelo especialista deve ser recomendado na primeira
               avalia&#231;&#227;o, visto que a associa&#231;&#227;o de hipertens&#227;o em pacientes com DM aumenta a chance
               de complica&#231;&#245;es oculares<xref ref-type="bibr" rid="B303">303</xref>. Na avalia&#231;&#227;o
               laboratorial, al&#233;m dos exames de rotina indicados para todos os hipertensos
               (colesterol total e fra&#231;&#245;es, glicemia, triglic&#233;rides, creatinina, c&#225;lculo do ritmo de
               filtra&#231;&#227;o glomerular, urina tipo 1, pot&#225;ssio, &#225;cido &#250;rico e eletrocardiograma)<xref ref-type="bibr" rid="B297">297</xref>, o paciente com DM e HAS tem indica&#231;&#227;o de
               ecocardiograma, teste ergom&#233;trico e pesquisa de microalbumin&#250;ria em amostra isolada
               ou de 24 horas<xref ref-type="bibr" rid="B304">304</xref>.</p>
      </sec>
      <sec>
        <title>6.c. Tratamento</title>
        <sec>
          <title>6.c.1. Metas</title>
          <p>Apesar de muita controv&#233;rsia sobre qual meta &#233; a ideal para o paciente com DM, as
                  metas de PA recomendadas pelas VI Diretrizes Brasileiras de Hipertens&#227;o<xref ref-type="bibr" rid="B297">297</xref> s&#227;o de 130/80 mmHg, independente da
                  presen&#231;a de complica&#231;&#245;es. As recomenda&#231;&#245;es europeias mais recentes padronizaram
                  que a PA deve inferior a 140/90 mmHg independente da condi&#231;&#227;o cl&#237;nica
                     associada<xref ref-type="bibr" rid="B305">305</xref>. Redu&#231;&#245;es maiores n&#227;o
                  demonstraram benef&#237;cios em pacientes com DM e n&#227;o s&#227;o recomendadas<xref ref-type="bibr" rid="B299">299</xref>.</p>
        </sec>
        <sec>
          <title>6.c.2. Tratamento n&#227;o medicamentoso</title>
          <p>O tratamento n&#227;o medicamentoso da HAS associada a DM inclui redu&#231;&#227;o do peso
                  corporal se o paciente for obeso ou estiver com sobrepeso, consumo de no m&#225;ximo 5
                  gramas de sal<xref ref-type="bibr" rid="B306">306</xref> (ou 2.000 mg de s&#243;dio),
                  dieta rica em frutas e vegetais e pobre em gorduras saturadas (Dietary Approaches
                  to Stop Hypertension [DASH])<xref ref-type="bibr" rid="B306">306</xref>,
                  exerc&#237;cios f&#237;sicos<xref ref-type="bibr" rid="B307">307</xref> (30 minutos, cinco
                  vezes por semana), abandono do fumo e do consumo de &#225;lcool e tratamento da apneia
                  obstrutiva do sono<xref ref-type="bibr" rid="B308">308</xref>, se existente. A
                  efic&#225;cia da redu&#231;&#227;o do conte&#250;do de sal na dieta em popula&#231;&#227;o espec&#237;fica de
                  pacientes com DM n&#227;o &#233; conhecida, sendo as indica&#231;&#245;es nesta popula&#231;&#227;o baseadas nos
                  estudos que inclu&#237;ram hipertensos com e sem DM.</p>
        </sec>
        <sec>
          <title>6.c.3 Tratamento medicamentoso</title>
          <p>Para pacientes com DM e PA entre 130-139 mmHg e 80-89 mmHg recomendam-se
                  modifica&#231;&#245;es do estilo de vida por um tempo m&#225;ximo de tr&#234;s meses<xref ref-type="bibr" rid="B298">298</xref>. Se neste per&#237;odo n&#227;o houver redu&#231;&#227;o
                  adequada da press&#227;o, o tratamento medicamentoso deve ser iniciado<xref ref-type="bibr" rid="B309">309</xref>. Por outro lado, se os n&#237;veis de PA
                  estiverem &#8805; 140/90 mmHg, al&#233;m do tratamento n&#227;o farmacol&#243;gico, o uso de medica&#231;&#245;es
                  anti-hipertensivas deve ser iniciado imediatamente<xref ref-type="bibr" rid="B308">308</xref>. Para se atingirem as metas de controle da PA no paciente com DM, &#233;
                  quase sempre necess&#225;rio iniciar o tratamento anti-hipertensivo com dois ou mais
                  f&#225;rmacos de classes diferentes. As VI Diretrizes Brasileiras de Hipertens&#227;o<xref ref-type="bibr" rid="B297">297</xref> recomendam que, em pacientes com DM sem
                  nefropatia, todos os agentes anti-hipertensivos podem ser utilizados (exceto
                  vasodilatadores diretos). Na presen&#231;a de doen&#231;a renal instalada, v&#225;rios estudos
                  t&#234;m demonstrado os benef&#237;cios dos IECAs e dos BRAs sobretudo nos portadores de
                  microalbumin&#250;ria (30-300mg/24 h)<xref ref-type="bibr" rid="B310">310</xref>.
                  Assim, estas classes s&#227;o as de primeira escolha para o in&#237;cio do tratamento de
                  pacientes com DM e HAS e altera&#231;&#245;es renais. Com base em estudos como o
                  Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
                     (ALLHAT)<xref ref-type="bibr" rid="B311">311</xref>, diur&#233;ticos e antagonistas
                  dos canais de c&#225;lcio (ACC) podem ser usados como primeira escolha para o
                  tratamento de pacientes com DM e HAS, pois tamb&#233;m t&#234;m efeito protetor similar aos
                  observados com IECA<xref ref-type="bibr" rid="B297">297</xref>. Recentemente
                  destacou-se que algumas associa&#231;&#245;es apresentam melhor perfil farmacol&#243;gico do que
                  outras em DM, como, por exemplo: a combina&#231;&#227;o de diur&#233;ticos com IECA, BRA ou ACC,
                  a combina&#231;&#227;o de ACC e IECA ou BRA e a combina&#231;&#227;o de ACC e betabloqueador<xref ref-type="bibr" rid="B312">312</xref>.</p>
          <p>
            <bold>Grau de recomenda&#231;&#227;o I</bold>
          </p>
          <list list-type="bullet">
            <list-item>
              <p>A meta para o controle da HAS deve ser uma PA &lt; 140 &#215; 90 mmHg.
                              <bold><italic>N&#237;vel de evid&#234;ncia A</italic></bold>.</p>
            </list-item>
            <list-item>
              <p>Os IECAs devem ser a primeira escolha terap&#234;utica. <bold><italic>N&#237;vel de
                              evid&#234;ncia A</italic></bold>.</p>
            </list-item>
          </list>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>7. Cirurgia bari&#225;trica e metab&#243;lica e redu&#231;&#227;o do risco cardiovascular</title>
      <p>No Brasil, &#233; crescente a preval&#234;ncia de obesidade, tendo aumentado de 11,4% da popula&#231;&#227;o
            em 2006 para 15,8% em 2011<xref ref-type="bibr" rid="B313">313</xref>. O excesso de peso
            corporal est&#225; relacionado com o aumento do risco cardiovascular<xref ref-type="bibr" rid="B314">314</xref> devido a diversas comorbidades, incluindo DM, hipertens&#227;o
            arterial e dislipidemia<xref ref-type="bibr" rid="B315">315</xref>. Por estas raz&#245;es a
            obesidade &#233; considerada um problema de sa&#250;de p&#250;blica, j&#225; que onera o Sistema &#218;nico de
            Sa&#250;de (SUS), cujos gastos anuais perfazem R$ 488 milh&#245;es com o tratamento de doen&#231;as
            relacionadas com a obesidade<xref ref-type="bibr" rid="B316">316</xref>.</p>
      <p>A obesidade m&#243;rbida usualmente &#233; refrat&#225;ria tanto &#224; dieta quanto &#224; terapia
            medicamentosa, mas responde bem &#224; cirurgia bari&#225;trica<xref ref-type="bibr" rid="B317">317</xref>, que tem se mostrado a estrat&#233;gia mais sustentada de perda ponderal<xref ref-type="bibr" rid="B318">318</xref>. Esta perda sustentada de peso reduz a
            incid&#234;ncia de DM2 e a mortalidade total<xref ref-type="bibr" rid="B314">314</xref>,
            sendo respons&#225;vel pela diminui&#231;&#227;o da estimativa do risco cardiovascular<xref ref-type="bibr" rid="B319">319</xref>.</p>
      <p>Uma revis&#227;o sistem&#225;tica<xref ref-type="bibr" rid="B315">315</xref> evidenciou que, num
            tempo de seguimento p&#243;s-operat&#243;rio de 34 meses, houve remiss&#227;o de HAS, DM e dislipidemia
            em, respectivamente, 68%, 75% e 71% dos indiv&#237;duos submetidos &#224; cirurgia bari&#225;trica.</p>
      <p>Semelhantemente, outra revis&#227;o sistem&#225;tica<xref ref-type="bibr" rid="B317">317</xref>
            ressaltou que o <italic>bypass</italic> g&#225;strico com Y de Roux (t&#233;cnica de cirurgia
            bari&#225;trica mais amplamente realizada na atualidade) previne o surgimento de DM em 99% a
            100% dos pacientes com intoler&#226;ncia &#224; glicose e promove a remiss&#227;o de 80% a 90% dos
            casos rec&#233;m-diagnosticados de DM2, melhorando ou resolvendo a hipertens&#227;o arterial em
            37% a 53% dos pacientes ou reduzindo a necessidade de anti-hipertensivos em 18% a 36%
            deles.</p>
      <p>Especificamente com rela&#231;&#227;o &#224; redu&#231;&#227;o da ocorr&#234;ncia de eventos cardiovasculares, Romeo
            et al.<xref ref-type="bibr" rid="B318">318</xref> avaliaram a ocorr&#234;ncia de IAM e AVE (o
            que viesse primeiro) fatais e n&#227;o fatais em todos os pacientes com DM que haviam
            participado do estudo Swedish Obese Subjects (SOS). Neste estudo, 4.047 pacientes obesos
            (com IMC &#8805; 34 kg/m<sup>2</sup> para homens e &#8805; 38 kg/m<sup>2</sup> para mulheres) foram
            selecionados de modo prospectivo, mas n&#227;o aleat&#243;rio, e em duas coortes: uma que seria
            submetida &#224; cirurgia bari&#225;trica (2.010 pacientes) e outra, ao tratamento n&#227;o cir&#250;rgico
            da obesidade (2.037 indiv&#237;duos). Apesar da natureza n&#227;o aleatorizada do estudo, a
            an&#225;lise estat&#237;stica mostrou que 16 pacientes portadores de DM2 precisariam ser
            submetidos a cirurgia bari&#225;trica para evitar a ocorr&#234;ncia de um IAM em 15 anos. Por
            outro lado, os autores n&#227;o observaram diminui&#231;&#227;o significativa na incid&#234;ncia de AVE.
            Al&#233;m da redu&#231;&#227;o da mortalidade total, estes resultados s&#227;o promissores no sentido de
            investigar se a remiss&#227;o do DM2 observada ap&#243;s a cirurgia bari&#225;trica levar&#225; &#224; redu&#231;&#227;o
            real do risco cardiovascular. Ainda com rela&#231;&#227;o aos desfechos cardiovasculares, um
            estudo recente envolvendo 2.458 pacientes muito obesos submetidos &#224; interven&#231;&#227;o
            cir&#250;rgica e acompanhados por tr&#234;s anos observou remiss&#227;o da HAS em 38,2% dos operados
            pela t&#233;cnica de Y de Roux e 17,4% pela t&#233;cnica de banda g&#225;strica<xref ref-type="bibr" rid="B320">320</xref>.</p>
      <p>No subgrupo de pacientes com DM ainda n&#227;o existem evid&#234;ncias contundentes com rela&#231;&#227;o &#224;
            indica&#231;&#227;o de cirurgia bari&#225;trica <italic>especificamente</italic> para preven&#231;&#227;o
            cardiovascular. Entretanto, pacientes com DM e IMC &gt; 40 kg/m<sup>2</sup> ou &gt; 35
               kg/m<sup>2</sup> podem se beneficiar da cirurgia bari&#225;trica, a depender da avalia&#231;&#227;o
            multiprofissional individualizada.</p>
    </sec>
  </body>
  <back>
    <ref-list>
      <title>Refer&#234;ncias</title>
      <ref id="B01">
        <label>1</label>
        <mixed-citation>1. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al.
               Heart disease and stroke statistics--2011 update: a report from the American Heart
               Association. American Heart Association Statistics Committee and Stroke Statistics
               Subcommittee. Circulation. 2011;123(4):e18-e209.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Roger</surname>
              <given-names>VL</given-names>
            </name>
            <name>
              <surname>Go</surname>
              <given-names>AS</given-names>
            </name>
            <name>
              <surname>Lloyd-Jones</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Adams</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Berry</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Brown</surname>
              <given-names>TM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Heart disease and stroke statistics--2011 update: a
                  report from the American Heart Association</article-title>
          <collab>American Heart Association Statistics Committee and Stroke Statistics
                  Subcommittee</collab>
          <source>Circulation</source>
          <year>2011</year>
          <volume>123</volume>
          <issue>4</issue>
          <fpage>e18</fpage>
          <lpage>e209</lpage>
        </element-citation>
      </ref>
      <ref id="B02">
        <label>2</label>
        <mixed-citation>2. Gregg EW, Cheng YJ, Saydah S, Cowie C, Garfield S, Geiss L, et al.
               Trends in death rates among US adults with and without diabetes between 1997 and 2006
               Findings from the National Health Interview Survey. Diabetes Care.
               2012;35(6):1252-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Gregg</surname>
              <given-names>EW</given-names>
            </name>
            <name>
              <surname>Cheng</surname>
              <given-names>YJ</given-names>
            </name>
            <name>
              <surname>Saydah</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Cowie</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Garfield</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Geiss</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Trends in death rates among US adults with and without
                  diabetes between 1997 and 2006 Findings from the National Health Interview
                  Survey</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>6</issue>
          <fpage>1252</fpage>
          <lpage>1257</lpage>
        </element-citation>
      </ref>
      <ref id="B03">
        <label>3</label>
        <mixed-citation>3. Chauhan HK. Diabesity: the 'Achilles Heel' of our modernized society.
               Rev Assoc Med Bras. 2012;58:399.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chauhan</surname>
              <given-names>HK</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabesity: the 'Achilles Heel' of our modernized
                  society</article-title>
          <source>Rev Assoc Med Bras</source>
          <year>2012</year>
          <volume>58</volume>
          <fpage>399</fpage>
          <lpage>399</lpage>
        </element-citation>
      </ref>
      <ref id="B04">
        <label>4</label>
        <mixed-citation>4. Unwin N, Whiting D, Guariguata L, Hennis A, Husseini A, Ji L, et al.
               Diabetes atlas. 5th ed. Brussels (Belgic):International Diabetes
               Federation(IDF);2011.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Unwin</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Whiting</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Guariguata</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Hennis</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Husseini</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Ji</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <source xml:lang="pt">Diabetes atlas</source>
          <edition>5th ed</edition>
          <publisher-loc>Brussels (Belgic)</publisher-loc>
          <publisher-name>International Diabetes Federation</publisher-name>
          <year>2011</year>
        </element-citation>
      </ref>
      <ref id="B05">
        <label>5</label>
        <mixed-citation>5. Monteiro C, Malta D, Moura E, Moura L, Moraes Neto O. Minist&#233;rio da
               Sa&#250;de. VIGITEL 2006 Brasil: vigil&#226;ncia de fatores de risco e prote&#231;&#227;o para doen&#231;as
               cr&#244;nicas por inqu&#233;rito telef&#244;nico. Bras&#237;lia; 2006.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>Monteiro</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Malta</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Moura</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Moura</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Moraes</surname>
              <given-names>O</given-names>
              <suffix>Neto</suffix>
            </name>
            <collab>Minist&#233;rio da Sa&#250;de</collab>
          </person-group>
          <source xml:lang="pt">VIGITEL 2006 Brasil: vigil&#226;ncia de fatores de risco e prote&#231;&#227;o
                  para doen&#231;as cr&#244;nicas por inqu&#233;rito telef&#244;nico</source>
          <publisher-loc>Bras&#237;lia</publisher-loc>
          <year>2006</year>
        </element-citation>
      </ref>
      <ref id="B06">
        <label>6</label>
        <mixed-citation>6. Schmidt MI, Duncan BB, Hoffmann JF, de Moura L, Malta DC, de Carvalho
               R. Prevalence of diabetes and hypertension based on self-reported morbidity survey,
               Brazil, 2006. Rev Sa&#250;de P&#250;blica. 2009;43(Suppl 2):74-82.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Schmidt</surname>
              <given-names>MI</given-names>
            </name>
            <name>
              <surname>Duncan</surname>
              <given-names>BB</given-names>
            </name>
            <name>
              <surname>Hoffmann</surname>
              <given-names>JF</given-names>
            </name>
            <name>
              <surname>de Moura</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Malta</surname>
              <given-names>DC</given-names>
            </name>
            <name>
              <surname>de Carvalho</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prevalence of diabetes and hypertension based on
                  self-reported morbidity survey, Brazil, 2006</article-title>
          <source>Rev Sa&#250;de P&#250;blica</source>
          <year>2009</year>
          <volume>43</volume>
          <supplement>Suppl 2</supplement>
          <fpage>74</fpage>
          <lpage>82</lpage>
        </element-citation>
      </ref>
      <ref id="B07">
        <label>7</label>
        <mixed-citation>7. Bahia LR, Araujo DV, Schaan BD, Dib SA, Negrato CA, Leao MPS, et al.
               The costs of type 2 Diabetes Mellitus outpatient care in the Brazilian public health
               system. Value Health. 2011;14:S137-40.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bahia</surname>
              <given-names>LR</given-names>
            </name>
            <name>
              <surname>Araujo</surname>
              <given-names>DV</given-names>
            </name>
            <name>
              <surname>Schaan</surname>
              <given-names>BD</given-names>
            </name>
            <name>
              <surname>Dib</surname>
              <given-names>SA</given-names>
            </name>
            <name>
              <surname>Negrato</surname>
              <given-names>CA</given-names>
            </name>
            <name>
              <surname>Leao</surname>
              <given-names>MPS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">The costs of type 2 Diabetes Mellitus outpatient care in
                  the Brazilian public health system</article-title>
          <source>Value Health</source>
          <year>2011</year>
          <volume>14</volume>
          <fpage>S137</fpage>
          <lpage>S140</lpage>
        </element-citation>
      </ref>
      <ref id="B08">
        <label>8</label>
        <mixed-citation>8. World Health Organization.(WHO). World health statistics 2012. Health
               status indicators. Geneva(Switzerland);2012.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>World Health Organization</collab>
          </person-group>
          <source xml:lang="en">World health statistics 2012. Health status indicators</source>
          <publisher-loc>Geneva(Switzerland)</publisher-loc>
          <year>2012</year>
        </element-citation>
      </ref>
      <ref id="B09">
        <label>9</label>
        <mixed-citation>9. World Health Organization.(WHO) Global health risks: mortality and
               burden of disease attributable to selected major risk.
               Geneva(Switzerland);2009.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>World Health Organization</collab>
          </person-group>
          <source xml:lang="en">Global health risks: mortality and burden of disease
                  attributable to selected major risk</source>
          <publisher-loc>Geneva(Switzerland)</publisher-loc>
          <year>2009</year>
        </element-citation>
      </ref>
      <ref id="B10">
        <label>10</label>
        <mixed-citation>10. Scheffel RS, Bortolanza D, Weber CS, Costa LA, Canani LH, Santos KG,
               et al. [Prevalence of micro and macroangiopatic chronic complications and their risk
               factors in the care of out patients with type 2 diabetes mellitus]. Rev Assoc Med
               Bras. 2004;50(3):263-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Scheffel</surname>
              <given-names>RS</given-names>
            </name>
            <name>
              <surname>Bortolanza</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Weber</surname>
              <given-names>CS</given-names>
            </name>
            <name>
              <surname>Costa</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Canani</surname>
              <given-names>LH</given-names>
            </name>
            <name>
              <surname>Santos</surname>
              <given-names>KG</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <trans-title xml:lang="en">Prevalence of micro and macroangiopatic chronic
                  complications and their risk factors in the care of out patients with type 2
                  diabetes mellitus</trans-title>
          <source>Rev Assoc Med Bras</source>
          <year>2004</year>
          <volume>50</volume>
          <issue>3</issue>
          <fpage>263</fpage>
          <lpage>267</lpage>
        </element-citation>
      </ref>
      <ref id="B11">
        <label>11</label>
        <mixed-citation>11. Santos PA, Sabino CP. Diabetes mellitus em pacientes coronariopatas:
               preval&#234;ncia e fatores de risco cardiovascular associado. Rev Soc Bras Cl&#237;n
               M&#233;dica(SBCM). 2012;10(6):469-75.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Santos</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Sabino</surname>
              <given-names>CP</given-names>
            </name>
          </person-group>
          <article-title xml:lang="pt">Diabetes mellitus em pacientes coronariopatas:
                  preval&#234;ncia e fatores de risco cardiovascular associado</article-title>
          <source>Rev Soc Bras Cl&#237;n M&#233;dica(SBCM)</source>
          <year>2012</year>
          <volume>10</volume>
          <issue>6</issue>
          <fpage>469</fpage>
          <lpage>475</lpage>
        </element-citation>
      </ref>
      <ref id="B12">
        <label>12</label>
        <mixed-citation>12. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk
               factors and 12 years cardiovascular mortality for men screened in the multiple risk
               factors intervention trial. Diabetes Care.1993;16(2):434-44.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Stamler</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Vaccaro</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Neaton</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Wentworth</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes, other risk factors and 12 years cardiovascular
                  mortality for men screened in the multiple risk factors intervention
                  trial</article-title>
          <source>Diabetes Care</source>
          <year>1993</year>
          <volume>16</volume>
          <issue>2</issue>
          <fpage>434</fpage>
          <lpage>444</lpage>
        </element-citation>
      </ref>
      <ref id="B13">
        <label>13</label>
        <mixed-citation>13. Schaan BD, Gus E. Cardiac risk profile in diabetes mellitus and
               impaired fasting glucose. Rev Sa&#250;de P&#250;blica 2004;38(4):529-36.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Schaan</surname>
              <given-names>BD</given-names>
            </name>
            <name>
              <surname>Gus</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Cardiac risk profile in diabetes mellitus and impaired
                  fasting glucose</article-title>
          <source>Rev Sa&#250;de P&#250;blica</source>
          <year>2004</year>
          <volume>38</volume>
          <issue>4</issue>
          <fpage>529</fpage>
          <lpage>536</lpage>
        </element-citation>
      </ref>
      <ref id="B14">
        <label>14</label>
        <mixed-citation>14. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes
               a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med.
               2009;26(2):142-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bulugahapitiya</surname>
              <given-names>U</given-names>
            </name>
            <name>
              <surname>Siyambalapitiya</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Sithole</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Idris</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Is diabetes a coronary risk equivalent? Systematic
                  review and meta-analysis</article-title>
          <source>Diabet Med</source>
          <year>2009</year>
          <volume>26</volume>
          <issue>2</issue>
          <fpage>142</fpage>
          <lpage>148</lpage>
        </element-citation>
      </ref>
      <ref id="B15">
        <label>15</label>
        <mixed-citation>15. Franklin SS, Thijs L, Li Y, Hansen TW, Boggia J, Liu YP, et al.
               Masked hypertension in Diabetes Mellitus treatment implications for clinical
               practice. Int database ambulatory, blood. Hypertension.
               2013;61(5):964-71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Franklin</surname>
              <given-names>SS</given-names>
            </name>
            <name>
              <surname>Thijs</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Hansen</surname>
              <given-names>TW</given-names>
            </name>
            <name>
              <surname>Boggia</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Liu</surname>
              <given-names>YP</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Masked hypertension in Diabetes Mellitus treatment
                  implications for clinical practice. Int database ambulatory, blood</article-title>
          <source>Hypertension</source>
          <year>2013</year>
          <volume>61</volume>
          <issue>5</issue>
          <fpage>964</fpage>
          <lpage>971</lpage>
        </element-citation>
      </ref>
      <ref id="B16">
        <label>16</label>
        <mixed-citation>16. Bozorgmanesh M, Hadaegh F, Mohebi R, Ghanbarian A, Eskandari F,
               Azizi F. Diabetic population mortality and cardiovascular risk attributable to
               hypertension: a decade follow-up from the Tehran Lipid and Glucose Study. Blood
               Press. 2013;22(5):317-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bozorgmanesh</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Hadaegh</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Mohebi</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Ghanbarian</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Eskandari</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Azizi</surname>
              <given-names>F</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic population mortality and cardiovascular risk
                  attributable to hypertension: a decade follow-up from the Tehran Lipid and Glucose
                  Study</article-title>
          <source>Blood Press</source>
          <year>2013</year>
          <volume>22</volume>
          <issue>5</issue>
          <fpage>317</fpage>
          <lpage>324</lpage>
        </element-citation>
      </ref>
      <ref id="B17">
        <label>17</label>
        <mixed-citation>17. Nauta ST, Deckers JW, Akkerhuis KM, van Domburg RT. Short- and
               long-term mortality after myocardial infarction in patients with and without
               diabetes: changes from 1985 to 2008. Diabetes Care.
               2012;35(10):2043-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nauta</surname>
              <given-names>ST</given-names>
            </name>
            <name>
              <surname>Deckers</surname>
              <given-names>JW</given-names>
            </name>
            <name>
              <surname>Akkerhuis</surname>
              <given-names>KM</given-names>
            </name>
            <name>
              <surname>van Domburg</surname>
              <given-names>RT</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Short- and long-term mortality after myocardial
                  infarction in patients with and without diabetes: changes from 1985 to
                  2008</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>10</issue>
          <fpage>2043</fpage>
          <lpage>2047</lpage>
        </element-citation>
      </ref>
      <ref id="B18">
        <label>18</label>
        <mixed-citation>18. Quadros A, Diemer F, Lima T, Abdalla R, Vizotto M, Gottschall CA, et
               al. [Percutaneous coronary intervention in diabetes mellitus: an updated analysis of
               medical practice]. Arq Bras Endocrinol Metabol. 2007;51(2):327-33.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Quadros</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Diemer</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Lima</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Abdalla</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Vizotto</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Gottschall</surname>
              <given-names>CA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <trans-title xml:lang="en">Percutaneous coronary intervention in diabetes mellitus:
                  an updated analysis of medical practice</trans-title>
          <source>Arq Bras Endocrinol Metabol</source>
          <year>2007</year>
          <volume>51</volume>
          <issue>2</issue>
          <fpage>327</fpage>
          <lpage>333</lpage>
        </element-citation>
      </ref>
      <ref id="B19">
        <label>19</label>
        <mixed-citation>19. Valensi P, Lorgis L, Cottin Y. Prevalence, incidence, predictive
               factors and prognosis of silent myocardial infarction: a review of the literature.
               Arch Cardiovasc Dis. 2011;104(3):178-88.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Valensi</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Lorgis</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Cottin</surname>
              <given-names>Y</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prevalence, incidence, predictive factors and prognosis
                  of silent myocardial infarctiona review of the literature</article-title>
          <source>Arch Cardiovasc Dis</source>
          <year>2011</year>
          <volume>104</volume>
          <issue>3</issue>
          <fpage>178</fpage>
          <lpage>188</lpage>
        </element-citation>
      </ref>
      <ref id="B20">
        <label>20</label>
        <mixed-citation>20. Sander D, Sander K, Poppert H. Stroke in type 2 diabetes. Br J
               Diabetes Vasc Dis. 2008;8(5):222-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sander</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Sander</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Poppert</surname>
              <given-names>H</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Stroke in type 2 diabetes</article-title>
          <source>Br J Diabetes Vasc Dis</source>
          <year>2008</year>
          <volume>8</volume>
          <issue>5</issue>
          <fpage>222</fpage>
          <lpage>229</lpage>
        </element-citation>
      </ref>
      <ref id="B21">
        <label>21</label>
        <mixed-citation>21. Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K,
               et al. Epidemiology of ischemic stroke in patients with diabetes: the greater
               Cincinnati/Northern Kentucky Stroke Study. Diabetes Care.
               2005;28(2):355-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kissela</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>Khoury</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Kleindorfer</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Woo</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Schneider</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Alwell</surname>
              <given-names>K</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Epidemiology of ischemic stroke in patients with
                  diabetes: the greater Cincinnati/Northern Kentucky Stroke Study</article-title>
          <source>Diabetes Care</source>
          <year>2005</year>
          <volume>28</volume>
          <issue>2</issue>
          <fpage>355</fpage>
          <lpage>359</lpage>
        </element-citation>
      </ref>
      <ref id="B22">
        <label>22</label>
        <mixed-citation>22. Canavan RJ, Unwin NC, Kelly WF, Connolly VM. Diabetes - and
               nondiabetes-related lower extremity amputation incidence before and after the
               introduction of better organized diabetes foot care: continuous longitudinal
               monitoring using a standard method. Diabetes Care.
               2008;31(3):459-63.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Canavan</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Unwin</surname>
              <given-names>NC</given-names>
            </name>
            <name>
              <surname>Kelly</surname>
              <given-names>WF</given-names>
            </name>
            <name>
              <surname>Connolly</surname>
              <given-names>VM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes - and nondiabetes-related lower extremity
                  amputation incidence before and after the introduction of better organized
                  diabetes foot care: continuous longitudinal monitoring using a standard
                  method</article-title>
          <source>Diabetes Care</source>
          <year>2008</year>
          <volume>31</volume>
          <issue>3</issue>
          <fpage>459</fpage>
          <lpage>463</lpage>
        </element-citation>
      </ref>
      <ref id="B23">
        <label>23</label>
        <mixed-citation>23. Clark N, Sheehan P, Edmonds M, Januzzi JL, Regensteiner J, Sanders
               L, et al. Peripheral arterial disease in people with diabetes. American Diabetic
               Association. Diabetes Care. 2003;26(12):3333-41.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Clark</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Sheehan</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Edmonds</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Januzzi</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Regensteiner</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Sanders</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Peripheral arterial disease in people with diabetes.
                  American Diabetic Association</article-title>
          <source>Diabetes Care</source>
          <year>2003</year>
          <volume>26</volume>
          <issue>12</issue>
          <fpage>3333</fpage>
          <lpage>3341</lpage>
        </element-citation>
      </ref>
      <ref id="B24">
        <label>24</label>
        <mixed-citation>24. L&#252;scher TF, Creager MA, Beckman JA, Cosentino F. Diabetes and
               vascular disease: pathophysiology, clinical consequences, and medical therapy: Part
               II. Circulation. 2003;108(12):1655-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>L&#252;scher</surname>
              <given-names>TF</given-names>
            </name>
            <name>
              <surname>Creager</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Beckman</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Cosentino</surname>
              <given-names>F</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes and vascular disease: pathophysiology, clinical
                  consequences, and medical therapy: Part II</article-title>
          <source>Circulation</source>
          <year>2003</year>
          <volume>108</volume>
          <issue>12</issue>
          <fpage>1655</fpage>
          <lpage>1661</lpage>
        </element-citation>
      </ref>
      <ref id="B25">
        <label>25</label>
        <mixed-citation>25. Kissela B, Air E. Diabetes: impact on stroke risk and poststroke
               recovery. Semin Neurol. 2006;26(1):100-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kissela</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Air</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes: impact on stroke risk and poststroke
                  recovery</article-title>
          <source>Semin Neurol</source>
          <year>2006</year>
          <volume>26</volume>
          <issue>1</issue>
          <fpage>100</fpage>
          <lpage>107</lpage>
        </element-citation>
      </ref>
      <ref id="B26">
        <label>26</label>
        <mixed-citation>26. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis:
               epidemiology, pathophysiology, and management. JAMA.
               2002;287(19):2570-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Beckman</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Creager</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Libby</surname>
              <given-names>P</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes and atherosclerosis: epidemiology,
                  pathophysiology, and management</article-title>
          <source>JAMA</source>
          <year>2002</year>
          <volume>287</volume>
          <issue>19</issue>
          <fpage>2570</fpage>
          <lpage>2581</lpage>
        </element-citation>
      </ref>
      <ref id="B27">
        <label>27</label>
        <mixed-citation>27. Haffner SM, Lehto S, R&#246;nnemaa T, Py&#246;r&#228;l&#228; K, Laakso M. Mortality from
               coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects
               with and without prior myocardial infarction. N Engl J Med.
               1998;339(4):229-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Haffner</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Lehto</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>R&#246;nnemaa</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Py&#246;r&#228;l&#228;</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Laakso</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Mortality from coronary heart disease in subjects with
                  type 2 diabetes and in nondiabetic subjects with and without prior myocardial
                  infarction</article-title>
          <source>N Engl J Med</source>
          <year>1998</year>
          <volume>339</volume>
          <issue>4</issue>
          <fpage>229</fpage>
          <lpage>234</lpage>
        </element-citation>
      </ref>
      <ref id="B28">
        <label>28</label>
        <mixed-citation>28. American Diabetes Association. Standards of medical care in
               diabetes--2013. Diabetes Care. 2013;36( Suppl 1):S11-66.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>American Diabetes Association</collab>
          </person-group>
          <article-title xml:lang="en">Standards of medical care in
                  diabetes--2013</article-title>
          <source>Diabetes Care</source>
          <year>2013</year>
          <volume>36</volume>
          <supplement>Suppl 1</supplement>
          <fpage>S11</fpage>
          <lpage>S66</lpage>
        </element-citation>
      </ref>
      <ref id="B29">
        <label>29</label>
        <mixed-citation>29. Xavier H, Izar M, Faria Neto J, Assad M, Rocha V, Sposito A, et al;
               Sociedade Brasileira de Cardiologia. V Diretriz brasileira de dislipidemias e
               Preven&#231;&#227;o da aterosclerose. Arq Bras Cardiol. 2013;101(4 supl
               1):1-20.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Xavier</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Izar</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Faria</surname>
              <given-names>J</given-names>
              <suffix>Neto</suffix>
            </name>
            <name>
              <surname>Assad</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Rocha</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Sposito</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <article-title xml:lang="pt">V Diretriz brasileira de dislipidemias e Preven&#231;&#227;o da
                  aterosclerose</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2013</year>
          <volume>101</volume>
          <issue>4</issue>
          <supplement>supl 1</supplement>
          <fpage>1</fpage>
          <lpage>20</lpage>
        </element-citation>
      </ref>
      <ref id="B30">
        <label>30</label>
        <mixed-citation>30. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the
               Framingham study. Circulation.1979;59(1):8-13.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kannel</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>McGee</surname>
              <given-names>DL</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes and cardiovascular risk factors: the Framingham
                  study</article-title>
          <source>Circulation</source>
          <year>1979</year>
          <volume>59</volume>
          <issue>1</issue>
          <fpage>8</fpage>
          <lpage>13</lpage>
        </element-citation>
      </ref>
      <ref id="B31">
        <label>31</label>
        <mixed-citation>31. Stevens RJ, Kothari V, Adler AI, Stratton IM. The UKPDS risk engine:
               a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). United
               Kingdom Prospective Diabetes Study (UKPDS) Group. Clin Sci (Lond)
               2001;101(6):671-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Stevens</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Kothari</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Adler</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Stratton</surname>
              <given-names>IM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The UKPDS risk engine: a model for the risk of coronary
                  heart disease in Type II diabetes (UKPDS 56)</article-title>
          <collab>United Kingdom Prospective Diabetes Study (UKPDS) Group</collab>
          <source>Clin Sci (Lond)</source>
          <year>2001</year>
          <volume>101</volume>
          <issue>6</issue>
          <fpage>671</fpage>
          <lpage>679</lpage>
        </element-citation>
      </ref>
      <ref id="B32">
        <label>32</label>
        <mixed-citation>32. Guzder RN, Gatling W, Mullee MA, Mehta RL, Byrne CD. Prognostic
               value of the Framingham cardiovascular risk equation and the UKPDS risk engine for
               coronary heart disease in newly diagnosed Type 2 diabetes: results from a United
               Kingdom study. Diabet Med. 2005;22(5):554-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Guzder</surname>
              <given-names>RN</given-names>
            </name>
            <name>
              <surname>Gatling</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Mullee</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Mehta</surname>
              <given-names>RL</given-names>
            </name>
            <name>
              <surname>Byrne</surname>
              <given-names>CD</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prognostic value of the Framingham cardiovascular risk
                  equation and the UKPDS risk engine for coronary heart disease in newly diagnosed
                  Type 2 diabetes: results from a United Kingdom study</article-title>
          <source>Diabet Med</source>
          <year>2005</year>
          <volume>22</volume>
          <issue>5</issue>
          <fpage>554</fpage>
          <lpage>562</lpage>
        </element-citation>
      </ref>
      <ref id="B33">
        <label>33</label>
        <mixed-citation>33. D'Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM,
               et al. General cardiovascular risk profile for use in primary care: the Framingham
               Heart Study. Circulation. 2008;117(6):743-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>D'Agostino</surname>
              <given-names>RB</given-names>
            </name>
            <name>
              <surname>Vasan</surname>
              <given-names>RS</given-names>
            </name>
            <name>
              <surname>Pencina</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Wolf</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Cobain</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Massaro</surname>
              <given-names>JM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">General cardiovascular risk profile for use in primary
                  care: the Framingham Heart Study</article-title>
          <source>Circulation</source>
          <year>2008</year>
          <volume>117</volume>
          <issue>6</issue>
          <fpage>743</fpage>
          <lpage>753</lpage>
        </element-citation>
      </ref>
      <ref id="B34">
        <label>34</label>
        <mixed-citation>34. Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, et
               al. Long-term prognosis associated with coronary calcification: observations from a
               registry of 25,253 patients. J Am Coll Cardiol. 2007;49(21):1860-70.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Budoff</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Shaw</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>Liu</surname>
              <given-names>ST</given-names>
            </name>
            <name>
              <surname>Weinstein</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Mosler</surname>
              <given-names>TP</given-names>
            </name>
            <name>
              <surname>Tseng</surname>
              <given-names>PH</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Long-term prognosis associated with coronary
                  calcification: observations from a registry of 25,253 patients</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2007</year>
          <volume>49</volume>
          <issue>21</issue>
          <fpage>1860</fpage>
          <lpage>1870</lpage>
        </element-citation>
      </ref>
      <ref id="B35">
        <label>35</label>
        <mixed-citation>35. Rochitte CE, Pinto IM, Fernandes JL, Filho CF, Jatene A, Carvalho
               AC, et al. [Cardiovascular magnetic resonance and computed tomography imaging
               guidelines of the Brazilian Society of Cardiology]. Grupo de Estudo em Resson&#226;ncia e
               Tomografia Cardiovascular (GERT) do Departamento de Cardiologia Cl&#237;nica da Sociedade
               Brasileira de Cardiologia. Arq Bras Cardiol. 2006;87(3):e60-100.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rochitte</surname>
              <given-names>CE</given-names>
            </name>
            <name>
              <surname>Pinto</surname>
              <given-names>IM</given-names>
            </name>
            <name>
              <surname>Fernandes</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Filho</surname>
              <given-names>CF</given-names>
            </name>
            <name>
              <surname>Jatene</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Carvalho</surname>
              <given-names>AC</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Cardiovascular magnetic resonance and computed
                  tomography imaging guidelines of the Brazilian Society of
                  Cardiology</article-title>
          <collab>Grupo de Estudo em Resson&#226;ncia e Tomografia Cardiovascular (GERT)</collab>
          <collab>Departamento de Cardiologia Cl&#237;nica</collab>
          <collab>Sociedade Brasileira de Cardiologia</collab>
          <source>Arq Bras Cardiol</source>
          <year>2006</year>
          <volume>87</volume>
          <issue>3</issue>
          <fpage>e60</fpage>
          <lpage>100</lpage>
        </element-citation>
      </ref>
      <ref id="B36">
        <label>36</label>
        <mixed-citation>36. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al.
               Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N
               Engl J Med.2008;358(13):1336-45.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Detrano</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Guerci</surname>
              <given-names>AD</given-names>
            </name>
            <name>
              <surname>Carr</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Bild</surname>
              <given-names>DE</given-names>
            </name>
            <name>
              <surname>Burke</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Folsom</surname>
              <given-names>AR</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary calcium as a predictor of coronary events in
                  four racial or ethnic groups</article-title>
          <source>N Engl J Med</source>
          <year>2008</year>
          <volume>358</volume>
          <issue>13</issue>
          <fpage>1336</fpage>
          <lpage>1345</lpage>
        </element-citation>
      </ref>
      <ref id="B37">
        <label>37</label>
        <mixed-citation>37. Erbel R, M&#246;hlenkamp S, Moebus S, Schmermund A, Lehmann N, Stang A,
               et al. Coronary risk stratification, discrimination, and reclassification improvement
               based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf
               Recall study. Heinz Nixdorf Recall Study Investigative Group. J Am Coll
               Cardiol.2010;56(17):1397-406.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Erbel</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>M&#246;hlenkamp</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Moebus</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Schmermund</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Lehmann</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Stang</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary risk stratification, discrimination, and
                  reclassification improvement based on quantification of subclinical coronary
                  atherosclerosis: the Heinz Nixdorf Recall study</article-title>
          <collab>Heinz Nixdorf Recall Study Investigative Group</collab>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>56</volume>
          <issue>17</issue>
          <fpage>1397</fpage>
          <lpage>1406</lpage>
        </element-citation>
      </ref>
      <ref id="B38">
        <label>38</label>
        <mixed-citation>38. Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of
               coronary artery calcium screening in subjects with and without diabetes. J Am Coll
               Cardiol. 2004;43(9):1663-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Raggi</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Shaw</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>Berman</surname>
              <given-names>DS</given-names>
            </name>
            <name>
              <surname>Callister</surname>
              <given-names>TQ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prognostic value of coronary artery calcium screening in
                  subjects with and without diabetes</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2004</year>
          <volume>43</volume>
          <issue>9</issue>
          <fpage>1663</fpage>
          <lpage>1669</lpage>
        </element-citation>
      </ref>
      <ref id="B39">
        <label>39</label>
        <mixed-citation>39. Maffei E, Seitun S, Nieman K, Martini C, Guaricci AI, Tedeschi C, et
               al. Assessment of coronary artery disease and calcified coronary plaque burden by
               computed tomography in patients with and without diabetes mellitus. Eur Radiol.
               2011;21(5):944-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Maffei</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Seitun</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Nieman</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Martini</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Guaricci</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Tedeschi</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Assessment of coronary artery disease and calcified
                  coronary plaque burden by computed tomography in patients with and without
                  diabetes mellitus</article-title>
          <source>Eur Radiol</source>
          <year>2011</year>
          <volume>21</volume>
          <issue>5</issue>
          <fpage>944</fpage>
          <lpage>953</lpage>
        </element-citation>
      </ref>
      <ref id="B40">
        <label>40</label>
        <mixed-citation>40. Agarwal S, Morgan T, Herrington DM, Xu J, Cox AJ, Freedman BI, et
               al. Coronary calcium score and prediction of all-cause mortality in diabetes: the
               diabetes heart study. Diabetes Care. 2011;34(5):1219-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Agarwal</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Morgan</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Herrington</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Xu</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Cox</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Freedman</surname>
              <given-names>BI</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary calcium score and prediction of all-cause
                  mortality in diabetes: the diabetes heart study</article-title>
          <source>Diabetes Care</source>
          <year>2011</year>
          <volume>34</volume>
          <issue>5</issue>
          <fpage>1219</fpage>
          <lpage>1224</lpage>
        </element-citation>
      </ref>
      <ref id="B41">
        <label>41</label>
        <mixed-citation>41. Kramer CK, Zinman B, Gross JL, Canani LH, Rodrigues TC, Azevedo MJ,
               et al. Coronary artery calcium score prediction of all cause mortality and
               cardiovascular events in people with type 2 diabetes: systematic review and
               meta-analysis. BMJ. 2013;346:F1654.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kramer</surname>
              <given-names>CK</given-names>
            </name>
            <name>
              <surname>Zinman</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Gross</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Canani</surname>
              <given-names>LH</given-names>
            </name>
            <name>
              <surname>Rodrigues</surname>
              <given-names>TC</given-names>
            </name>
            <name>
              <surname>Azevedo</surname>
              <given-names>MJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary artery calcium score prediction of all cause
                  mortality and cardiovascular events in people with type 2 diabetes: systematic
                  review and meta-analysis</article-title>
          <source>BMJ</source>
          <year>2013</year>
          <volume>346</volume>
          <fpage>F1654</fpage>
          <lpage>F1654</lpage>
        </element-citation>
      </ref>
      <ref id="B42">
        <label>42</label>
        <mixed-citation>42. Elkeles RS, Godsland IF, Feher MD, Rubens MB, Roughton M, Nugara F,
               et al. Coronary calcium measurement improves prediction of cardiovascular events in
               asymptomatic patients with type 2 diabetes: the PREDICT study. PREDICT Study Group.
               Eur Heart J. 2008;29(18):2244-51.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Elkeles</surname>
              <given-names>RS</given-names>
            </name>
            <name>
              <surname>Godsland</surname>
              <given-names>IF</given-names>
            </name>
            <name>
              <surname>Feher</surname>
              <given-names>MD</given-names>
            </name>
            <name>
              <surname>Rubens</surname>
              <given-names>MB</given-names>
            </name>
            <name>
              <surname>Roughton</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Nugara</surname>
              <given-names>F</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary calcium measurement improves prediction of
                  cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT
                  study</article-title>
          <collab>PREDICT Study Group</collab>
          <source>Eur Heart J</source>
          <year>2008</year>
          <volume>29</volume>
          <issue>18</issue>
          <fpage>2244</fpage>
          <lpage>2251</lpage>
        </element-citation>
      </ref>
      <ref id="B43">
        <label>43</label>
        <mixed-citation>43. Agarwal S, Cox AJ, Herrington DM, Jorgensen NW, Xu J, Freedman BI,
               et al. Coronary calcium score predicts cardiovascular mortality in diabetes: diabetes
               heart study. Diabetes Care. 2013;36(4):972-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Agarwal</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Cox</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Herrington</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Jorgensen</surname>
              <given-names>NW</given-names>
            </name>
            <name>
              <surname>Xu</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Freedman</surname>
              <given-names>BI</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary calcium score predicts cardiovascular mortality
                  in diabetes: diabetes heart study</article-title>
          <source>Diabetes Care</source>
          <year>2013</year>
          <volume>36</volume>
          <issue>4</issue>
          <fpage>972</fpage>
          <lpage>977</lpage>
        </element-citation>
      </ref>
      <ref id="B44">
        <label>44</label>
        <mixed-citation>44. Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, et al. Risk
               stratification in uncomplicated type 2 diabetes: prospective evaluation of the
               combined use of coronary artery calcium imaging and selective myocardial perfusion
               scintigraphy. Eur Heart J. 2006;27(6):713-21.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Anand</surname>
              <given-names>DV</given-names>
            </name>
            <name>
              <surname>Lim</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Hopkins</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Corder</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Shaw</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>Sharp</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Risk stratification in uncomplicated type 2 diabetes:
                  prospective evaluation of the combined use of coronary artery calcium imaging and
                  selective myocardial perfusion scintigraphy</article-title>
          <source>Eur Heart J</source>
          <year>2006</year>
          <volume>27</volume>
          <issue>6</issue>
          <fpage>713</fpage>
          <lpage>721</lpage>
        </element-citation>
      </ref>
      <ref id="B45">
        <label>45</label>
        <mixed-citation>45. Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Ninuma H, Gottlieb
               I, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med.
               2008;359(22):2324-36.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Miller</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Rochitte</surname>
              <given-names>CE</given-names>
            </name>
            <name>
              <surname>Dewey</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Arbab-Zadeh</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Ninuma</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Gottlieb</surname>
              <given-names>I</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diagnostic performance of coronary angiography by 64-row
                  CT</article-title>
          <source>N Engl J Med</source>
          <year>2008</year>
          <volume>359</volume>
          <issue>22</issue>
          <fpage>2324</fpage>
          <lpage>2336</lpage>
        </element-citation>
      </ref>
      <ref id="B46">
        <label>46</label>
        <mixed-citation>46. Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem
               CA, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography:
               a prospective, multicenter, multivendor study. J Am Coll Cardiol.
               2008;52(25):2135-44.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Meijboom</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>Meijs</surname>
              <given-names>MF</given-names>
            </name>
            <name>
              <surname>Schuijf</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Cramer</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Mollet</surname>
              <given-names>NR</given-names>
            </name>
            <name>
              <surname>van Mieghem</surname>
              <given-names>CA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diagnostic accuracy of 64-slice computed tomography
                  coronary angiography: a prospective, multicenter, multivendor
                  study</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2008</year>
          <volume>52</volume>
          <issue>25</issue>
          <fpage>2135</fpage>
          <lpage>2144</lpage>
        </element-citation>
      </ref>
      <ref id="B47">
        <label>47</label>
        <mixed-citation>47. Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, et
               al. Diagnostic performance of 64-multidetector row coronary computed tomographic
               angiography for evaluation of coronary artery stenosis in individuals without known
               coronary artery disease: results from the prospective multicenter ACCURACY
               (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing
               Invasive Coronary Angiography) trial. J Am Coll Cardiol.
               2008;52(21):1724-32.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Budoff</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Dowe</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Jollis</surname>
              <given-names>JG</given-names>
            </name>
            <name>
              <surname>Gitter</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sutherland</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Halamert</surname>
              <given-names>E</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diagnostic performance of 64-multidetector row coronary
                  computed tomographic angiography for evaluation of coronary artery stenosis in
                  individuals without known coronary artery disease: results from the prospective
                  multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of
                  Individuals Undergoing Invasive Coronary Angiography) trial</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2008</year>
          <volume>52</volume>
          <issue>21</issue>
          <fpage>1724</fpage>
          <lpage>1732</lpage>
        </element-citation>
      </ref>
      <ref id="B48">
        <label>48</label>
        <mixed-citation>48. Chow BJ, Small G, Yam Y, Chen L, Achenbach S, Al-Mallah M, et al.
               (Incremental prognostic value of cardiac computed tomography in coronary artery
               disease using CONFIRM: COroNary computed tomography angiography evaluation for
               clinical outcomes: an InteRnational Multicenter registry. CONFIRM Investigators. Circ
               Cardiovasc Imaging. 2011;4(5):463-72.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chow</surname>
              <given-names>BJ</given-names>
            </name>
            <name>
              <surname>Small</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Yam</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Achenbach</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Al-Mallah</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">(Incremental prognostic value of cardiac computed
                  tomography in coronary artery disease using CONFIRM: COroNary computed tomography
                  angiography evaluation for clinical outcomes: an InteRnational Multicenter
                  registry. CONFIRM Investigators</article-title>
          <source>Circ Cardiovasc Imaging</source>
          <year>2011</year>
          <volume>4</volume>
          <issue>5</issue>
          <fpage>463</fpage>
          <lpage>472</lpage>
        </element-citation>
      </ref>
      <ref id="B49">
        <label>49</label>
        <mixed-citation>49. Van Werkhoven JM, Cademartiri F, Seitun S, Maffei E, Palumbo A,
               Martini C,et al. Diabetes: prognostic value of CT coronary angiography--comparison
               with a nondiabetic population. Radiology. 2010;256(1):83-92.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Van Werkhoven</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Cademartiri</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Seitun</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Maffei</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Palumbo</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Martini</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diabetes: prognostic value of CT coronary
                  angiography--comparison with a nondiabetic population</article-title>
          <source>Radiology</source>
          <year>2010</year>
          <volume>256</volume>
          <issue>1</issue>
          <fpage>83</fpage>
          <lpage>92</lpage>
        </element-citation>
      </ref>
      <ref id="B50">
        <label>50</label>
        <mixed-citation>50. Mark DB, Berman DS, Budoff MJ, Carr JJ, Gerber TC, Hecht HS, et al.
               ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus document on coronary computed
               tomographic angiography: a report of the American College of Cardiology Foundation
               Task Force on Expert Consensus Documents. Circulation.
               2010;121(22):2509-43.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mark</surname>
              <given-names>DB</given-names>
            </name>
            <name>
              <surname>Berman</surname>
              <given-names>DS</given-names>
            </name>
            <name>
              <surname>Budoff</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Carr</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Gerber</surname>
              <given-names>TC</given-names>
            </name>
            <name>
              <surname>Hecht</surname>
              <given-names>HS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus
                  document on coronary computed tomographic angiography: a report of the American
                  College of Cardiology Foundation Task Force on Expert Consensus
                  Documents</article-title>
          <source>Circulation</source>
          <year>2010</year>
          <volume>121</volume>
          <issue>22</issue>
          <fpage>2509</fpage>
          <lpage>2543</lpage>
        </element-citation>
      </ref>
      <ref id="B51">
        <label>51</label>
        <mixed-citation>51. Bernard S, S&#233;rusclat A, Targe F, Charri&#232;re S, Roth O, Beaune J, et
               al. Incremental predictive value of carotid ultrasonography in the assessment of
               coronary risk in a cohort of asymptomatic type 2 diabetic subjects. Diabetes Care.
               2005;28(5):1158-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bernard</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>S&#233;rusclat</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Targe</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Charri&#232;re</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Roth</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Beaune</surname>
              <given-names>J</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Incremental predictive value of carotid ultrasonography
                  in the assessment of coronary risk in a cohort of asymptomatic type 2 diabetic
                  subjects</article-title>
          <source>Diabetes Care</source>
          <year>2005</year>
          <volume>28</volume>
          <issue>5</issue>
          <fpage>1158</fpage>
          <lpage>1162</lpage>
        </element-citation>
      </ref>
      <ref id="B52">
        <label>52</label>
        <mixed-citation>52. Yoshida M, Mita T, Yamamoto R, Shimizu T, Ikeda F, Ohmura C, et al.
               Combination of the Framingham risk score and carotid intima-media thickness improves
               the prediction of cardiovascular events in patients with type 2 diabetes. Diabetes
               Care. 2012;35(1):178-80.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Yoshida</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Mita</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Yamamoto</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Shimizu</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Ikeda</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Ohmura</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Combination of the Framingham risk score and carotid
                  intima-media thickness improves the prediction of cardiovascular events in
                  patients with type 2 diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>1</issue>
          <fpage>178</fpage>
          <lpage>180</lpage>
        </element-citation>
      </ref>
      <ref id="B53">
        <label>53</label>
        <mixed-citation>53. Lacroix P, Aboyans V, Criqui MH, Bertin F, Bouhamed T, Archambeaud
               F, et al. Type-2 diabetes and carotid stenosis: a proposal for a screening strategy
               in asymptomatic patients. Vasc Med. 2006;11(2):93-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lacroix</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Aboyans</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Criqui</surname>
              <given-names>MH</given-names>
            </name>
            <name>
              <surname>Bertin</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Bouhamed</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Archambeaud</surname>
              <given-names>F</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Type-2 diabetes and carotid stenosis: a proposal for a
                  screening strategy in asymptomatic patients</article-title>
          <source>Vasc Med</source>
          <year>2006</year>
          <volume>11</volume>
          <issue>2</issue>
          <fpage>93</fpage>
          <lpage>99</lpage>
        </element-citation>
      </ref>
      <ref id="B54">
        <label>54</label>
        <mixed-citation>54. Dinneen SF, Gerstein HC. The association of microalbuminuria and
               mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the
               literature. Arch Intern Med 1997;157(13):1413-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dinneen</surname>
              <given-names>SF</given-names>
            </name>
            <name>
              <surname>Gerstein</surname>
              <given-names>HC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The association of microalbuminuria and mortality in
                  non-insulin-dependent diabetes mellitus. A systematic overview of the
                  literature</article-title>
          <source>Arch Intern Med</source>
          <year>1997</year>
          <volume>157</volume>
          <issue>13</issue>
          <fpage>1413</fpage>
          <lpage>1418</lpage>
        </element-citation>
      </ref>
      <ref id="B55">
        <label>55</label>
        <mixed-citation>55. Neil A, Hawkins M, Potok M, Thorogood M, Cohen D, Mann J. A
               prospective population-based study of microalbuminuria as a predictor of mortality in
               NIDDM. Diabetes Care. 1993;16(7):996-1003.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Neil</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Hawkins</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Potok</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Thorogood</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Mann</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">A prospective population-based study of microalbuminuria
                  as a predictor of mortality in NIDDM</article-title>
          <source>Diabetes Care</source>
          <year>1993</year>
          <volume>16</volume>
          <issue>7</issue>
          <fpage>996</fpage>
          <lpage>1003</lpage>
        </element-citation>
      </ref>
      <ref id="B56">
        <label>56</label>
        <mixed-citation>56. Norman PE, Davis WA, Bruce DG, Davis TM. Peripheral arterial disease
               and risk of cardiac death in type 2 diabetes: the Fremantle Diabetes Study. Diabetes
               Care. 2006;29(3):575-80.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Norman</surname>
              <given-names>PE</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>WA</given-names>
            </name>
            <name>
              <surname>Bruce</surname>
              <given-names>DG</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>TM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Peripheral arterial disease and risk of cardiac death in
                  type 2 diabetes: the Fremantle Diabetes Study</article-title>
          <source>Diabetes Care</source>
          <year>2006</year>
          <volume>29</volume>
          <issue>3</issue>
          <fpage>575</fpage>
          <lpage>580</lpage>
        </element-citation>
      </ref>
      <ref id="B57">
        <label>57</label>
        <mixed-citation>57. Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee
               D, et al. Aspirin for primary prevention of cardiovascular events in people with
               diabetes: a position statement of the American Diabetes Association, a scientific
               statement of the American Heart Association, and an expert consensus document of the
               American College of Cardiology Foundation. Circulation.
               2010;121(24):2694-701.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Pignone</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Alberts</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Colwell</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Cushman</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Inzucchi</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Mukherjee</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Aspirin for primary prevention of cardiovascular events
                  in people with diabetes: a position statement of the American Diabetes
                  Association, a scientific statement of the American Heart Association, and an
                  expert consensus document of the American College of Cardiology
                  Foundation</article-title>
          <source>Circulation</source>
          <year>2010</year>
          <volume>121</volume>
          <issue>24</issue>
          <fpage>2694</fpage>
          <lpage>2701</lpage>
        </element-citation>
      </ref>
      <ref id="B58">
        <label>58</label>
        <mixed-citation>58. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et
               al. Efficacy and safety of more intensive lowering of LDL cholesterol: a
               meta-analysis of data from 170,000 participants in 26 randomised trials. Cholesterol
               Treatment Trialists' (CTT) Collaboration. Lancet.
               2010;376(9678):1670-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Baigent</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Blackwell</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Emberson</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Holland</surname>
              <given-names>LE</given-names>
            </name>
            <name>
              <surname>Reith</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Bhala</surname>
              <given-names>N</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Efficacy and safety of more intensive lowering of LDL
                  cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised
                  trials. Cholesterol Treatment Trialists' (CTT) Collaboration</article-title>
          <source>Lancet</source>
          <year>2010</year>
          <volume>376</volume>
          <issue>9678</issue>
          <fpage>1670</fpage>
          <lpage>1681</lpage>
        </element-citation>
      </ref>
      <ref id="B59">
        <label>59</label>
        <mixed-citation>59. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et
               al. Statins and risk of incident diabetes: a collaborative meta-analysis of
               randomised statin trials. Lancet. 2010;375(9716):735-42.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sattar</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Preiss</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Murray</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Welsh</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Buckley</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>de Craen</surname>
              <given-names>AJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Statins and risk of incident diabetes: a collaborative
                  meta-analysis of randomised statin trials</article-title>
          <source>Lancet</source>
          <year>2010</year>
          <volume>375</volume>
          <issue>9716</issue>
          <fpage>735</fpage>
          <lpage>742</lpage>
        </element-citation>
      </ref>
      <ref id="B60">
        <label>60</label>
        <mixed-citation>60. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ.
               Cardiovascular benefits and diabetes risks of statin therapy in primary prevention:
               an analysis from the JUPITER trial. Lancet. 2012;380(9841):565-71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ridker</surname>
              <given-names>PM</given-names>
            </name>
            <name>
              <surname>Pradhan</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>MacFadyen</surname>
              <given-names>JG</given-names>
            </name>
            <name>
              <surname>Libby</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Glynn</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Cardiovascular benefits and diabetes risks of statin
                  therapy in primary prevention: an analysis from the JUPITER trial</article-title>
          <source>Lancet</source>
          <year>2012</year>
          <volume>380</volume>
          <issue>9841</issue>
          <fpage>565</fpage>
          <lpage>571</lpage>
        </element-citation>
      </ref>
      <ref id="B61">
        <label>61</label>
        <mixed-citation>61. Zhou Y, Yuan Y, Cai RR, Huang Y, Xia WQ, Yang Y, et al. Statin
               therapy on glycaemic control in type 2 diabetes: a meta-analysis. Expert Opin
               Pharmacother. 2013;14(12):1575-84.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zhou</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Yuan</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Cai</surname>
              <given-names>RR</given-names>
            </name>
            <name>
              <surname>Huang</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Xia</surname>
              <given-names>WQ</given-names>
            </name>
            <name>
              <surname>Yang</surname>
              <given-names>Y</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Statin therapy on glycaemic control in type 2 diabetes:
                  a meta-analysis</article-title>
          <source>Expert Opin Pharmacother</source>
          <year>2013</year>
          <volume>14</volume>
          <issue>12</issue>
          <fpage>1575</fpage>
          <lpage>1584</lpage>
        </element-citation>
      </ref>
      <ref id="B62">
        <label>62</label>
        <mixed-citation>62. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects
               of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.
               Lancet. 2010;375(9729):1875-84.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jun</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Foote</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Lv</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Neal</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Patel</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Nicholls</surname>
              <given-names>SJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of fibrates on cardiovascular outcomes: a
                  systematic review and meta-analysis</article-title>
          <source>Lancet</source>
          <year>2010</year>
          <volume>375</volume>
          <issue>9729</issue>
          <fpage>1875</fpage>
          <lpage>1884</lpage>
        </element-citation>
      </ref>
      <ref id="B63">
        <label>63</label>
        <mixed-citation>63. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, et
               al. Effects of combination lipid therapy in type 2 diabetes mellitus. ACCORD Study
               Group. N Engl J Med.2010;362(17):1563-74.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ginsberg</surname>
              <given-names>HN</given-names>
            </name>
            <name>
              <surname>Elam</surname>
              <given-names>MB</given-names>
            </name>
            <name>
              <surname>Lovato</surname>
              <given-names>LC</given-names>
            </name>
            <name>
              <surname>Crouse</surname>
              <given-names>JR</given-names>
            </name>
            <name>
              <surname>Leiter</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Linz</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of combination lipid therapy in type 2 diabetes
                  mellitus</article-title>
          <collab>ACCORD Study Group</collab>
          <source>N Engl J Med</source>
          <year>2010</year>
          <volume>362</volume>
          <issue>17</issue>
          <fpage>1563</fpage>
          <lpage>1574</lpage>
        </element-citation>
      </ref>
      <ref id="B64">
        <label>64</label>
        <mixed-citation>64. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens
               P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving
               intensive statin therapy. AIM-HIGH Investigators. N Engl J Med.
               2011;365(24):2255-67.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Boden</surname>
              <given-names>WE</given-names>
            </name>
            <name>
              <surname>Probstfield</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Anderson</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Chaitman</surname>
              <given-names>BR</given-names>
            </name>
            <name>
              <surname>Desvignes-Nickens</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Koprowicz</surname>
              <given-names>K</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Niacin in patients with low HDL cholesterol levels
                  receiving intensive statin therapy</article-title>
          <collab>AIM-HIGH Investigators</collab>
          <source>N Engl J Med</source>
          <year>2011</year>
          <volume>365</volume>
          <issue>24</issue>
          <fpage>2255</fpage>
          <lpage>2267</lpage>
        </element-citation>
      </ref>
      <ref id="B65">
        <label>65</label>
        <mixed-citation>65. Weil J, Colin-Jones D, Langman M, Lawson D, Logan R, Murphy M, et
               al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ.
               1995;310(6983):827-30.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Weil</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Colin-Jones</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Langman</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Lawson</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Logan</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Murphy</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prophylactic aspirin and risk of peptic ulcer
                  bleeding</article-title>
          <source>BMJ</source>
          <year>1995</year>
          <volume>310</volume>
          <issue>6983</issue>
          <fpage>827</fpage>
          <lpage>830</lpage>
        </element-citation>
      </ref>
      <ref id="B66">
        <label>66</label>
        <mixed-citation>66. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown
               DL. Aspirin for the primary prevention of cardiovascular events in women and men: a
               sex-specific meta-analysis of randomized controlled trials. JAMA.
               2006;295(3):306-13.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Berger</surname>
              <given-names>JS</given-names>
            </name>
            <name>
              <surname>Roncaglioni</surname>
              <given-names>MC</given-names>
            </name>
            <name>
              <surname>Avanzini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Pangrazzi</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Tognoni</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Brown</surname>
              <given-names>DL</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Aspirin for the primary prevention of cardiovascular
                  events in women and men: a sex-specific meta-analysis of randomized controlled
                  trials</article-title>
          <source>JAMA</source>
          <year>2006</year>
          <volume>295</volume>
          <issue>3</issue>
          <fpage>306</fpage>
          <lpage>313</lpage>
        </element-citation>
      </ref>
      <ref id="B67">
        <label>67</label>
        <mixed-citation>67. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et
               al. Aspirin in the primary and secondary prevention of vascular disease:
               collaborative meta-analysis of individual participant data from randomised trials.
               Antithrombotic Trialists' (ATT) Collaboration. Lancet.
               2009;373(9678):1849-60.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Baigent</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Blackwell</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Collins</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Emberson</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Godwin</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Peto</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Aspirin in the primary and secondary prevention of
                  vascular disease: collaborative meta-analysis of individual participant data from
                  randomised trials</article-title>
          <collab>Antithrombotic Trialists' (ATT) Collaboration</collab>
          <source>Lancet</source>
          <year>2009</year>
          <volume>373</volume>
          <issue>9678</issue>
          <fpage>1849</fpage>
          <lpage>1860</lpage>
        </element-citation>
      </ref>
      <ref id="B68">
        <label>68</label>
        <mixed-citation>68. Aspirin effects on mortality and morbidity in patients with diabetes
               mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators.
               JAMA. 1992;268(10):1292-300.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Aspirin effects on mortality and morbidity in patients
                  with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14 </article-title>
          <collab>ETDRS Investigators</collab>
          <source>JAMA</source>
          <year>1992</year>
          <volume>268</volume>
          <issue>10</issue>
          <fpage>1292</fpage>
          <lpage>1300</lpage>
        </element-citation>
      </ref>
      <ref id="B69">
        <label>69</label>
        <mixed-citation>69. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, et al.
               Low-dose aspirin for primary prevention of atherosclerotic events in patients with
               type 2 diabetes: a randomized controlled trial. JAMA.
               2008;300(18):2134-41.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ogawa</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Nakayama</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Morimoto</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Uemura</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Kanauchi</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Doi</surname>
              <given-names>N</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Low-dose aspirin for primary prevention of
                  atherosclerotic events in patients with type 2 diabetes: a randomized controlled
                  trial</article-title>
          <source>JAMA</source>
          <year>2008</year>
          <volume>300</volume>
          <issue>18</issue>
          <fpage>2134</fpage>
          <lpage>2141</lpage>
        </element-citation>
      </ref>
      <ref id="B70">
        <label>70</label>
        <mixed-citation>70. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, et
               al. The prevention of progression of arterial disease and diabetes (POPADAD) trial:
               factorial randomised placebo controlled trial of aspirin and antioxidants in patients
               with diabetes and asymptomatic peripheral arterial disease. BMJ.
               2008;337:a1840.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Belch</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>MacCuish</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Campbell</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Cobbe</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Taylor</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Prescott</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">The prevention of progression of arterial disease and
                  diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin
                  and antioxidants in patients with diabetes and asymptomatic peripheral arterial
                  disease</article-title>
          <source>BMJ</source>
          <year>2008</year>
          <volume>337</volume>
          <fpage>a1840</fpage>
          <lpage>a1840</lpage>
        </element-citation>
      </ref>
      <ref id="B71">
        <label>71</label>
        <mixed-citation>71. Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et
               al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J
               (Clin Res Ed). 1988;296(6618):313-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Peto</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Gray</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Collins</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Wheatley</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Hennekens</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Jamrozik</surname>
              <given-names>K</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Randomised trial of prophylactic daily aspirin in
                  British male doctors</article-title>
          <source>Br Med J (Clin Res Ed)</source>
          <year>1988</year>
          <volume>296</volume>
          <issue>6618</issue>
          <fpage>313</fpage>
          <lpage>316</lpage>
        </element-citation>
      </ref>
      <ref id="B72">
        <label>72</label>
        <mixed-citation>72. Final report on the aspirin component of the ongoing Physicians'
               Health Study. Steering Committee of the Physicians' Health Study Research Group. N
               Engl J Med. 1989;321(3):129-35.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Final report on the aspirin component of the ongoing
                  Physicians' Health Study</article-title>
          <collab>Steering Committee of the Physicians' Health Study Research Group</collab>
          <source>N Engl J Med</source>
          <year>1989</year>
          <volume>321</volume>
          <issue>3</issue>
          <fpage>129</fpage>
          <lpage>135</lpage>
        </element-citation>
      </ref>
      <ref id="B73">
        <label>73</label>
        <mixed-citation>73. Thrombosis prevention trial: randomised trial of low-intensity oral
               anticoagulation with warfarin and low-dose aspirin in the primary prevention of
               ischaemic heart disease in men at increased risk. The Medical Research Council's
               General Practice Research Framework. Lancet. 1998;351(9098):233-41.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Thrombosis prevention trial: randomised trial of
                  low-intensity oral anticoagulation with warfarin and low-dose aspirin in the
                  primary prevention of ischaemic heart disease in men at increased risk. The
                  Medical Research Council's General Practice Research Framework</article-title>
          <source>Lancet</source>
          <year>1998</year>
          <volume>351</volume>
          <issue>9098</issue>
          <fpage>233</fpage>
          <lpage>241</lpage>
        </element-citation>
      </ref>
      <ref id="B74">
        <label>74</label>
        <mixed-citation>74. Hansson L, Zanchetti A, Carruthers SG, Dahl&#246;f B, Elmfeldt D, Julius
               S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in
               patients with hypertension: principal results of the Hypertension Optimal Treatment
               (HOT) randomised trial. HOT Study Group.
               Lancet.1998;351(9118):1755-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hansson</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Zanchetti</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Carruthers</surname>
              <given-names>SG</given-names>
            </name>
            <name>
              <surname>Dahl&#246;f</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Elmfeldt</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Julius</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of intensive blood-pressure lowering and
                  low-dose aspirin in patients with hypertension: principal results of the
                  Hypertension Optimal Treatment (HOT) randomised trial</article-title>
          <collab>HOT Study Group</collab>
          <source>Lancet</source>
          <year>1998</year>
          <volume>351</volume>
          <issue>9118</issue>
          <fpage>1755</fpage>
          <lpage>1762</lpage>
        </element-citation>
      </ref>
      <ref id="B75">
        <label>75</label>
        <mixed-citation>75. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G,
               Nicolucci A. Primary prevention of cardiovascular events with low-dose aspirin and
               vitamin E in type 2 diabetic patients: results of the Primary Prevention Project
               (PPP) trial. PPP Collaborative Group. Diabetes Care.
               2003;26(12):3264-72.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sacco</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Pellegrini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Roncaglioni</surname>
              <given-names>MC</given-names>
            </name>
            <name>
              <surname>Avanzini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Tognoni</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Nicolucci</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Primary prevention of cardiovascular events with
                  low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary
                  Prevention Project (PPP) trial</article-title>
          <collab>PPP Collaborative Group</collab>
          <source>Diabetes Care</source>
          <year>2003</year>
          <volume>26</volume>
          <issue>12</issue>
          <fpage>3264</fpage>
          <lpage>3272</lpage>
        </element-citation>
      </ref>
      <ref id="B76">
        <label>76</label>
        <mixed-citation>76. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al.
               A randomized trial of low-dose aspirin in the primary prevention of cardiovascular
               disease in women. N Engl J Med. 2005;352(13)1293-304.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ridker</surname>
              <given-names>PM</given-names>
            </name>
            <name>
              <surname>Cook</surname>
              <given-names>NR</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>IM</given-names>
            </name>
            <name>
              <surname>Gordon</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Gaziano</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Manson</surname>
              <given-names>JE</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">A randomized trial of low-dose aspirin in the primary
                  prevention of cardiovascular disease in women</article-title>
          <source>N Engl J Med</source>
          <year>2005</year>
          <volume>352</volume>
          <issue>13</issue>
          <fpage>1293</fpage>
          <lpage>1304</lpage>
        </element-citation>
      </ref>
      <ref id="B77">
        <label>77</label>
        <mixed-citation>77. De Gaetano G. Low-dose aspirin and vitamin E in people at
               cardiovascular risk: a randomised trial in general practice. Collaborative Group of
               the Primary Prevention Project. Lancet. 2001;357(9250):89-95.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>De Gaetano</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Low-dose aspirin and vitamin E in people at
                  cardiovascular risk: a randomised trial in general practice</article-title>
          <collab>Collaborative Group of the Primary Prevention Project</collab>
          <source>Lancet</source>
          <year>2001</year>
          <volume>357</volume>
          <issue>9250</issue>
          <fpage>89</fpage>
          <lpage>95</lpage>
        </element-citation>
      </ref>
      <ref id="B78">
        <label>78</label>
        <mixed-citation>78. De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G,
               Tognoni G, et al. Aspirin for primary prevention of cardiovascular events in people
               with diabetes: meta-analysis of randomised controlled trials. BMJ.
               2009;339:b4531.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>De Berardis</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Sacco</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Strippoli</surname>
              <given-names>GF</given-names>
            </name>
            <name>
              <surname>Pellegrini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Graziano</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Tognoni</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Aspirin for primary prevention of cardiovascular events
                  in people with diabetes: meta-analysis of randomised controlled
                  trials</article-title>
          <source>BMJ</source>
          <year>2009</year>
          <volume>339</volume>
          <fpage>b4531</fpage>
          <lpage>b4531</lpage>
        </element-citation>
      </ref>
      <ref id="B79">
        <label>79</label>
        <mixed-citation>79. Zhang C, Sun A, Zhang P, Wu C, Zhang S, Fu M, et al. Aspirin for
               primary prevention of cardiovascular events in patients with diabetes: a
               meta-analysis. Diabetes Res Clin Pract. 2010;87(2):211-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zhang</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Sun</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Zhang</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Wu</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Zhang</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Fu</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Aspirin for primary prevention of cardiovascular events
                  in patients with diabetes: a meta-analysis</article-title>
          <source>Diabetes Res Clin Pract</source>
          <year>2010</year>
          <volume>87</volume>
          <issue>2</issue>
          <fpage>211</fpage>
          <lpage>218</lpage>
        </element-citation>
      </ref>
      <ref id="B80">
        <label>80</label>
        <mixed-citation>80. De Berardis G, Lucisano G, D'Ettorre A, Pellegrini F, Lepore V,
               Tognoni G, et al. Association of aspirin use with major bleeding in patients with and
               without diabetes. JAMA. 2012;307(21):2286-94.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>De Berardis</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Lucisano</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>D'Ettorre</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Pellegrini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Lepore</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Tognoni</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Association of aspirin use with major bleeding in
                  patients with and without diabetes</article-title>
          <source>JAMA</source>
          <year>2012</year>
          <volume>307</volume>
          <issue>21</issue>
          <fpage>2286</fpage>
          <lpage>2294</lpage>
        </element-citation>
      </ref>
      <ref id="B81">
        <label>81</label>
        <mixed-citation>81. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones
               DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular
               disease in women--2011 update: a guideline from the American Heart Association.
               American Heart Association. J Am Coll Cardiol. 2011;57(18):1404-23.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mosca</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Benjamin</surname>
              <given-names>EJ</given-names>
            </name>
            <name>
              <surname>Berra</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Bezanson</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Dolor</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Lloyd-Jones</surname>
              <given-names>DM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effectiveness-based guidelines for the prevention of
                  cardiovascular disease in women--2011 update: a guideline from the American Heart
                  Association</article-title>
          <collab>American Heart Association</collab>
          <source>J Am Coll Cardiol</source>
          <year>2011</year>
          <volume>57</volume>
          <issue>18</issue>
          <fpage>1404</fpage>
          <lpage>1423</lpage>
        </element-citation>
      </ref>
      <ref id="B82">
        <label>82</label>
        <mixed-citation>82. Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, et
               al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective
               Diabetes Study risk engine. Stroke.2002;33(7):1776-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kothari</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Stevens</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Adler</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Stratton</surname>
              <given-names>IM</given-names>
            </name>
            <name>
              <surname>Manley</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Neil</surname>
              <given-names>HA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">UKPDS 60: risk of stroke in type 2 diabetes estimated by
                  the UK Prospective Diabetes Study risk engine</article-title>
          <source>Stroke</source>
          <year>2002</year>
          <volume>33</volume>
          <issue>7</issue>
          <fpage>1776</fpage>
          <lpage>1781</lpage>
        </element-citation>
      </ref>
      <ref id="B83">
        <label>83</label>
        <mixed-citation>83. Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM. UKPDS Outcomes
               Model 2: a new version of a model to simulate lifetime health outcomes of patients
               with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective
               Diabetes Study: UKPDS 82. Diabetologia. 2013;56(9):1925-33.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hayes</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Leal</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Gray</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Holman</surname>
              <given-names>RR</given-names>
            </name>
            <name>
              <surname>Clarke</surname>
              <given-names>PM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">UKPDS Outcomes Model 2: a new version of a model to
                  simulate lifetime health outcomes of patients with type 2 diabetes mellitus using
                  data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS
                  82</article-title>
          <source>Diabetologia</source>
          <year>2013</year>
          <volume>56</volume>
          <issue>9</issue>
          <fpage>1925</fpage>
          <lpage>1933</lpage>
        </element-citation>
      </ref>
      <ref id="B84">
        <label>84</label>
        <mixed-citation>84. Leal J, Hayes AJ, Gray AM, Holman RR, Clarke PM. Temporal Validation
               of the UKPDS Outcomes Model Using 10-Year Posttrial Monitoring Data. Diabetes Care.
               2013;36(6):1541-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Leal</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Hayes</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Gray</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Holman</surname>
              <given-names>RR</given-names>
            </name>
            <name>
              <surname>Clarke</surname>
              <given-names>PM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Temporal Validation of the UKPDS Outcomes Model Using
                  10-Year Posttrial Monitoring Data</article-title>
          <source>Diabetes Care</source>
          <year>2013</year>
          <volume>36</volume>
          <issue>6</issue>
          <fpage>1541</fpage>
          <lpage>1546</lpage>
        </element-citation>
      </ref>
      <ref id="B85">
        <label>85</label>
        <mixed-citation>85. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE.
               Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2
               diabetes. Diabetes Care. 2002;25(7):1129-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hu</surname>
              <given-names>FB</given-names>
            </name>
            <name>
              <surname>Stampfer</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Haffner</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Solomon</surname>
              <given-names>CG</given-names>
            </name>
            <name>
              <surname>Willett</surname>
              <given-names>WC</given-names>
            </name>
            <name>
              <surname>Manson</surname>
              <given-names>JE</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Elevated risk of cardiovascular disease prior to
                  clinical diagnosis of type 2 diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2002</year>
          <volume>25</volume>
          <issue>7</issue>
          <fpage>1129</fpage>
          <lpage>1134</lpage>
        </element-citation>
      </ref>
      <ref id="B86">
        <label>86</label>
        <mixed-citation>86. Bradley RF, Schonfeld A. Diminished pain in diabetic patients with
               acute myocardial infarction. Geriatrics.1962;17:322-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bradley</surname>
              <given-names>RF</given-names>
            </name>
            <name>
              <surname>Schonfeld</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diminished pain in diabetic patients with acute
                  myocardial infarction</article-title>
          <source>Geriatrics</source>
          <year>1962</year>
          <volume>17</volume>
          <fpage>322</fpage>
          <lpage>326</lpage>
        </element-citation>
      </ref>
      <ref id="B87">
        <label>87</label>
        <mixed-citation>87. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized
               myocardial infarction. An update on the Framingham study. N Engl J Med.
               1984;311(1):1144-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kannel</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>Abbott</surname>
              <given-names>RD</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Incidence and prognosis of unrecognized myocardial
                  infarction. An update on the Framingham study</article-title>
          <source>N Engl J Med</source>
          <year>1984</year>
          <volume>311</volume>
          <issue>1</issue>
          <fpage>1144</fpage>
          <lpage>1147</lpage>
        </element-citation>
      </ref>
      <ref id="B88">
        <label>88</label>
        <mixed-citation>88. Chiariello M, Indolfi C. Silent myocardial ischemia in patients with
               diabetes mellitus. Circulation. 1996;93(12):2089-91.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chiariello</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Indolfi</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Silent myocardial ischemia in patients with diabetes
                  mellitus</article-title>
          <source>Circulation</source>
          <year>1996</year>
          <volume>93</volume>
          <issue>12</issue>
          <fpage>2089</fpage>
          <lpage>2091</lpage>
        </element-citation>
      </ref>
      <ref id="B89">
        <label>89</label>
        <mixed-citation>89. Caracciolo EA, Chaitman BR, Forman SA, Stone PH, Bourassa MG, Sopko
               G, et al. Diabetics with coronary disease have a prevalence of asymptomatic ischemia
               during exercise treadmill testing and ambulatory ischemia monitoring similar to that
               of nondiabetic patients. An ACIP database study. ACIP Investigators. Asymptomatic
               Cardiac Ischemia Pilot Investigators. Circulation.
               1996;93(12):2097-105.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Caracciolo</surname>
              <given-names>EA</given-names>
            </name>
            <name>
              <surname>Chaitman</surname>
              <given-names>BR</given-names>
            </name>
            <name>
              <surname>Forman</surname>
              <given-names>SA</given-names>
            </name>
            <name>
              <surname>Stone</surname>
              <given-names>PH</given-names>
            </name>
            <name>
              <surname>Bourassa</surname>
              <given-names>MG</given-names>
            </name>
            <name>
              <surname>Sopko</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diabetics with coronary disease have a prevalence of
                  asymptomatic ischemia during exercise treadmill testing and ambulatory ischemia
                  monitoring similar to that of nondiabetic patients. An ACIP database study. ACIP
                  Investigators. Asymptomatic Cardiac Ischemia Pilot Investigators</article-title>
          <source>Circulation</source>
          <year>1996</year>
          <volume>93</volume>
          <issue>12</issue>
          <fpage>2097</fpage>
          <lpage>2105</lpage>
        </element-citation>
      </ref>
      <ref id="B90">
        <label>90</label>
        <mixed-citation>90. Callaham PR, Froelicher VF, Klein J, Risch M, Dubach P, Friis R.
               Exercise-induced silent ischemia: age, diabetes mellitus, previous myocardial
               infarction and prognosis. J Am Coll Cardiol.1989;14(5):1175-80.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Callaham</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Froelicher</surname>
              <given-names>VF</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Risch</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Dubach</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Friis</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Exercise-induced silent ischemia: age, diabetes
                  mellitus, previous myocardial infarction and prognosis</article-title>
          <source>J Am Coll Cardiol</source>
          <year>1989</year>
          <volume>14</volume>
          <issue>5</issue>
          <fpage>1175</fpage>
          <lpage>1180</lpage>
        </element-citation>
      </ref>
      <ref id="B91">
        <label>91</label>
        <mixed-citation>91. Langer A, Freeman MR, Josse RG, Steiner G, Armstrong PW. Detection
               of silent myocardial ischemia in diabetes mellitus. Am J Cardiol.
               1991;67(13):1073-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Langer</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Freeman</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Josse</surname>
              <given-names>RG</given-names>
            </name>
            <name>
              <surname>Steiner</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Armstrong</surname>
              <given-names>PW</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Detection of silent myocardial ischemia in diabetes
                  mellitus</article-title>
          <source>Am J Cardiol</source>
          <year>1991</year>
          <volume>67</volume>
          <issue>13</issue>
          <fpage>1073</fpage>
          <lpage>1078</lpage>
        </element-citation>
      </ref>
      <ref id="B92">
        <label>92</label>
        <mixed-citation>92. Cohn PF. Silent myocardial ischemia. Ann Intern Med.
               1988;109(4):312-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cohn</surname>
              <given-names>PF</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Silent myocardial ischemia</article-title>
          <source>Ann Intern Med</source>
          <year>1988</year>
          <volume>109</volume>
          <issue>4</issue>
          <fpage>312</fpage>
          <lpage>317</lpage>
        </element-citation>
      </ref>
      <ref id="B93">
        <label>93</label>
        <mixed-citation>93. Davis TM, Fortun P, Mulder J, Davis WA, Bruce DG. Silent myocardial
               infarction and its prognosis in a community-based cohort of Type 2 diabetic patients:
               the Fremantle Diabetes Study. Fremantle Diabetes Study. Diabetologia.
               2004;47(3):395-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Davis</surname>
              <given-names>TM</given-names>
            </name>
            <name>
              <surname>Fortun</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Mulder</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>WA</given-names>
            </name>
            <name>
              <surname>Bruce</surname>
              <given-names>DG</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Silent myocardial infarction and its prognosis in a
                  community-based cohort of Type 2 diabetic patients: the Fremantle Diabetes Study.
                  Fremantle Diabetes Study</article-title>
          <source>Diabetologia</source>
          <year>2004</year>
          <volume>47</volume>
          <issue>3</issue>
          <fpage>395</fpage>
          <lpage>399</lpage>
        </element-citation>
      </ref>
      <ref id="B94">
        <label>94</label>
        <mixed-citation>94. Van der Sijde JN, Boiten HJ, Sozzi FB, Elhendy A, van Domburg RT,
               Schinkel AF. Long-term prognostic value of dobutamine stress echocardiography in
               diabetic patients with limited exercise capability: a 13-year follow-up study.
               Diabetes Care. 2012;35(3):634-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Van der Sijde</surname>
              <given-names>JN</given-names>
            </name>
            <name>
              <surname>Boiten</surname>
              <given-names>HJ</given-names>
            </name>
            <name>
              <surname>Sozzi</surname>
              <given-names>FB</given-names>
            </name>
            <name>
              <surname>Elhendy</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>van Domburg</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Schinkel</surname>
              <given-names>AF</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Long-term prognostic value of dobutamine stress
                  echocardiography in diabetic patients with limited exercise capability: a 13-year
                  follow-up study</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>3</issue>
          <fpage>634</fpage>
          <lpage>639</lpage>
        </element-citation>
      </ref>
      <ref id="B95">
        <label>95</label>
        <mixed-citation>95. Sociedade Brasileira de Cardiologia. [Guidelines of chronic coronary
               disease: stable angina]. Arq Bras Cardiol. 2004;83(Suppl 2):6-43.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <trans-title xml:lang="en">Guidelines of chronic coronary disease: stable
                  angina</trans-title>
          <source>Arq Bras Cardiol</source>
          <year>2004</year>
          <volume>83</volume>
          <supplement>Suppl 2</supplement>
          <fpage>6</fpage>
          <lpage>43</lpage>
        </element-citation>
      </ref>
      <ref id="B96">
        <label>96</label>
        <mixed-citation>96. Vanzetto G, Halimi S, Hammoud T, Fagret D, Benhamou PY, Cordonnier
               D, et al. Prediction of cardiovascular events in clinically selected high-risk NIDDM
               patients. Prognostic value of exercise stress test and thallium-201 single-photon
               emission computed tomography. Diabetes Care. 1999;22(1):19-26.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vanzetto</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Halimi</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Hammoud</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Fagret</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Benhamou</surname>
              <given-names>PY</given-names>
            </name>
            <name>
              <surname>Cordonnier</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prediction of cardiovascular events in clinically
                  selected high-risk NIDDM patients. Prognostic value of exercise stress test and
                  thallium-201 single-photon emission computed tomography</article-title>
          <source>Diabetes Care</source>
          <year>1999</year>
          <volume>22</volume>
          <issue>1</issue>
          <fpage>19</fpage>
          <lpage>26</lpage>
        </element-citation>
      </ref>
      <ref id="B97">
        <label>97</label>
        <mixed-citation>97. Young LH, Wackers FJ, Chyun DA, Davey JA, Barrett EJ, Taillefer R,
               et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in
               patients with type 2 diabetes: the DIAD study: a randomized controlled trial. DIAD
               Investigators. JAMA. 2009;301(15):1547-55.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Young</surname>
              <given-names>LH</given-names>
            </name>
            <name>
              <surname>Wackers</surname>
              <given-names>FJ</given-names>
            </name>
            <name>
              <surname>Chyun</surname>
              <given-names>DA</given-names>
            </name>
            <name>
              <surname>Davey</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Barrett</surname>
              <given-names>EJ</given-names>
            </name>
            <name>
              <surname>Taillefer</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Cardiac outcomes after screening for asymptomatic
                  coronary artery disease in patients with type 2 diabetes: the DIAD study: a
                  randomized controlled trial</article-title>
          <collab>DIAD Investigators</collab>
          <source>JAMA</source>
          <year>2009</year>
          <volume>301</volume>
          <issue>15</issue>
          <fpage>1547</fpage>
          <lpage>1555</lpage>
        </element-citation>
      </ref>
      <ref id="B98">
        <label>98</label>
        <mixed-citation>98. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial
               perfusion SPECT. J Nucl Cardiol. 2004;11(2):171-85.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Shaw</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>Iskandrian</surname>
              <given-names>AE</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prognostic value of gated myocardial perfusion
                  SPECT</article-title>
          <source>J Nucl Cardiol</source>
          <year>2004</year>
          <volume>11</volume>
          <issue>2</issue>
          <fpage>171</fpage>
          <lpage>185</lpage>
        </element-citation>
      </ref>
      <ref id="B99">
        <label>99</label>
        <mixed-citation>99. Giri S, Shaw LJ, Murthy DR, Travin MI, Miller DD, Hachamovitch R, et
               al. Impact of diabetes on the risk stratification using stress single-photon emission
               computed tomography myocardial perfusion imaging in patients with symptoms suggestive
               of coronary artery disease. Circulation. 2002;105(1):32-40.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Giri</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Shaw</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>Murthy</surname>
              <given-names>DR</given-names>
            </name>
            <name>
              <surname>Travin</surname>
              <given-names>MI</given-names>
            </name>
            <name>
              <surname>Miller</surname>
              <given-names>DD</given-names>
            </name>
            <name>
              <surname>Hachamovitch</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Impact of diabetes on the risk stratification using
                  stress single-photon emission computed tomography myocardial perfusion imaging in
                  patients with symptoms suggestive of coronary artery disease</article-title>
          <source>Circulation</source>
          <year>2002</year>
          <volume>105</volume>
          <issue>1</issue>
          <fpage>32</fpage>
          <lpage>40</lpage>
        </element-citation>
      </ref>
      <ref id="B100">
        <label>100</label>
        <mixed-citation>100. Kang X, Berman DS, Lewin HC, Cohen I, Friedman JD, Germano G, et
               al. Incremental prognostic value of myocardial perfusion single photon emission
               computed tomography in patients with diabetes mellitus. Am Heart J. 1999;138(6
               Pt1):1025-32.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kang</surname>
              <given-names>X</given-names>
            </name>
            <name>
              <surname>Berman</surname>
              <given-names>DS</given-names>
            </name>
            <name>
              <surname>Lewin</surname>
              <given-names>HC</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Friedman</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Germano</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Incremental prognostic value of myocardial perfusion
                  single photon emission computed tomography in patients with diabetes
                  mellitus</article-title>
          <source>Am Heart J</source>
          <year>1999</year>
          <volume>138</volume>
          <issue>6</issue>
          <issue-part>Pt 1</issue-part>
          <fpage>1025</fpage>
          <lpage>1032</lpage>
        </element-citation>
      </ref>
      <ref id="B101">
        <label>101</label>
        <mixed-citation>101. Miller TD, Rajagopalan N, Hodge DO, Frye RL, Gibbons RJ. Yield of
               stress single-photon emission computed tomography in asymptomatic patients with
               diabetes. Am Heart J. 2004;147(5):890-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Miller</surname>
              <given-names>TD</given-names>
            </name>
            <name>
              <surname>Rajagopalan</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Hodge</surname>
              <given-names>DO</given-names>
            </name>
            <name>
              <surname>Frye</surname>
              <given-names>RL</given-names>
            </name>
            <name>
              <surname>Gibbons</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Yield of stress single-photon emission computed
                  tomography in asymptomatic patients with diabetes</article-title>
          <source>Am Heart J</source>
          <year>2004</year>
          <volume>147</volume>
          <issue>5</issue>
          <fpage>890</fpage>
          <lpage>896</lpage>
        </element-citation>
      </ref>
      <ref id="B102">
        <label>102</label>
        <mixed-citation>102. Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, Di Carli G, et al.
               Improved cardiac risk assessment with noninvasive measures of coronary flow reserve.
               Circulation.2011;124(20):2215-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Murthy</surname>
              <given-names>VL</given-names>
            </name>
            <name>
              <surname>Naya</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Foster</surname>
              <given-names>CR</given-names>
            </name>
            <name>
              <surname>Hainer</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Gaber</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Di Carli</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Improved cardiac risk assessment with noninvasive
                  measures of coronary flow reserve</article-title>
          <source>Circulation</source>
          <year>2011</year>
          <volume>124</volume>
          <issue>20</issue>
          <fpage>2215</fpage>
          <lpage>2224</lpage>
        </element-citation>
      </ref>
      <ref id="B103">
        <label>103</label>
        <mixed-citation>103. Elhendy A, van Domburg RT, Poldermans D, Bax JJ, Nierop PR,
               Geleijnse ML, et al. Safety and feasibility of dobutamine-atropine stress
               echocardiography for the diagnosis of coronary artery disease in diabetic patients
               unable to perform an exercise stress test. Diabetes Care.
               1998;21(11):1797-802.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Elhendy</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>van Domburg</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Poldermans</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Bax</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Nierop</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Geleijnse</surname>
              <given-names>ML</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Safety and feasibility of dobutamine-atropine stress
                  echocardiography for the diagnosis of coronary artery disease in diabetic patients
                  unable to perform an exercise stress test</article-title>
          <source>Diabetes Care</source>
          <year>1998</year>
          <volume>21</volume>
          <issue>11</issue>
          <fpage>1797</fpage>
          <lpage>1802</lpage>
        </element-citation>
      </ref>
      <ref id="B104">
        <label>104</label>
        <mixed-citation>104. Sozzi FB, Elhendy A, Roelandt JR, van Domburg RT, Schinkel AF,
               Vourvouri EC, et al. Prognostic value of dobutamine stress echocardiography in
               patients with diabetes. Diabetes Care. 2003;26(4):1074-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sozzi</surname>
              <given-names>FB</given-names>
            </name>
            <name>
              <surname>Elhendy</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Roelandt</surname>
              <given-names>JR</given-names>
            </name>
            <name>
              <surname>van Domburg</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Schinkel</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Vourvouri</surname>
              <given-names>EC</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prognostic value of dobutamine stress echocardiography
                  in patients with diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2003</year>
          <volume>26</volume>
          <issue>4</issue>
          <fpage>1074</fpage>
          <lpage>1078</lpage>
        </element-citation>
      </ref>
      <ref id="B105">
        <label>105</label>
        <mixed-citation>105. Cortigiani L, Bigi R, Sicari R, Landi P, Bovenzi F, Picano E.
               Prognostic value of pharmacological stress echocardiography in diabetic and
               nondiabetic patients with known or suspected coronary artery disease. J Am Coll
               Cardiol. 2006;47(3):605-10.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cortigiani</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Bigi</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Sicari</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Landi</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Bovenzi</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Picano</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prognostic value of pharmacological stress
                  echocardiography in diabetic and nondiabetic patients with known or suspected
                  coronary artery disease</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2006</year>
          <volume>47</volume>
          <issue>3</issue>
          <fpage>605</fpage>
          <lpage>610</lpage>
        </element-citation>
      </ref>
      <ref id="B106">
        <label>106</label>
        <mixed-citation>106. Barbosa M, Nunes M, Campos Filho O, Camarozano A, Rabischoffsky A,
               Maciel B, et al; Sociedade Brasileira de Cardiologia. Diretrizes das indica&#231;&#245;es da
               ecocardiografia. Arq Bras Cardiol. 2009;93(6 supl 3):e265-e302.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Barbosa</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Nunes</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Campos</surname>
              <given-names>O</given-names>
              <suffix>Filho</suffix>
            </name>
            <name>
              <surname>Camarozano</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Rabischoffsky</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Maciel</surname>
              <given-names>B</given-names>
            </name>
            <etal>et al</etal>
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <article-title xml:lang="pt">Diretrizes das indica&#231;&#245;es da
                  ecocardiografia</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2009</year>
          <volume>93</volume>
          <issue>6</issue>
          <supplement>supl 3</supplement>
          <fpage>e265</fpage>
          <lpage>e302</lpage>
        </element-citation>
      </ref>
      <ref id="B107">
        <label>107</label>
        <mixed-citation>107. Fliser D, Laville M, Covic A, Fouque D, Vanholder R, Juillard L, et
               al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease
               Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney
               injury: part 1: definitions, conservative management and contrast-induced
               nephropathy. Nephrol Dial Transplant. 2012;27912):4263-72.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fliser</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Laville</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Covic</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Fouque</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Vanholder</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Juillard</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">A European Renal Best Practice (ERBP) position statement
                  on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice
                  guidelines on acute kidney injury: part 1: definitions, conservative management
                  and contrast-induced nephropathy</article-title>
          <source>Nephrol Dial Transplant</source>
          <year>2012</year>
          <volume>27912</volume>
          <fpage>4263</fpage>
          <lpage>4272</lpage>
        </element-citation>
      </ref>
      <ref id="B108">
        <label>108</label>
        <mixed-citation>108. American Diabetes Association. Standards of medical care in
               diabetes,2011. Diabetes Care. 2011;34( Suppl 1):S11-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>American Diabetes Association</collab>
          </person-group>
          <article-title xml:lang="en">Standards of medical care in
                  diabetes,2011</article-title>
          <source>Diabetes Care</source>
          <year>2011</year>
          <volume>34</volume>
          <supplement>Suppl 1</supplement>
          <fpage>S11</fpage>
          <lpage>S61</lpage>
        </element-citation>
      </ref>
      <ref id="B109">
        <label>109</label>
        <mixed-citation>109. Sun Z, Fu Q, Cao L, Jin W, Cheng L, Li Z. Intravenous
               N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of
               randomized, controlled trials. PLoS One. 2013;8(1):e55124.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sun</surname>
              <given-names>Z</given-names>
            </name>
            <name>
              <surname>Fu</surname>
              <given-names>Q</given-names>
            </name>
            <name>
              <surname>Cao</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Jin</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Cheng</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>Z</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Intravenous N-acetylcysteine for prevention of
                  contrast-induced nephropathy: a meta-analysis of randomized, controlled
                  trials</article-title>
          <source>PLoS One</source>
          <year>2013</year>
          <volume>8</volume>
          <issue>1</issue>
          <elocation-id>e55124</elocation-id>
        </element-citation>
      </ref>
      <ref id="B110">
        <label>110</label>
        <mixed-citation>110. Jang JS, Jin HY, Seo JS, Yang TH, Kim DK, Kim TH, et al. Sodium
               bicarbonate therapy for the prevention of contrast-induced acute kidney injury - a
               systematic review and meta-analysis. Circ J. 2012;76(9):2255-65.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jang</surname>
              <given-names>JS</given-names>
            </name>
            <name>
              <surname>Jin</surname>
              <given-names>HY</given-names>
            </name>
            <name>
              <surname>Seo</surname>
              <given-names>JS</given-names>
            </name>
            <name>
              <surname>Yang</surname>
              <given-names>TH</given-names>
            </name>
            <name>
              <surname>Kim</surname>
              <given-names>DK</given-names>
            </name>
            <name>
              <surname>Kim</surname>
              <given-names>TH</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Sodium bicarbonate therapy for the prevention of
                  contrast-induced acute kidney injury - a systematic review and
                  meta-analysis</article-title>
          <source>Circ J</source>
          <year>2012</year>
          <volume>76</volume>
          <issue>9</issue>
          <fpage>2255</fpage>
          <lpage>2265</lpage>
        </element-citation>
      </ref>
      <ref id="B111">
        <label>111</label>
        <mixed-citation>111. Dai B, Liu Y, Fu L, Li Y, Zhang J, Mei C. Effect of theophylline on
               prevention of contrast-induced acute kidney injury: a meta-analysis of randomized
               controlled trials. Am J Kidney Dis. 2012;60(3):360-70.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dai</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Liu</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Fu</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Zhang</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Mei</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effect of theophylline on prevention of contrast-induced
                  acute kidney injurya meta-analysis of randomized controlled trials</article-title>
          <source>Am J Kidney Dis</source>
          <year>2012</year>
          <volume>60</volume>
          <issue>3</issue>
          <fpage>360</fpage>
          <lpage>370</lpage>
        </element-citation>
      </ref>
      <ref id="B112">
        <label>112</label>
        <mixed-citation>112. Li Y, Liu Y, Fu L, Mei C, Dai B. Efficacy of short-term high-dose
               statin in preventing contrast-induced nephropathy: a meta-analysis of seven
               randomized controlled trials. PLoS One. 2012;7(4):e34450.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Li</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Liu</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Fu</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Mei</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Dai</surname>
              <given-names>B</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Efficacy of short-term high-dose statin in preventing
                  contrast-induced nephropathy: a meta-analysis of seven randomized controlled
                  trials</article-title>
          <source>PLoS One</source>
          <year>2012</year>
          <volume>7</volume>
          <issue>4</issue>
          <elocation-id>e34450</elocation-id>
        </element-citation>
      </ref>
      <ref id="B113">
        <label>113</label>
        <mixed-citation>113. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z,
               et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary
               disease. FAME 2 Trial Investigators. N Engl J Med.
               2012;367(11):991-1001.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>De Bruyne</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Pijls</surname>
              <given-names>NH</given-names>
            </name>
            <name>
              <surname>Kalesan</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Barbato</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Tonino</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Piroth</surname>
              <given-names>Z</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Fractional flow reserve-guided PCI versus medical
                  therapy in stable coronary disease</article-title>
          <collab>FAME 2 Trial Investigators</collab>
          <source>N Engl J Med</source>
          <year>2012</year>
          <volume>367</volume>
          <issue>11</issue>
          <fpage>991</fpage>
          <lpage>1001</lpage>
        </element-citation>
      </ref>
      <ref id="B114">
        <label>114</label>
        <mixed-citation>114. Aarnoudse W, Fearon WF, Manoharan G, Geven M, van de Vosse F,
               Rutten M, et al. Epicardial stenosis severity does not affect minimal
               microcirculatory resistance. Circulation. 2004;110(15):2137-42.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Aarnoudse</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Fearon</surname>
              <given-names>WF</given-names>
            </name>
            <name>
              <surname>Manoharan</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Geven</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
            <name>
              <surname>van de Vosse</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Rutten</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Epicardial stenosis severity does not affect minimal
                  microcirculatory resistance</article-title>
          <source>Circulation</source>
          <year>2004</year>
          <volume>110</volume>
          <issue>15</issue>
          <fpage>2137</fpage>
          <lpage>2142</lpage>
        </element-citation>
      </ref>
      <ref id="B115">
        <label>115</label>
        <mixed-citation>115. Zhang Y, Farooq V, Garcia-Garcia H, Bourantas C, Tian N, Donq S, et
               al. Comparison of intravascular ultrasound versus angiography-guided drug-eluting
               stent implantation: a meta-analysis of one randomised trial and ten observational
               studies involving 19,619 patients. EuroIntervention.
               2012;8(7)855-65.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zhang</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Farooq</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Garcia-Garcia</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Bourantas</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Tian</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Donq</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Comparison of intravascular ultrasound versus
                  angiography-guided drug-eluting stent implantation: a meta-analysis of one
                  randomised trial and ten observational studies involving 19,619
                  patients</article-title>
          <source>EuroIntervention</source>
          <year>2012</year>
          <volume>8</volume>
          <volume>7</volume>
          <fpage>855</fpage>
          <lpage>865</lpage>
        </element-citation>
      </ref>
      <ref id="B116">
        <label>116</label>
        <mixed-citation>116. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP,
               et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and
               management of patients with stable ischemic heart disease: a report of the American
               College of Cardiology Foundation/American Heart Association task force on practice
               guidelines, and the American College of Physicians, American Association for Thoracic
               Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular
               Angiography and Interventions, and Society of Thoracic Surgeons. Circulation.
               2012;126(25):e354-471.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fihn</surname>
              <given-names>SD</given-names>
            </name>
            <name>
              <surname>Gardin</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Abrams</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Berra</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Blankenship</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Dallas</surname>
              <given-names>AP</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the
                  diagnosis and management of patients with stable ischemic heart disease: a report
                  of the American College of Cardiology Foundation/American Heart Association task
                  force on practice guidelines, and the American College of Physicians, American
                  Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association,
                  Society for Cardiovascular Angiography and Interventions, and Society of Thoracic
                  Surgeons</article-title>
          <source>Circulation</source>
          <year>2012</year>
          <volume>126</volume>
          <issue>25</issue>
          <fpage>e354</fpage>
          <lpage>e471</lpage>
        </element-citation>
      </ref>
      <ref id="B117">
        <label>117</label>
        <mixed-citation>117. The effect of intensive treatment of diabetes on the development
               and progression of long-term complications in insulin-dependent diabetes mellitus.
               The Diabetes Control and Complications Trial Research Group. N Engl J Med.
               1993;329(14):977-86.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">The effect of intensive treatment of diabetes on the
                  development and progression of long-term complications in insulin-dependent
                  diabetes mellitus</article-title>
          <collab>The Diabetes Control and Complications Trial Research Group</collab>
          <source>N Engl J Med</source>
          <year>1993</year>
          <volume>329</volume>
          <issue>14</issue>
          <fpage>977</fpage>
          <lpage>986</lpage>
        </element-citation>
      </ref>
      <ref id="B118">
        <label>118</label>
        <mixed-citation>118. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term
               intensified insulin treatment on the development of microvascular complications of
               diabetes mellitus. N Engl J Med. 1993;329(5):304-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Reichard</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Nilsson</surname>
              <given-names>BY</given-names>
            </name>
            <name>
              <surname>Rosenqvist</surname>
              <given-names>U</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The effect of long-term intensified insulin treatment on
                  the development of microvascular complications of diabetes
                  mellitus</article-title>
          <source>N Engl J Med</source>
          <year>1993</year>
          <volume>329</volume>
          <issue>5</issue>
          <fpage>304</fpage>
          <lpage>309</lpage>
        </element-citation>
      </ref>
      <ref id="B119">
        <label>119</label>
        <mixed-citation>119. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year
               follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.
               2008;359(15):1577-89.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Holman</surname>
              <given-names>RR</given-names>
            </name>
            <name>
              <surname>Paul</surname>
              <given-names>SK</given-names>
            </name>
            <name>
              <surname>Bethel</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Matthews</surname>
              <given-names>DR</given-names>
            </name>
            <name>
              <surname>Neil</surname>
              <given-names>HA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">10-year follow-up of intensive glucose control in type 2
                  diabetes</article-title>
          <source>N Engl J Med</source>
          <year>2008</year>
          <volume>359</volume>
          <issue>15</issue>
          <fpage>1577</fpage>
          <lpage>1589</lpage>
        </element-citation>
      </ref>
      <ref id="B120">
        <label>120</label>
        <mixed-citation>120. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a
               multifactorial intervention on mortality in type 2 diabetes. N Engl J Med.
               2008;358(6):580-91.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Gaede</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Lund-Andersen</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Parving</surname>
              <given-names>HH</given-names>
            </name>
            <name>
              <surname>Pedersen</surname>
              <given-names>O</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effect of a multifactorial intervention on mortality in
                  type 2 diabetes</article-title>
          <source>N Engl J Med</source>
          <year>2008</year>
          <volume>358</volume>
          <issue>6</issue>
          <fpage>580</fpage>
          <lpage>591</lpage>
        </element-citation>
      </ref>
      <ref id="B121">
        <label>121</label>
        <mixed-citation>121. Nordin C. The case for hypoglycaemia as a proarrhythmic event:
               basic and clinical evidence. Diabetologia. 2010;53(8):1552-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nordin</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The case for hypoglycaemia as a proarrhythmic event:
                  basic and clinical evidence</article-title>
          <source>Diabetologia</source>
          <year>2010</year>
          <volume>53</volume>
          <issue>8</issue>
          <fpage>1552</fpage>
          <lpage>1561</lpage>
        </element-citation>
      </ref>
      <ref id="B122">
        <label>122</label>
        <mixed-citation>122. Innerfield RJ. Metformin-associated mortality in U.S. studies. N
               Engl J Med. 1996;334(24):1611-2.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Innerfield</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Metformin-associated mortality in US.
                  studies</article-title>
          <source>N Engl J Med</source>
          <year>1996</year>
          <volume>334</volume>
          <issue>24</issue>
          <fpage>1611</fpage>
          <lpage>1612</lpage>
        </element-citation>
      </ref>
      <ref id="B123">
        <label>123</label>
        <mixed-citation>123. Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M.
               Antihyperglycemic treatment in diabetics with coronary disease: increased
               metformin-associated mortality over a 5-year follow-up.
               Cardiology.1999;91(3):195-202.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fisman</surname>
              <given-names>EZ</given-names>
            </name>
            <name>
              <surname>Tenenbaum</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Benderly</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Goldbourt</surname>
              <given-names>U</given-names>
            </name>
            <name>
              <surname>Behar</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Motro</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Antihyperglycemic treatment in diabetics with coronary
                  disease: increased metformin-associated mortality over a 5-year
                  follow-up</article-title>
          <source>Cardiology</source>
          <year>1999</year>
          <volume>91</volume>
          <issue>3</issue>
          <fpage>195</fpage>
          <lpage>202</lpage>
        </element-citation>
      </ref>
      <ref id="B124">
        <label>124</label>
        <mixed-citation>124. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin
               on cardiovascular events and mortality: a meta-analysis of randomized clinical
               trials. Diabetes Obes Metab. 2011;13(3):221-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lamanna</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Monami</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Marchionni</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Mannucci</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effect of metformin on cardiovascular events and
                  mortality: a meta-analysis of randomized clinical trials</article-title>
          <source>Diabetes Obes Metab</source>
          <year>2011</year>
          <volume>13</volume>
          <issue>3</issue>
          <fpage>221</fpage>
          <lpage>228</lpage>
        </element-citation>
      </ref>
      <ref id="B125">
        <label>125</label>
        <mixed-citation>125. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality
               associated with the use of metformin compared with sulfonylurea monotherapy in type 2
               diabetes. Diabetes Care.2002;25(12):2244-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Johnson</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Simpson</surname>
              <given-names>SH</given-names>
            </name>
            <name>
              <surname>Toth</surname>
              <given-names>EL</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Decreased mortality associated with the use of metformin
                  compared with sulfonylurea monotherapy in type 2 diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2002</year>
          <volume>25</volume>
          <issue>12</issue>
          <fpage>2244</fpage>
          <lpage>2248</lpage>
        </element-citation>
      </ref>
      <ref id="B126">
        <label>126</label>
        <mixed-citation>126. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM,
               et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of
               mitochondrial permeability transition pore opening. Basic Res
               Cardiol.2008;103(3):274-84.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bhamra</surname>
              <given-names>GS</given-names>
            </name>
            <name>
              <surname>Hausenloy</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Davidson</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Carr</surname>
              <given-names>RD</given-names>
            </name>
            <name>
              <surname>Paiva</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Wynne</surname>
              <given-names>AM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Metformin protects the ischemic heart by the
                  Akt-mediated inhibition of mitochondrial permeability transition pore
                  opening</article-title>
          <source>Basic Res Cardiol</source>
          <year>2008</year>
          <volume>103</volume>
          <issue>3</issue>
          <fpage>274</fpage>
          <lpage>284</lpage>
        </element-citation>
      </ref>
      <ref id="B127">
        <label>127</label>
        <mixed-citation>127. Kravchuk E, Grineva E, Bairamov A, Galagudza M, Vlasov T. The
               effect of metformin on the myocardial tolerance to ischemia-reperfusion injury in the
               rat model of diabetes mellitus type II. Exp Diabetes Res.
               2011;2011:907496.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kravchuk</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Grineva</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Bairamov</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Galagudza</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Vlasov</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The effect of metformin on the myocardial tolerance to
                  ischemia-reperfusion injury in the rat model of diabetes mellitus type
                  II</article-title>
          <source>Exp Diabetes Res</source>
          <year>2011</year>
          <volume>2011</volume>
          <fpage>907496</fpage>
          <lpage>907496</lpage>
        </element-citation>
      </ref>
      <ref id="B128">
        <label>128</label>
        <mixed-citation>128. Wu GT, Wang L, Li J, Zhu WZ. Effects of glibenclamide, glimepiride,
               and gliclazide on ischemic preconditioning in rat heart. Chin Med Sci J.
               2007;22(3):162-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wu</surname>
              <given-names>GT</given-names>
            </name>
            <name>
              <surname>Wang</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Zhu</surname>
              <given-names>WZ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effects of glibenclamide, glimepiride, and gliclazide on
                  ischemic preconditioning in rat heart</article-title>
          <source>Chin Med Sci J</source>
          <year>2007</year>
          <volume>22</volume>
          <issue>3</issue>
          <fpage>162</fpage>
          <lpage>168</lpage>
        </element-citation>
      </ref>
      <ref id="B129">
        <label>129</label>
        <mixed-citation>129. Ferreira BM, Moffa PJ, Falc&#227;o A, Uchida A, Camargo P, Pereyra P, et
               al. The effects of glibenclamide, a K(ATP) channel blocker, on the warm-up
               phenomenon. Ann Noninvasive Electrocardiol. 2005;10(3)356-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ferreira</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>Moffa</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>Falc&#227;o</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Uchida</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Camargo</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Pereyra</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">The effects of glibenclamide, a K(ATP) channel blocker,
                  on the warm-up phenomenon</article-title>
          <source>Ann Noninvasive Electrocardiol</source>
          <year>2005</year>
          <volume>10</volume>
          <issue>3</issue>
          <fpage>356</fpage>
          <lpage>362</lpage>
        </element-citation>
      </ref>
      <ref id="B130">
        <label>130</label>
        <mixed-citation>130. Hueb W, Uchida AH, Gersh BJ, Betti RT, Lopes N, Moffa PJ, et al.
               Effect of a hypoglycemic agent on ischemic preconditioning in patients with type 2
               diabetes and stable angina pectoris. Coron Artery Dis.
               2007;18(1):55-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hueb</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Uchida</surname>
              <given-names>AH</given-names>
            </name>
            <name>
              <surname>Gersh</surname>
              <given-names>BJ</given-names>
            </name>
            <name>
              <surname>Betti</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Lopes</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Moffa</surname>
              <given-names>PJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effect of a hypoglycemic agent on ischemic
                  preconditioning in patients with type 2 diabetes and stable angina
                  pectoris</article-title>
          <source>Coron Artery Dis</source>
          <year>2007</year>
          <volume>18</volume>
          <issue>1</issue>
          <fpage>55</fpage>
          <lpage>59</lpage>
        </element-citation>
      </ref>
      <ref id="B131">
        <label>131</label>
        <mixed-citation>131. Rahmi RM, Uchida AH, Rezende PC, Lima EG, Garzillo CL, Favarato D,
               et al. Effect of hypoglycemic agents on ischemic preconditioning in patients with
               type 2 diabetes and symptomatic coronary artery disease. Diabetes Care.
               2013;36(6):1654-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rahmi</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Uchida</surname>
              <given-names>AH</given-names>
            </name>
            <name>
              <surname>Rezende</surname>
              <given-names>PC</given-names>
            </name>
            <name>
              <surname>Lima</surname>
              <given-names>EG</given-names>
            </name>
            <name>
              <surname>Garzillo</surname>
              <given-names>CL</given-names>
            </name>
            <name>
              <surname>Favarato</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effect of hypoglycemic agents on ischemic
                  preconditioning in patients with type 2 diabetes and symptomatic coronary artery
                  disease</article-title>
          <source>Diabetes Care</source>
          <year>2013</year>
          <volume>36</volume>
          <issue>6</issue>
          <fpage>1654</fpage>
          <lpage>1659</lpage>
        </element-citation>
      </ref>
      <ref id="B132">
        <label>132</label>
        <mixed-citation>132. Van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH,
               Rutten GE, van Weel C. Alpha-glucosidase inhibitors for patients with type 2
               diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care.
               2005;28(1):154-63.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Van de Laar</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Lucassen</surname>
              <given-names>PL</given-names>
            </name>
            <name>
              <surname>Akkermans</surname>
              <given-names>RP</given-names>
            </name>
            <name>
              <surname>van de Lisdonk</surname>
              <given-names>EH</given-names>
            </name>
            <name>
              <surname>Rutten</surname>
              <given-names>GE</given-names>
            </name>
            <name>
              <surname>van Weel</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Alpha-glucosidase inhibitors for patients with type 2
                  diabetes: results from a Cochrane systematic review and
                  meta-analysis</article-title>
          <source>Diabetes Care</source>
          <year>2005</year>
          <volume>28</volume>
          <issue>1</issue>
          <fpage>154</fpage>
          <lpage>163</lpage>
        </element-citation>
      </ref>
      <ref id="B133">
        <label>133</label>
        <mixed-citation>133. Fields AV, Patterson B, Karnik AA, Shannon RP. Glucagon-like
               peptide-1 and myocardial protection: more than glycemic control. Clin Cardiol.
               2009;32(5):236-43.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fields</surname>
              <given-names>AV</given-names>
            </name>
            <name>
              <surname>Patterson</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Karnik</surname>
              <given-names>AA</given-names>
            </name>
            <name>
              <surname>Shannon</surname>
              <given-names>RP</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Glucagon-like peptide-1 and myocardial protection: more
                  than glycemic control</article-title>
          <source>Clin Cardiol</source>
          <year>2009</year>
          <volume>32</volume>
          <issue>5</issue>
          <fpage>236</fpage>
          <lpage>243</lpage>
        </element-citation>
      </ref>
      <ref id="B134">
        <label>134</label>
        <mixed-citation>134. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris
               GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
               EXAMINE Investigators. N Engl J Med. 2013;369(14):1327-35.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>White</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>Cannon</surname>
              <given-names>CP</given-names>
            </name>
            <name>
              <surname>Heller</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Nissen</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Bergenstal</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Bakris</surname>
              <given-names>GL</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Alogliptin after acute coronary syndrome in patients
                  with type 2 diabetes</article-title>
          <collab>EXAMINE Investigators</collab>
          <source>N Engl J Med</source>
          <year>2013</year>
          <volume>369</volume>
          <issue>14</issue>
          <fpage>1327</fpage>
          <lpage>1335</lpage>
        </element-citation>
      </ref>
      <ref id="B135">
        <label>135</label>
        <mixed-citation>135. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg
               B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes
               mellitus. SAVOR-TIMI 53 Steering Committee and Investigators. N Engl J Med.
               2013;369(14):1317-26.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Scirica</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>Bhatt</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Braunwald</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Steg</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Davidson</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Hirshberg</surname>
              <given-names>B</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Saxagliptin and cardiovascular outcomes in patients with
                  type 2 diabetes mellitus</article-title>
          <collab>SAVOR-TIMI 53 Steering Committee and Investigators</collab>
          <source>N Engl J Med</source>
          <year>2013</year>
          <volume>369</volume>
          <issue>14</issue>
          <fpage>1317</fpage>
          <lpage>1326</lpage>
        </element-citation>
      </ref>
      <ref id="B136">
        <label>136</label>
        <mixed-citation>136. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of
               myocardial infarction and death from cardiovascular causes. N Engl J Med.
               2007;356(24):2457-71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nissen</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Wolski</surname>
              <given-names>K</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effect of rosiglitazone on the risk of myocardial
                  infarction and death from cardiovascular causes</article-title>
          <source>N Engl J Med</source>
          <year>2007</year>
          <volume>356</volume>
          <issue>24</issue>
          <fpage>2457</fpage>
          <lpage>2471</lpage>
        </element-citation>
      </ref>
      <ref id="B137">
        <label>137</label>
        <mixed-citation>137. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C,
               Worrall C, et al. Risk of acute myocardial infarction, stroke, heart failure, and
               death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA.
               2010;304(4):411-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Graham</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Ouellet-Hellstrom</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>MaCurdy</surname>
              <given-names>TE</given-names>
            </name>
            <name>
              <surname>Ali</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Sholley</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Worrall</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Risk of acute myocardial infarction, stroke, heart
                  failure, and death in elderly Medicare patients treated with rosiglitazone or
                  pioglitazone</article-title>
          <source>JAMA</source>
          <year>2010</year>
          <volume>304</volume>
          <issue>4</issue>
          <fpage>411</fpage>
          <lpage>418</lpage>
        </element-citation>
      </ref>
      <ref id="B138">
        <label>138</label>
        <mixed-citation>138. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti
               M, Moules IK, et al. Secondary prevention of macrovascular events in patients with
               type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In
               macroVascular Events): a randomised controlled trial. PROactive investigators.
               Lancet. 2005;366(9493):1279-89.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dormandy</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Charbonnel</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Eckland</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Erdmann</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Massi-Benedetti</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Moules</surname>
              <given-names>IK</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Secondary prevention of macrovascular events in patients
                  with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical
                  Trial In macroVascular Events): a randomised controlled trial</article-title>
          <collab>PROactive investigators</collab>
          <source>Lancet</source>
          <year>2005</year>
          <volume>366</volume>
          <issue>9493</issue>
          <fpage>1279</fpage>
          <lpage>1289</lpage>
        </element-citation>
      </ref>
      <ref id="B139">
        <label>139</label>
        <mixed-citation>139. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk
               of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis
               of randomized trials. JAMA. 2007;298(10):1180-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lincoff</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Wolski</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Nicholls</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Nissen</surname>
              <given-names>SE</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Pioglitazone and risk of cardiovascular events in
                  patients with type 2 diabetes mellitus: a meta-analysis of randomized
                  trials</article-title>
          <source>JAMA</source>
          <year>2007</year>
          <volume>298</volume>
          <issue>10</issue>
          <fpage>1180</fpage>
          <lpage>1188</lpage>
        </element-citation>
      </ref>
      <ref id="B140">
        <label>140</label>
        <mixed-citation>140. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck
               M,et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach:
               position statement of the American Diabetes Association (ADA) and the European
               Association for the Study of Diabetes (EASD). American Diabetes Association (ADA).
               European Association for the Study of Diabetes (EASD). Diabetes Care.
               2012;35(6):1364-79.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Inzucchi</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Bergenstal</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Buse</surname>
              <given-names>JB</given-names>
            </name>
            <name>
              <surname>Diamant</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Ferrannini</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Nauck</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Management of hyperglycemia in type 2 diabetes: a
                  patient-centered approach: position statement of the American Diabetes Association
                  (ADA) and the European Association for the Study of Diabetes
                  (EASD)</article-title>
          <collab>American Diabetes Association (ADA)</collab>
          <collab>European Association for the Study of Diabetes (EASD)</collab>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>6</issue>
          <fpage>1364</fpage>
          <lpage>1379</lpage>
        </element-citation>
      </ref>
      <ref id="B141">
        <label>141</label>
        <mixed-citation>141. Intensive blood-glucose control with sulphonylureas or insulin
               compared with conventional treatment and risk of complications in patients with type
               2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet.
               1998;352(9131):837-53.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Intensive blood-glucose control with sulphonylureas or
                  insulin compared with conventional treatment and risk of complications in patients
                  with type 2 diabetes (UKPDS 33)</article-title>
          <collab>UK Prospective Diabetes Study (UKPDS) Group</collab>
          <source>Lancet</source>
          <year>1998</year>
          <volume>352</volume>
          <issue>9131</issue>
          <fpage>837</fpage>
          <lpage>853</lpage>
        </element-citation>
      </ref>
      <ref id="B142">
        <label>142</label>
        <mixed-citation>142. Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor
               JM,et al. A randomized trial of therapies for type 2 diabetes and coronary artery
               disease. BARI 2D Study Group. N Engl J Med. 2009;360(24):2503-15.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Frye</surname>
              <given-names>RL</given-names>
            </name>
            <name>
              <surname>August</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Brooks</surname>
              <given-names>MM</given-names>
            </name>
            <name>
              <surname>Hardison</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Kelsey</surname>
              <given-names>SF</given-names>
            </name>
            <name>
              <surname>MacGregor</surname>
              <given-names>JM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">A randomized trial of therapies for type 2 diabetes and
                  coronary artery disease</article-title>
          <collab>BARI 2D Study Group</collab>
          <source>N Engl J Med</source>
          <year>2009</year>
          <volume>360</volume>
          <issue>24</issue>
          <fpage>2503</fpage>
          <lpage>2515</lpage>
        </element-citation>
      </ref>
      <ref id="B143">
        <label>143</label>
        <mixed-citation>143. Smith SC, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA,
               et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with
               coronary and other atherosclerotic vascular disease: 2011 update: a guideline from
               the American Heart Association and American College of Cardiology Foundation endorsed
               by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J
               Am Coll Cardiol. 2011;58(25):2432-46.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Smith</surname>
              <given-names>SC</given-names>
            </name>
            <name>
              <surname>Benjamin</surname>
              <given-names>EJ</given-names>
            </name>
            <name>
              <surname>Bonow</surname>
              <given-names>RO</given-names>
            </name>
            <name>
              <surname>Braun</surname>
              <given-names>LT</given-names>
            </name>
            <name>
              <surname>Creager</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Franklin</surname>
              <given-names>BA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">AHA/ACCF secondary prevention and risk reduction therapy
                  for patients with coronary and other atherosclerotic vascular disease: 2011
                  update: a guideline from the American Heart Association and American College of
                  Cardiology Foundation endorsed by the World Heart Federation and the Preventive
                  Cardiovascular Nurses Association</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2011</year>
          <volume>58</volume>
          <issue>25</issue>
          <fpage>2432</fpage>
          <lpage>2446</lpage>
        </element-citation>
      </ref>
      <ref id="B144">
        <label>144</label>
        <mixed-citation>144. Effects of ramipril on cardiovascular and microvascular outcomes in
               people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.
               Heart Outcomes Prevention Evaluation Study Investigators. Lancet.
               2000;355(9200):253-9.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Effects of ramipril on cardiovascular and microvascular
                  outcomes in people with diabetes mellitus: results of the HOPE study and
                  MICRO-HOPE substudy</article-title>
          <collab>Heart Outcomes Prevention Evaluation Study Investigators</collab>
          <source>Lancet</source>
          <year>2000</year>
          <volume>355</volume>
          <issue>9200</issue>
          <fpage>253</fpage>
          <lpage>259</lpage>
        </element-citation>
      </ref>
      <ref id="B145">
        <label>145</label>
        <mixed-citation>145. Sica DA. Cardiovascular morbidity and mortality in patients with
               diabetes in the Losartan Intervention For Endpoint reduction in hypertension study
               (LIFE): a randomised trial against atenolol. Curr Hypertens Rep.
               2002;4(4):321-3.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sica</surname>
              <given-names>DA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Cardiovascular morbidity and mortality in patients with
                  diabetes in the Losartan Intervention For Endpoint reduction in hypertension study
                  (LIFE): a randomised trial against atenolol</article-title>
          <source>Curr Hypertens Rep</source>
          <year>2002</year>
          <volume>4</volume>
          <issue>4</issue>
          <fpage>321</fpage>
          <lpage>323</lpage>
        </element-citation>
      </ref>
      <ref id="B146">
        <label>146</label>
        <mixed-citation>146. Jacobsen P, Rossing K, Parving HH. Single versus dual blockade of
               the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or
               angiotensin II receptor blockers) in diabetic nephropathy. Curr Opin Nephrol
               Hypertens. 2004;13(3):319-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jacobsen</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Rossing</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Parving</surname>
              <given-names>HH</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Single versus dual blockade of the renin-angiotensin
                  system (angiotensin-converting enzyme inhibitors and/or angiotensin II receptor
                  blockers) in diabetic nephropathy</article-title>
          <source>Curr Opin Nephrol Hypertens</source>
          <year>2004</year>
          <volume>13</volume>
          <issue>3</issue>
          <fpage>319</fpage>
          <lpage>324</lpage>
        </element-citation>
      </ref>
      <ref id="B147">
        <label>147</label>
        <mixed-citation>147. Hellemons ME, Persson F, Bakker SJ, Rossing P, Parving HH, De Zeeuw
               D, et al. Initial angiotensin receptor blockade-induced decrease in albuminuria is
               associated with long-term renal outcome in type 2 diabetic patients with
               microalbuminuria: a post hoc analysis of the IRMA-2 trial. Diabetes Care
               2011;34(9):2078-83.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hellemons</surname>
              <given-names>ME</given-names>
            </name>
            <name>
              <surname>Persson</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Bakker</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Rossing</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Parving</surname>
              <given-names>HH</given-names>
            </name>
            <name>
              <surname>De Zeeuw</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Initial angiotensin receptor blockade-induced decrease
                  in albuminuria is associated with long-term renal outcome in type 2 diabetic
                  patients with microalbuminuria: a post hoc analysis of the IRMA-2
                  trial</article-title>
          <source>Diabetes Care</source>
          <year>2011</year>
          <volume>34</volume>
          <issue>9</issue>
          <fpage>2078</fpage>
          <lpage>2083</lpage>
        </element-citation>
      </ref>
      <ref id="B148">
        <label>148</label>
        <mixed-citation>148. Konstam MA, Kronenberg MW, Rousseau MF, Udelson JE, Melin J,
               Stewart D, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on
               the long-term progression of left ventricular dilatation in patients with
               asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction)
               Investigators. Circulation. 1993;88(5 Pt1):2277-83.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Konstam</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Kronenberg</surname>
              <given-names>MW</given-names>
            </name>
            <name>
              <surname>Rousseau</surname>
              <given-names>MF</given-names>
            </name>
            <name>
              <surname>Udelson</surname>
              <given-names>JE</given-names>
            </name>
            <name>
              <surname>Melin</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Stewart</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of the angiotensin converting enzyme inhibitor
                  enalapril on the long-term progression of left ventricular dilatation in patients
                  with asymptomatic systolic dysfunction</article-title>
          <collab>SOLVD (Studies of Left Ventricular Dysfunction) Investigators</collab>
          <source>Circulation</source>
          <year>1993</year>
          <volume>88</volume>
          <issue>5</issue>
          <issue-part>Pt 1</issue-part>
          <fpage>2277</fpage>
          <lpage>2283</lpage>
        </element-citation>
      </ref>
      <ref id="B149">
        <label>149</label>
        <mixed-citation>149. Effect of ramipril on mortality and morbidity of survivors of acute
               myocardial infarction with clinical evidence of heart failure. The Acute Infarction
               Ramipril Efficacy (AIRE) Study Investigators. Lancet.
               1993;342(9200):821-8.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Effect of ramipril on mortality and morbidity of
                  survivors of acute myocardial infarction with clinical evidence of heart failure </article-title>
          <collab>The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators</collab>
          <source>Lancet</source>
          <year>1993</year>
          <volume>342</volume>
          <issue>9200</issue>
          <fpage>821</fpage>
          <lpage>828</lpage>
        </element-citation>
      </ref>
      <ref id="B150">
        <label>150</label>
        <mixed-citation>150. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S.
               Angiotensin-converting-enzyme inhibitors in stable vascular disease without left
               ventricular systolic dysfunction or heart failure: a combined analysis of three
               trials. Lancet. 2006;368(9535):581-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dagenais</surname>
              <given-names>GR</given-names>
            </name>
            <name>
              <surname>Pogue</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Fox</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Simoons</surname>
              <given-names>ML</given-names>
            </name>
            <name>
              <surname>Yusuf</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Angiotensin-converting-enzyme inhibitors in stable
                  vascular disease without left ventricular systolic dysfunction or heart failure: a
                  combined analysis of three trials</article-title>
          <source>Lancet</source>
          <year>2006</year>
          <volume>368</volume>
          <issue>9535</issue>
          <fpage>581</fpage>
          <lpage>588</lpage>
        </element-citation>
      </ref>
      <ref id="B151">
        <label>151</label>
        <mixed-citation>151. Bell DS. Treatment of diabetic hypertension. Diabetes Obes Metab.
               2009;11(5):433-44.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bell</surname>
              <given-names>DS</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Treatment of diabetic hypertension</article-title>
          <source>Diabetes Obes Metab</source>
          <year>2009</year>
          <volume>11</volume>
          <issue>5</issue>
          <fpage>433</fpage>
          <lpage>444</lpage>
        </element-citation>
      </ref>
      <ref id="B152">
        <label>152</label>
        <mixed-citation>152. Haas SJ, Vos T, Gilbert RE, Krum H. Are beta-blockers as
               efficacious in patients with diabetes mellitus as in patients without diabetes
               mellitus who have chronic heart failure? A meta-analysis of large-scale clinical
               trials. Am Heart J. 2003;146(5):848-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Haas</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Vos</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Gilbert</surname>
              <given-names>RE</given-names>
            </name>
            <name>
              <surname>Krum</surname>
              <given-names>H</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Are beta-blockers as efficacious in patients with
                  diabetes mellitus as in patients without diabetes mellitus who have chronic heart
                  failure? A meta-analysis of large-scale clinical trials</article-title>
          <source>Am Heart J</source>
          <year>2003</year>
          <volume>146</volume>
          <issue>5</issue>
          <fpage>848</fpage>
          <lpage>853</lpage>
        </element-citation>
      </ref>
      <ref id="B153">
        <label>153</label>
        <mixed-citation>153. Houghton T, Freemantle N, Cleland JG. Are beta-blockers effective
               in patients who develop heart failure soon after myocardial infarction? A
               meta-regression analysis of randomised trials. Eur J Heart Fail.
               2000;2(3):333-40.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Houghton</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Freemantle</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Cleland</surname>
              <given-names>JG</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Are beta-blockers effective in patients who develop
                  heart failure soon after myocardial infarction? A meta-regression analysis of
                  randomised trials</article-title>
          <source>Eur J Heart Fail</source>
          <year>2000</year>
          <volume>2</volume>
          <issue>3</issue>
          <fpage>333</fpage>
          <lpage>340</lpage>
        </element-citation>
      </ref>
      <ref id="B154">
        <label>154</label>
        <mixed-citation>154. Ryd&#233;n L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et
               al;ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in
               collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and
               cardiovascular diseases of the European Society of Cardiology (ESC) and developed in
               collaboration with the European Association for the Study of Diabetes (EASD). Eur
               Heart J.2007;28(1):98-136.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ryd&#233;n</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Grant</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>Anker</surname>
              <given-names>SD</given-names>
            </name>
            <name>
              <surname>Berne</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Cosentino</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Danchin</surname>
              <given-names>N</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ESC Guidelines on diabetes.pre-diabetes.and
                  cardiovascular diseases developed in collaboration with the EASD: the Task Force
                  on diabetes.pre-diabetes.and cardiovascular diseases of the European Society of
                  Cardiology and developed in collaboration with the European Association for the
                  Study of Diabetes</article-title>
          <source>Eur Heart J</source>
          <year>2007</year>
          <volume>28</volume>
          <issue>1</issue>
          <fpage>98</fpage>
          <lpage>136</lpage>
        </element-citation>
      </ref>
      <ref id="B155">
        <label>155</label>
        <mixed-citation>155. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al.
               Guidelines on myocardial revascularization. Task Force on Myocardial
               Revascularization of the European. Society of Cardiology (ESC) and the European
               Association for Cardio-Thoracic Surgery (EACTS). European Association for
               Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J.
               2010;31(20):2501-55.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wijns</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Kolh</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Danchin</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Di Mario</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Falk</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Folliguet</surname>
              <given-names>T</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Guidelines on myocardial revascularization. Task Force
                  on Myocardial Revascularization of the European. Society of Cardiology (ESC) and
                  the European Association for Cardio-Thoracic Surgery (EACTS)</article-title>
          <collab>European Association for Percutaneous Cardiovascular Interventions
                  (EAPCI)</collab>
          <source>Eur Heart J</source>
          <year>2010</year>
          <volume>31</volume>
          <issue>20</issue>
          <fpage>2501</fpage>
          <lpage>2555</lpage>
        </element-citation>
      </ref>
      <ref id="B156">
        <label>156</label>
        <mixed-citation>156. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG,
               et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of
               the American College of Cardiology Foundation/American Heart Association Task Force
               on Practice Guidelines. Developed in collaboration with the American Association for
               Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of
               Thoracic Surgeons. J Am Coll Cardiol. 2011;58(24):e123-210.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hillis</surname>
              <given-names>LD</given-names>
            </name>
            <name>
              <surname>Smith</surname>
              <given-names>PK</given-names>
            </name>
            <name>
              <surname>Anderson</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Bittl</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Bridges</surname>
              <given-names>CR</given-names>
            </name>
            <name>
              <surname>Byrne</surname>
              <given-names>JG</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft
                  Surgery. A report of the American College of Cardiology Foundation/American Heart
                  Association Task Force on Practice Guidelines. Developed in collaboration with the
                  American Association for Thoracic Surgery, Society of Cardiovascular
                  Anesthesiologists, and Society of Thoracic Surgeons</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2011</year>
          <volume>58</volume>
          <issue>24</issue>
          <fpage>e123</fpage>
          <lpage>e210</lpage>
        </element-citation>
      </ref>
      <ref id="B157">
        <label>157</label>
        <mixed-citation>157. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B,
               et al. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention: a report
               of the American College of Cardiology Foundation/American Heart Association Task
               Force on Practice Guidelines and the Society for Cardiovascular Angiography and
               Interventions. J Am Coll Cardiol. 2011;58(24):e44-122.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Levine</surname>
              <given-names>GN</given-names>
            </name>
            <name>
              <surname>Bates</surname>
              <given-names>ER</given-names>
            </name>
            <name>
              <surname>Blankenship</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Bailey</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Bittl</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Cercek</surname>
              <given-names>B</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2011 ACCF/AHA/SCAI Guideline for percutaneous coronary
                  intervention: a report of the American College of Cardiology Foundation/American
                  Heart Association Task Force on Practice Guidelines and the Society for
                  Cardiovascular Angiography and Interventions</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2011</year>
          <volume>58</volume>
          <issue>24</issue>
          <fpage>e44</fpage>
          <lpage>122</lpage>
        </element-citation>
      </ref>
      <ref id="B158">
        <label>158</label>
        <mixed-citation>158. Myers WO, Blackstone EH, Davis K, Foster ED, Kaiser GC. CASS
               Registry long term surgical survival. Coronary Artery Surgery Study. J Am Coll
               Cardiol. 1999;33(2):488-98.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Myers</surname>
              <given-names>WO</given-names>
            </name>
            <name>
              <surname>Blackstone</surname>
              <given-names>EH</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Foster</surname>
              <given-names>ED</given-names>
            </name>
            <name>
              <surname>Kaiser</surname>
              <given-names>GC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">CASS Registry long term surgical survival. Coronary
                  Artery Surgery Study</article-title>
          <source>J Am Coll Cardiol</source>
          <year>1999</year>
          <volume>33</volume>
          <issue>2</issue>
          <fpage>488</fpage>
          <lpage>498</lpage>
        </element-citation>
      </ref>
      <ref id="B159">
        <label>159</label>
        <mixed-citation>159. Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S,
               et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary
               artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting
               stents. J Am Coll Cardiol. 2010;55(11):1067-75.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Banning</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Westaby</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Morice</surname>
              <given-names>MC</given-names>
            </name>
            <name>
              <surname>Kappetein</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Mohr</surname>
              <given-names>FW</given-names>
            </name>
            <name>
              <surname>Berti</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diabetic and nondiabetic patients with left main and/or
                  3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and
                  paclitaxel-eluting stents</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>55</volume>
          <issue>11</issue>
          <fpage>1067</fpage>
          <lpage>1075</lpage>
        </element-citation>
      </ref>
      <ref id="B160">
        <label>160</label>
        <mixed-citation>160. Comparison of coronary bypass surgery with angioplasty in patients
               with multivessel disease. The Bypass Angioplasty Revascularization Investigation
               (BARI) Investigators. N Engl J Med. 1996;335(4):217-25.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Comparison of coronary bypass surgery with angioplasty
                  in patients with multivessel disease</article-title>
          <collab>The Bypass Angioplasty Revascularization Investigation (BARI)
                  Investigators</collab>
          <source>N Engl J Med</source>
          <year>1996</year>
          <volume>335</volume>
          <issue>4</issue>
          <fpage>217</fpage>
          <lpage>225</lpage>
        </element-citation>
      </ref>
      <ref id="B161">
        <label>161</label>
        <mixed-citation>161. Soares PR, Hueb WA, Lemos PA, Lopes N, Martinez EE, Cesar LA, et
               al. Coronary revascularization (surgical or percutaneous) decreases mortality after
               the first year in diabetic subjects but not in nondiabetic subjects with multivessel
               disease: an analysis from the Medicine, Angioplasty, or Surgery Study (MASS II).
               Circulation. 2006;114(1 Suppl):I420-4.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Soares</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Hueb</surname>
              <given-names>WA</given-names>
            </name>
            <name>
              <surname>Lemos</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Lopes</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Martinez</surname>
              <given-names>EE</given-names>
            </name>
            <name>
              <surname>Cesar</surname>
              <given-names>LA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary revascularization (surgical or percutaneous)
                  decreases mortality after the first year in diabetic subjects but not in
                  nondiabetic subjects with multivessel disease: an analysis from the Medicine,
                  Angioplasty, or Surgery Study (MASS II)</article-title>
          <source>Circulation</source>
          <year>2006</year>
          <volume>114</volume>
          <issue>1</issue>
          <supplement>Suppl</supplement>
          <fpage>I420</fpage>
          <lpage>I424</lpage>
        </element-citation>
      </ref>
      <ref id="B162">
        <label>162</label>
        <mixed-citation>162. Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM,
               et al. Coronary artery bypass surgery compared with percutaneous coronary
               interventions for multivessel disease: a collaborative analysis of individual patient
               data from ten randomised trials. Lancet. 2009;373(9670):1190-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hlatky</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Boothroyd</surname>
              <given-names>DB</given-names>
            </name>
            <name>
              <surname>Bravata</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Boersma</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Booth</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Brooks</surname>
              <given-names>MM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Coronary artery bypass surgery compared with
                  percutaneous coronary interventions for multivessel disease: a collaborative
                  analysis of individual patient data from ten randomised trials</article-title>
          <source>Lancet</source>
          <year>2009</year>
          <volume>373</volume>
          <issue>9670</issue>
          <fpage>1190</fpage>
          <lpage>1197</lpage>
        </element-citation>
      </ref>
      <ref id="B163">
        <label>163</label>
        <mixed-citation>163. Stettler C, Allemann S, Wandel S, Kastrati A, Morice MC, Sch&#246;mig A,
               et al. Drug eluting and bare metal stents in people with and without diabetes:
               collaborative network meta-analysis. BMJ. 2008;337:a1331.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Stettler</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Allemann</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Wandel</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Kastrati</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Morice</surname>
              <given-names>MC</given-names>
            </name>
            <name>
              <surname>Sch&#246;mig</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Drug eluting and bare metal stents in people with and
                  without diabetes: collaborative network meta-analysis</article-title>
          <source>BMJ</source>
          <year>2008</year>
          <volume>337</volume>
          <fpage>a1331</fpage>
          <lpage>a1331</lpage>
        </element-citation>
      </ref>
      <ref id="B164">
        <label>164</label>
        <mixed-citation>164. Kapur A, Hall RJ, Malik IS, Qureshi AC, Butts J, de Belder M, et
               al. Randomized comparison of percutaneous coronary intervention with coronary artery
               bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery
               Revascularization in Diabetes) trial. J Am Coll Cardiol.
               2010;55(5):432-40.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kapur</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Hall</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Malik</surname>
              <given-names>IS</given-names>
            </name>
            <name>
              <surname>Qureshi</surname>
              <given-names>AC</given-names>
            </name>
            <name>
              <surname>Butts</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>de Belder</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Randomized comparison of percutaneous coronary
                  intervention with coronary artery bypass grafting in diabetic patients. 1-year
                  results of the CARDia (Coronary Artery Revascularization in Diabetes)
                  trial</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>55</volume>
          <issue>5</issue>
          <fpage>432</fpage>
          <lpage>440</lpage>
        </element-citation>
      </ref>
      <ref id="B165">
        <label>165</label>
        <mixed-citation>165. Onuma Y, Wykrzykowska JJ, Garg S, Vranckx P, Serruys PW. 5-Year
               follow-up of coronary revascularization in diabetic patients with multivessel
               coronary artery disease: insights from ARTS (arterial revascularization therapy
               study)-II and ARTS-I trials. ARTS I and II Investigators. JACC Cardiovasc Interv.
               2011;4(3):317-23.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Onuma</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Wykrzykowska</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Garg</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Vranckx</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Serruys</surname>
              <given-names>PW</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">5-Year follow-up of coronary revascularization in
                  diabetic patients with multivessel coronary artery disease: insights from ARTS
                  (arterial revascularization therapy study)-II and ARTS-I trials. ARTS I and II
                  Investigators</article-title>
          <source>JACC Cardiovasc Interv</source>
          <year>2011</year>
          <volume>4</volume>
          <issue>3</issue>
          <fpage>317</fpage>
          <lpage>323</lpage>
        </element-citation>
      </ref>
      <ref id="B166">
        <label>166</label>
        <mixed-citation>166. Kappetein AP, Head SJ, Morice MC, Banning AP, Serruys PW, Mohr FW,
               et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year
               results comparing outcomes of bypass surgery and percutaneous coronary intervention
               in the SYNTAX trial. SYNTAX Investigators. Eur J Cardiothorac Surg.
               2013;43(5):1006-13.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kappetein</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Head</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Morice</surname>
              <given-names>MC</given-names>
            </name>
            <name>
              <surname>Banning</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Serruys</surname>
              <given-names>PW</given-names>
            </name>
            <name>
              <surname>Mohr</surname>
              <given-names>FW</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Treatment of complex coronary artery disease in patients
                  with diabetes: 5-year results comparing outcomes of bypass surgery and
                  percutaneous coronary intervention in the SYNTAX trial</article-title>
          <collab>SYNTAX Investigators</collab>
          <source>Eur J Cardiothorac Surg</source>
          <year>2013</year>
          <volume>43</volume>
          <issue>5</issue>
          <fpage>1006</fpage>
          <lpage>1013</lpage>
        </element-citation>
      </ref>
      <ref id="B167">
        <label>167</label>
        <mixed-citation>167. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et
               al. Strategies for multivessel revascularization in patients with diabetes. FREEDOM
               Trial Investigators. N Engl J Med. 2012;367(25):2375-84.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Farkouh</surname>
              <given-names>ME</given-names>
            </name>
            <name>
              <surname>Domanski</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sleeper</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Siami</surname>
              <given-names>FS</given-names>
            </name>
            <name>
              <surname>Dangas</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Mack</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Strategies for multivessel revascularization in patients
                  with diabetes</article-title>
          <collab>FREEDOM Trial Investigators</collab>
          <source>N Engl J Med</source>
          <year>2012</year>
          <volume>367</volume>
          <issue>25</issue>
          <fpage>2375</fpage>
          <lpage>2384</lpage>
        </element-citation>
      </ref>
      <ref id="B168">
        <label>168</label>
        <mixed-citation>168. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon
               CP, et al. Diabetes and mortality following acute coronary syndromes. JAMA.
               2007;298(7):765-75.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Donahoe</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Stewart</surname>
              <given-names>GC</given-names>
            </name>
            <name>
              <surname>McCabe</surname>
              <given-names>CH</given-names>
            </name>
            <name>
              <surname>Mohanavelu</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Murphy</surname>
              <given-names>SA</given-names>
            </name>
            <name>
              <surname>Cannon</surname>
              <given-names>CP</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diabetes and mortality following acute coronary
                  syndromes</article-title>
          <source>JAMA</source>
          <year>2007</year>
          <volume>298</volume>
          <issue>7</issue>
          <fpage>765</fpage>
          <lpage>775</lpage>
        </element-citation>
      </ref>
      <ref id="B169">
        <label>169</label>
        <mixed-citation>169. Amin AP, Marso SP. Acute coronary syndrome in the patient with
               diabetes: is the management different? Curr Cardiol Rep.
               2010;12(4):321-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Amin</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Marso</surname>
              <given-names>SP</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Acute coronary syndrome in the patient with diabetes: is
                  the management different?</article-title>
          <source>Curr Cardiol Rep</source>
          <year>2010</year>
          <volume>12</volume>
          <issue>4</issue>
          <fpage>321</fpage>
          <lpage>329</lpage>
        </element-citation>
      </ref>
      <ref id="B170">
        <label>170</label>
        <mixed-citation>170. Canto JG, Fincher C, Kiefe CI, Allison JJ, Li Q, Funkhouser E, et
               al. Atypical presentations among Medicare beneficiaries with unstable angina
               pectoris. Am J Cardiol. 2002;90(3):248-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Canto</surname>
              <given-names>JG</given-names>
            </name>
            <name>
              <surname>Fincher</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Kiefe</surname>
              <given-names>CI</given-names>
            </name>
            <name>
              <surname>Allison</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>Q</given-names>
            </name>
            <name>
              <surname>Funkhouser</surname>
              <given-names>E</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Atypical presentations among Medicare beneficiaries with
                  unstable angina pectoris</article-title>
          <source>Am J Cardiol</source>
          <year>2002</year>
          <volume>90</volume>
          <issue>3</issue>
          <fpage>248</fpage>
          <lpage>253</lpage>
        </element-citation>
      </ref>
      <ref id="B171">
        <label>171</label>
        <mixed-citation>171. Culic V, Eterovic D, Miric D, Silic N. Symptom presentation of
               acute myocardial infarction: influence of sex, age, and risk factors. Am Heart J.
               2002;144(6):1012-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Culic</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Eterovic</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Miric</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Silic</surname>
              <given-names>N</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Symptom presentation of acute myocardial infarction:
                  influence of sex, age, and risk factors</article-title>
          <source>Am Heart J</source>
          <year>2002</year>
          <volume>144</volume>
          <issue>6</issue>
          <fpage>1012</fpage>
          <lpage>1017</lpage>
        </element-citation>
      </ref>
      <ref id="B172">
        <label>172</label>
        <mixed-citation>172. Brieger D, Eagle KA, Goodman SG, Steg PG, Budaj A, White K, et al.
               Acute coronary syndromes without chest pain, an underdiagnosed and undertreated
               high-risk group: insights from the Global Registry of Acute Coronary Events. GRACE
               Investigators. Chest. 2004;126(2):461-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Brieger</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Eagle</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Goodman</surname>
              <given-names>SG</given-names>
            </name>
            <name>
              <surname>Steg</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Budaj</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>K</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Acute coronary syndromes without chest pain, an
                  underdiagnosed and undertreated high-risk group: insights from the Global Registry
                  of Acute Coronary Events</article-title>
          <collab>GRACE Investigators</collab>
          <source>Chest</source>
          <year>2004</year>
          <volume>126</volume>
          <issue>2</issue>
          <fpage>461</fpage>
          <lpage>469</lpage>
        </element-citation>
      </ref>
      <ref id="B173">
        <label>173</label>
        <mixed-citation>173. Nicolau J, Timerman A, Piegas L, Marin-Neto J, Rassi Junior A;
               Sociedade Brasileira de Cardiologia. [Guidelines for unstable angina and
               non-ST-segment elevation myocardial infarction of the Brazilian Society of Cardiology
               (II Edition,2007)]. Arq Bras Cardiol. 2007;89(4):e89-131.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nicolau</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Timerman</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Piegas</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Marin-Neto</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Rassi</surname>
              <given-names>A</given-names>
              <suffix>Junior</suffix>
            </name>
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <article-title xml:lang="en">Guidelines for unstable angina and non-ST-segment
                  elevation myocardial infarction of the Brazilian Society of
                  Cardiology</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2007</year>
          <volume>89</volume>
          <issue>4</issue>
          <fpage>e89</fpage>
          <lpage>131</lpage>
        </element-citation>
      </ref>
      <ref id="B174">
        <label>174</label>
        <mixed-citation>174. Diercks DB, Peacock WF, Hiestand BC, Chen AY, Pollack CV, Kirk JD,
               et al. Frequency and consequences of recording an electrocardiogram &gt;10 minutes after
               arrival in an emergency room in non-ST-segment elevation acute coronary syndromes
               (from the CRUSADE Initiative). Am J Cardiol. 2006;97(4):437-42.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Diercks</surname>
              <given-names>DB</given-names>
            </name>
            <name>
              <surname>Peacock</surname>
              <given-names>WF</given-names>
            </name>
            <name>
              <surname>Hiestand</surname>
              <given-names>BC</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>AY</given-names>
            </name>
            <name>
              <surname>Pollack</surname>
              <given-names>CV</given-names>
            </name>
            <name>
              <surname>Kirk</surname>
              <given-names>JD</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Frequency and consequences of recording an
                  electrocardiogram &gt;10 minutes after arrival in an emergency room in
                  non-ST-segment elevation acute coronary syndromes (from the CRUSADE
                  Initiative)</article-title>
          <source>Am J Cardiol</source>
          <year>2006</year>
          <volume>97</volume>
          <issue>4</issue>
          <fpage>437</fpage>
          <lpage>442</lpage>
        </element-citation>
      </ref>
      <ref id="B175">
        <label>175</label>
        <mixed-citation>175. Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, et
               al. Universal definition of myocardial infarction. Joint ESC/ACCF/AHA/WHF Task Force
               for the Redefinition of Myocardial Infarction. Circulation.
               2007;116(22):2634-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Thygesen</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Alpert</surname>
              <given-names>JS</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>HD</given-names>
            </name>
            <name>
              <surname>Jaffe</surname>
              <given-names>AS</given-names>
            </name>
            <name>
              <surname>Apple</surname>
              <given-names>FS</given-names>
            </name>
            <name>
              <surname>Galvani</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Universal definition of myocardial infarction. Joint
                  ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial
                  Infarction</article-title>
          <source>Circulation</source>
          <year>2007</year>
          <volume>116</volume>
          <issue>22</issue>
          <fpage>2634</fpage>
          <lpage>2653</lpage>
        </element-citation>
      </ref>
      <ref id="B176">
        <label>176</label>
        <mixed-citation>176. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al.
               ESC Guidelines for the management of acute coronary syndromes in patients presenting
               without persistent ST-segment elevation: The Task Force for the management of acute
               coronary syndromes (ACS) in patients presenting without persistent ST-segment
               elevation of the European Society of Cardiology (ESC). ESC Committee for Practice
               Guidelines. Eur Heart J. 2011;32(23):2999-3054.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hamm</surname>
              <given-names>CW</given-names>
            </name>
            <name>
              <surname>Bassand</surname>
              <given-names>JP</given-names>
            </name>
            <name>
              <surname>Agewall</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Bax</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Boersma</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Bueno</surname>
              <given-names>H</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ESC Guidelines for the management of acute coronary
                  syndromes in patients presenting without persistent ST-segment elevation: The Task
                  Force for the management of acute coronary syndromes (ACS) in patients presenting
                  without persistent ST-segment elevation of the European Society of Cardiology
                  (ESC)</article-title>
          <collab>ESC Committee for Practice Guidelines</collab>
          <source>Eur Heart J</source>
          <year>2011</year>
          <volume>32</volume>
          <issue>23</issue>
          <fpage>2999</fpage>
          <lpage>3054</lpage>
        </element-citation>
      </ref>
      <ref id="B177">
        <label>177</label>
        <mixed-citation>177. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS,
               et al. A prospective natural-history study of coronary atherosclerosis. PROSPECT
               Investigators. N Engl J Med. 2011;364(3):226-35.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Stone</surname>
              <given-names>GW</given-names>
            </name>
            <name>
              <surname>Maehara</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Lansky</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>de Bruyne</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Cristea</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Mintz</surname>
              <given-names>GS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">A prospective natural-history study of coronary
                  atherosclerosis</article-title>
          <collab>PROSPECT Investigators</collab>
          <source>N Engl J Med</source>
          <year>2011</year>
          <volume>364</volume>
          <issue>3</issue>
          <fpage>226</fpage>
          <lpage>235</lpage>
        </element-citation>
      </ref>
      <ref id="B178">
        <label>178</label>
        <mixed-citation>178. Lev EI, Battler A, Behar S, Porter A, Haim M, Boyko V, et al.
               Frequency, characteristics, and outcome of patients hospitalized with acute coronary
               syndromes with undetermined electrocardiographic patterns. Am J Cardiol.
               2003;91(2):224-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lev</surname>
              <given-names>EI</given-names>
            </name>
            <name>
              <surname>Battler</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Behar</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Porter</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Haim</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Boyko</surname>
              <given-names>V</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Frequency, characteristics, and outcome of patients
                  hospitalized with acute coronary syndromes with undetermined electrocardiographic
                  patterns</article-title>
          <source>Am J Cardiol</source>
          <year>2003</year>
          <volume>91</volume>
          <issue>2</issue>
          <fpage>224</fpage>
          <lpage>227</lpage>
        </element-citation>
      </ref>
      <ref id="B179">
        <label>179</label>
        <mixed-citation>179. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, et
               al. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute
               coronary syndromes. Circulation. 2004;109(4):465-70.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Okamatsu</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Takano</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sakai</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Ishibashi</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Uemura</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Takano</surname>
              <given-names>T</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Elevated troponin T levels and lesion characteristics in
                  non-ST-elevation acute coronary syndromes</article-title>
          <source>Circulation</source>
          <year>2004</year>
          <volume>109</volume>
          <issue>4</issue>
          <fpage>465</fpage>
          <lpage>470</lpage>
        </element-citation>
      </ref>
      <ref id="B180">
        <label>180</label>
        <mixed-citation>180. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, et al.
               Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl
               J Med. 2009;361(9):868-77.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Keller</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Zeller</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Peetz</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Tzikas</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Roth</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Czyz</surname>
              <given-names>E</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Sensitive troponin I assay in early diagnosis of acute
                  myocardial infarction</article-title>
          <source>N Engl J Med</source>
          <year>2009</year>
          <volume>361</volume>
          <issue>9</issue>
          <fpage>868</fpage>
          <lpage>877</lpage>
        </element-citation>
      </ref>
      <ref id="B181">
        <label>181</label>
        <mixed-citation>181. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C,
               Hartwiger S,et al. Early diagnosis of myocardial infarction with sensitive cardiac
               troponin assays. N Engl J Med. 2009;361(9):858-67.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Reichlin</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Hochholzer</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Bassetti</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Steuer</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Stelzig</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Hartwiger</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Early diagnosis of myocardial infarction with sensitive
                  cardiac troponin assays</article-title>
          <source>N Engl J Med</source>
          <year>2009</year>
          <volume>361</volume>
          <issue>9</issue>
          <fpage>858</fpage>
          <lpage>867</lpage>
        </element-citation>
      </ref>
      <ref id="B182">
        <label>182</label>
        <mixed-citation>182. Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, et
               al. Recommendations for the use of cardiac troponin measurement in acute cardiac
               care. Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute
               Cardiac Care. Eur Heart J. 2010;31(18):2197-204.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Thygesen</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Mair</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Katus</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Plebani</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Venge</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Collinson</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Recommendations for the use of cardiac troponin
                  measurement in acute cardiac care</article-title>
          <collab>Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute
                  Cardiac Care</collab>
          <source>Eur Heart J</source>
          <year>2010</year>
          <volume>31</volume>
          <issue>18</issue>
          <fpage>2197</fpage>
          <lpage>2204</lpage>
        </element-citation>
      </ref>
      <ref id="B183">
        <label>183</label>
        <mixed-citation>183. Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of
               cardiac troponin I and T for subsequent death in end-stage renal disease.
               Circulation. 2002;106(23):2941-5.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Apple</surname>
              <given-names>FS</given-names>
            </name>
            <name>
              <surname>Murakami</surname>
              <given-names>MM</given-names>
            </name>
            <name>
              <surname>Pearce</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Herzog</surname>
              <given-names>CA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Predictive value of cardiac troponin I and T for
                  subsequent death in end-stage renal disease</article-title>
          <source>Circulation</source>
          <year>2002</year>
          <volume>106</volume>
          <issue>23</issue>
          <fpage>2941</fpage>
          <lpage>2945</lpage>
        </element-citation>
      </ref>
      <ref id="B184">
        <label>184</label>
        <mixed-citation>184. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T.
               Emergency room triage of patients with acute chest pain by means of rapid testing for
               cardiac troponin T or troponin I. N Engl J Med.
               1997;337(23):1648-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hamm</surname>
              <given-names>CW</given-names>
            </name>
            <name>
              <surname>Goldmann</surname>
              <given-names>BU</given-names>
            </name>
            <name>
              <surname>Heeschen</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Kreymann</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Berger</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Meinertz</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Emergency room triage of patients with acute chest pain
                  by means of rapid testing for cardiac troponin T or troponin I</article-title>
          <source>N Engl J Med</source>
          <year>1997</year>
          <volume>337</volume>
          <issue>23</issue>
          <fpage>1648</fpage>
          <lpage>1653</lpage>
        </element-citation>
      </ref>
      <ref id="B185">
        <label>185</label>
        <mixed-citation>185. Aviles RJ, Askari AT, Lindahl B, Wallentin L, Jia G, Ohman EM, et
               al. Troponin T levels in patients with acute coronary syndromes, with or without
               renal dysfunction. N Engl J Med. 2002;346(26):2047-52.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Aviles</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Askari</surname>
              <given-names>AT</given-names>
            </name>
            <name>
              <surname>Lindahl</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Wallentin</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Jia</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Ohman</surname>
              <given-names>EM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Troponin T levels in patients with acute coronary
                  syndromes, with or without renal dysfunction</article-title>
          <source>N Engl J Med</source>
          <year>2002</year>
          <volume>346</volume>
          <issue>26</issue>
          <fpage>2047</fpage>
          <lpage>2052</lpage>
        </element-citation>
      </ref>
      <ref id="B186">
        <label>186</label>
        <mixed-citation>186. Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos
               JA, et al. TIMI risk score for ST-elevation myocardial infarction: A convenient,
               bedside, clinical score for risk assessment at presentation: An intravenous nPA for
               treatment of infarcting myocardium early II trial substudy. Circulation.
               2000;102(17):2031-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Morrow</surname>
              <given-names>DA</given-names>
            </name>
            <name>
              <surname>Antman</surname>
              <given-names>EM</given-names>
            </name>
            <name>
              <surname>Charlesworth</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Cairns</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Murphy</surname>
              <given-names>SA</given-names>
            </name>
            <name>
              <surname>de Lemos</surname>
              <given-names>JA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">TIMI risk score for ST-elevation myocardial infarction.
                  A convenient, bedside, clinical score for risk assessment at presentation: An
                  intravenous nPA for treatment of infarcting myocardium early II trial
                  substudy</article-title>
          <source>Circulation</source>
          <year>2000</year>
          <volume>102</volume>
          <issue>17</issue>
          <fpage>2031</fpage>
          <lpage>2037</lpage>
        </element-citation>
      </ref>
      <ref id="B187">
        <label>187</label>
        <mixed-citation>187. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G,
               et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for
               prognostication and therapeutic decision making. JAMA.
               2000;284(7):835-42.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Antman</surname>
              <given-names>EM</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Bernink</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>McCabe</surname>
              <given-names>CH</given-names>
            </name>
            <name>
              <surname>Horacek</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Papuchis</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">The TIMI risk score for unstable angina/non-ST elevation
                  MI: A method for prognostication and therapeutic decision making</article-title>
          <source>JAMA</source>
          <year>2000</year>
          <volume>284</volume>
          <issue>7</issue>
          <fpage>835</fpage>
          <lpage>842</lpage>
        </element-citation>
      </ref>
      <ref id="B188">
        <label>188</label>
        <mixed-citation>188. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf
               F, et al. Prediction of risk of death and myocardial infarction in the six months
               after presentation with acute coronary syndrome: prospective multinational
               observational study (GRACE). BMJ. 2006;333(7578):1091.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fox</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Dabbous</surname>
              <given-names>OH</given-names>
            </name>
            <name>
              <surname>Goldberg</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Pieper</surname>
              <given-names>KS</given-names>
            </name>
            <name>
              <surname>Eagle</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Van de Werf</surname>
              <given-names>F</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prediction of risk of death and myocardial infarction in
                  the six months after presentation with acute coronary syndrome: prospective
                  multinational observational study (GRACE)</article-title>
          <source>BMJ</source>
          <year>2006</year>
          <volume>333</volume>
          <issue>7578</issue>
          <fpage>1091</fpage>
          <lpage>1091</lpage>
        </element-citation>
      </ref>
      <ref id="B189">
        <label>189</label>
        <mixed-citation>189. Dotevall A, Hasdai D, Wallentin L, Battler A, Rosengren A. Diabetes
               mellitus: clinical presentation and outcome in men and women with acute coronary
               syndromes. Data from the Euro Heart Survey ACS. Diabet Med.
               2005;22(11):1542-50.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dotevall</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Hasdai</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Wallentin</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Battler</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Rosengren</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetes mellitus: clinical presentation and outcome in
                  men and women with acute coronary syndromes</article-title>
          <collab>Data from the Euro Heart Survey ACS</collab>
          <source>Diabet Med</source>
          <year>2005</year>
          <volume>22</volume>
          <issue>11</issue>
          <fpage>1542</fpage>
          <lpage>1550</lpage>
        </element-citation>
      </ref>
      <ref id="B190">
        <label>190</label>
        <mixed-citation>190. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE, et
               al. 2012 ACCF/AHA focused update of the guideline for the management of patients with
               unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline
               and replacing the 2011 focused update): a report of the American College of
               Cardiology Foundation/American Heart Association Task Force on practice guidelines.
               Circulation. 2012;126(7):875-910.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Jneid</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Anderson</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Wright</surname>
              <given-names>RS</given-names>
            </name>
            <name>
              <surname>Adams</surname>
              <given-names>CD</given-names>
            </name>
            <name>
              <surname>Bridges</surname>
              <given-names>CR</given-names>
            </name>
            <name>
              <surname>Casey</surname>
              <given-names>DE</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2012 ACCF/AHA focused update of the guideline for the
                  management of patients with unstable angina/Non-ST-elevation myocardial infarction
                  (updating the 2007 guideline and replacing the 2011 focused update): a report of
                  the American College of Cardiology Foundation/American Heart Association Task
                  Force on practice guidelines</article-title>
          <source>Circulation</source>
          <year>2012</year>
          <volume>126</volume>
          <issue>7</issue>
          <fpage>875</fpage>
          <lpage>910</lpage>
        </element-citation>
      </ref>
      <ref id="B191">
        <label>191</label>
        <mixed-citation>191. National Research Council. Clinical practice guidelines we can
               trust. Washington,DC: The National Academic Press;2011.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>National Research Council</collab>
          </person-group>
          <source xml:lang="en">Clinical practice guidelines we can trust</source>
          <publisher-loc>Washington,DC</publisher-loc>
          <publisher-name>The National Academic Press</publisher-name>
          <year>2011</year>
        </element-citation>
      </ref>
      <ref id="B192">
        <label>192</label>
        <mixed-citation>192. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE,
               et al. ACC/AHA 2007 guidelines for the management of patients with unstable
               angina/non ST-elevation myocardial infarction: a report of the American College of
               Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
               Committee to Revise the 2002 Guidelines for the management of patients with unstable
               angina/non ST-elevation myocardial infarction): developed in collaboration with the
               American College of Emergency Physicians, the Society for Cardiovascular Angiography
               and Interventions, and the Society of Thoracic Surgeons: endorsed by the American
               Association of Cardiovascular and Pulmonary Rehabilitation and the Society for
               Academic Emergency Medicine. Circulation. 2007;116(7):e148-304.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Anderson</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Adams</surname>
              <given-names>CD</given-names>
            </name>
            <name>
              <surname>Antman</surname>
              <given-names>EM</given-names>
            </name>
            <name>
              <surname>Bridges</surname>
              <given-names>CR</given-names>
            </name>
            <name>
              <surname>Califf</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Casey</surname>
              <given-names>DE</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ACC/AHA 2007 guidelines for the management of patients
                  with unstable angina/non ST-elevation myocardial infarction: a report of the
                  American College of Cardiology/American Heart Association Task Force on Practice
                  Guidelines (Writing Committee to Revise the 2002 Guidelines for the management of
                  patients with unstable angina/non ST-elevation myocardial infarction): developed
                  in collaboration with the American College of Emergency Physicians, the Society
                  for Cardiovascular Angiography and Interventions, and the Society of Thoracic
                  Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary
                  Rehabilitation and the Society for Academic Emergency Medicine</article-title>
          <source>Circulation</source>
          <year>2007</year>
          <volume>116</volume>
          <issue>7</issue>
          <fpage>e148</fpage>
          <lpage>e304</lpage>
        </element-citation>
      </ref>
      <ref id="B193">
        <label>193</label>
        <mixed-citation>193. Invasive compared with non-invasive treatment in unstable
               coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin
               and Fast Revascularisation during InStability in Coronary artery disease
               Investigators. Lancet. 1999;354(9180):708-15.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Invasive compared with non-invasive treatment in
                  unstable coronary-artery disease: FRISC II prospective randomised multicentre
                  study</article-title>
          <collab>FRagmin and Fast Revascularisation during InStability in Coronary artery
                  disease Investigators</collab>
          <source>Lancet</source>
          <year>1999</year>
          <volume>354</volume>
          <issue>9180</issue>
          <fpage>708</fpage>
          <lpage>715</lpage>
        </element-citation>
      </ref>
      <ref id="B194">
        <label>194</label>
        <mixed-citation>194. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein
               H, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous
               coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized
               trial. Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for
               Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. JAMA.
               2006;295(13):1531-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kastrati</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Mehilli</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Neumann</surname>
              <given-names>FJ</given-names>
            </name>
            <name>
              <surname>Dotzer</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>ten Berg</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Bollwein</surname>
              <given-names>H</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Abciximab in patients with acute coronary syndromes
                  undergoing percutaneous coronary intervention after clopidogrel pretreatment: the
                  ISAR-REACT 2 randomized trial. Intracoronary Stenting and Antithrombotic: Regimen
                  Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial
                  Investigators</article-title>
          <source>JAMA</source>
          <year>2006</year>
          <volume>295</volume>
          <issue>13</issue>
          <fpage>1531</fpage>
          <lpage>1538</lpage>
        </element-citation>
      </ref>
      <ref id="B195">
        <label>195</label>
        <mixed-citation>195. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E.
               Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable
               coronary-artery disease: the FRISC II invasive randomised trial. FRISC II
               Investigators. Fast Revascularisation during Instability in Coronary artery disease.
               Lancet. 2000;356(9223):9-16.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wallentin</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Lagerqvist</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Husted</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Kontny</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Stahle</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Swahn</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Outcome at 1 year after an invasive compared with a
                  non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive
                  randomised trial. FRISC II Investigators. Fast Revascularisation during
                  Instability in Coronary artery disease</article-title>
          <source>Lancet</source>
          <year>2000</year>
          <volume>356</volume>
          <issue>9223</issue>
          <fpage>9</fpage>
          <lpage>16</lpage>
        </element-citation>
      </ref>
      <ref id="B196">
        <label>196</label>
        <mixed-citation>196. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis
               N, et al. Comparison of early invasive and conservative strategies in patients with
               unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor
               tirofiban. TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an
               Invasive or Conservative Strategy)--Thrombolysis in Myocardial Infarction 18
               Investigators. N Engl J Med. 2001;344(25):1879-87.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cannon</surname>
              <given-names>CP</given-names>
            </name>
            <name>
              <surname>Weintraub</surname>
              <given-names>WS</given-names>
            </name>
            <name>
              <surname>Demopoulos</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Vicari</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Frey</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Lakkis</surname>
              <given-names>N</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Comparison of early invasive and conservative strategies
                  in patients with unstable coronary syndromes treated with the glycoprotein
                  IIb/IIIa inhibitor tirofiban. TACTICS (Treat Angina with Aggrastat and Determine
                  Cost of Therapy with an Invasive or Conservative Strategy)--Thrombolysis in
                  Myocardial Infarction 18 Investigators</article-title>
          <source>N Engl J Med</source>
          <year>2001</year>
          <volume>344</volume>
          <issue>25</issue>
          <fpage>1879</fpage>
          <lpage>1887</lpage>
        </element-citation>
      </ref>
      <ref id="B197">
        <label>197</label>
        <mixed-citation>197. Hasin T, Hochadel M, Gitt AK, Behar S, Bueno H, Hasin Y. Comparison
               of treatment and outcome of acute coronary syndrome in patients with versus patients
               without diabetes mellitus. Am J Cardiol. 2009;103(6):772-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hasin</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Hochadel</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Gitt</surname>
              <given-names>AK</given-names>
            </name>
            <name>
              <surname>Behar</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Bueno</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Hasin</surname>
              <given-names>Y</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Comparison of treatment and outcome of acute coronary
                  syndrome in patients with versus patients without diabetes
                  mellitus</article-title>
          <source>Am J Cardiol</source>
          <year>2009</year>
          <volume>103</volume>
          <issue>6</issue>
          <fpage>772</fpage>
          <lpage>778</lpage>
        </element-citation>
      </ref>
      <ref id="B198">
        <label>198</label>
        <mixed-citation>198. De Luca G, Gibson CM, Bellandi F, Noc M, Dudek D, Zeymer U, et al.
               Diabetes mellitus is associated with distal embolization, impaired myocardial
               perfusion, and higher mortality in patients with ST-segment elevation myocardial
               infarction treated with primary angioplasty and glycoprotein IIb-IIIa inhibitors.
               Atherosclerosis. 2009;207(1):181-5.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>De Luca</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Gibson</surname>
              <given-names>CM</given-names>
            </name>
            <name>
              <surname>Bellandi</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Noc</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Dudek</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Zeymer</surname>
              <given-names>U</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diabetes mellitus is associated with distal
                  embolization, impaired myocardial perfusion, and higher mortality in patients with
                  ST-segment elevation myocardial infarction treated with primary angioplasty and
                  glycoprotein IIb-IIIa inhibitors</article-title>
          <source>Atherosclerosis</source>
          <year>2009</year>
          <volume>207</volume>
          <issue>1</issue>
          <fpage>181</fpage>
          <lpage>185</lpage>
        </element-citation>
      </ref>
      <ref id="B199">
        <label>199</label>
        <mixed-citation>199. Piegas L, Feitosa G, Mattos L, Nicolau J, Rossi Neto J, Timerman A;
               Sociedade Brasileira de Cardiologia. [IV Guidelines of Sociedade Brasileira de
               Cardiologia for treatment of acute myocardial infarction with ST-segment elevation].
               Arq Bras Cardiol. 2009;93(6 Suppl 2):e179-264.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Piegas</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Feitosa</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Mattos</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Nicolau</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Rossi</surname>
              <given-names>J</given-names>
              <suffix>Neto</suffix>
            </name>
            <name>
              <surname>Timerman</surname>
              <given-names>A</given-names>
            </name>
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <trans-title xml:lang="en">IV Guidelines of Sociedade Brasileira de Cardiologia for
                  treatment of acute myocardial infarction with ST-segment elevation</trans-title>
          <source>Arq Bras Cardiol</source>
          <year>2009</year>
          <volume>93</volume>
          <issue>6</issue>
          <supplement>Suppl 2</supplement>
          <fpage>e179</fpage>
          <lpage>e264</lpage>
        </element-citation>
      </ref>
      <ref id="B200">
        <label>200</label>
        <mixed-citation>200. Serrano Jr C, Fenelon G, Soeiro A, Nicolau J, Piegas L, Montenegro
               S. Diretrizes brasileiras de antiagregantes plaquet&#225;rios e anticoagulantes em
               cardiologia. Arq Bras Cardiol.2013;1(3 Suppl 3):1-95.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Serrano</surname>
              <given-names>C</given-names>
              <suffix>Jr</suffix>
            </name>
            <name>
              <surname>Fenelon</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Soeiro</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Nicolau</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Piegas</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Montenegro</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title xml:lang="pt">Diretrizes brasileiras de antiagregantes plaquet&#225;rios e
                  anticoagulantes em cardiologia</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2013</year>
          <volume>1</volume>
          <issue>3</issue>
          <supplement>Suppl 3</supplement>
          <fpage>1</fpage>
          <lpage>95</lpage>
        </element-citation>
      </ref>
      <ref id="B201">
        <label>201</label>
        <mixed-citation>201. Januzzi JL, Cannon CP, Di Battiste PM, Murphy S, Weintraub W,
               Braunwald E. Effects of renal insufficiency on early invasive management in patients
               with acute coronary syndromes (The TACTICS-TIMI 18 Trial). TACTICS-TIMI 18
               Investigators. Am J Cardiol. 2002;90(11):1246-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Januzzi</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Cannon</surname>
              <given-names>CP</given-names>
            </name>
            <name>
              <surname>Di Battiste</surname>
              <given-names>PM</given-names>
            </name>
            <name>
              <surname>Murphy</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Weintraub</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Braunwald</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effects of renal insufficiency on early invasive
                  management in patients with acute coronary syndromes (The TACTICS-TIMI 18 Trial) </article-title>
          <collab>TACTICS-TIMI 18 Investigators</collab>
          <source>Am J Cardiol</source>
          <year>2002</year>
          <volume>90</volume>
          <issue>11</issue>
          <fpage>1246</fpage>
          <lpage>1249</lpage>
        </element-citation>
      </ref>
      <ref id="B202">
        <label>202</label>
        <mixed-citation>202. Indications for fibrinolytic therapy in suspected acute myocardial
               infarction: collaborative overview of early mortality and major morbidity results
               from all randomised trials of more than 1000 patients. Fibrinolytic Therapy
               Trialists' (FTT) Collaborative Group. Lancet. 1994;343(8893):311-22.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Indications for fibrinolytic therapy in suspected acute
                  myocardial infarction: collaborative overview of early mortality and major
                  morbidity results from all randomised trials of more than 1000
                  patients</article-title>
          <collab>Fibrinolytic Therapy Trialists' (FTT) Collaborative Group</collab>
          <source>Lancet</source>
          <year>1994</year>
          <volume>343</volume>
          <issue>8893</issue>
          <fpage>311</fpage>
          <lpage>322</lpage>
        </element-citation>
      </ref>
      <ref id="B203">
        <label>203</label>
        <mixed-citation>203. Grines C, Patel A, Zijlstra F, Weaver WD, Granger C, Simes RJ.
               Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute
               myocardial infarction: six-month follow up and analysis of individual patient data
               from randomized trials. PCAT Collaborators. Percutaneous transluminal coronary
               angioplasty. Am Heart J. 2003;145(1):47-57.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Grines</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Patel</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Zijlstra</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Weaver</surname>
              <given-names>WD</given-names>
            </name>
            <name>
              <surname>Granger</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Simes</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Primary coronary angioplasty compared with intravenous
                  thrombolytic therapy for acute myocardial infarctionsix-month follow up and
                  analysis of individual patient data from randomized trials. PCAT Collaborators.
                  Percutaneous transluminal coronary angioplasty</article-title>
          <source>Am Heart J</source>
          <year>2003</year>
          <volume>145</volume>
          <issue>1</issue>
          <fpage>47</fpage>
          <lpage>57</lpage>
        </element-citation>
      </ref>
      <ref id="B204">
        <label>204</label>
        <mixed-citation>204. Indications for ACE inhibitors in the early treatment of acute
               myocardial infarction: systematic overview of individual data from 100,000 patients
               in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group.
               Circulation. 1998;97(22):2202-12.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Indications for ACE inhibitors in the early treatment of
                  acute myocardial infarction: systematic overview of individual data from 100,000
                  patients in randomized trials</article-title>
          <collab>ACE Inhibitor Myocardial Infarction Collaborative Group</collab>
          <source>Circulation</source>
          <year>1998</year>
          <volume>97</volume>
          <issue>22</issue>
          <fpage>2202</fpage>
          <lpage>2212</lpage>
        </element-citation>
      </ref>
      <ref id="B205">
        <label>205</label>
        <mixed-citation>205. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al.
               Eplerenone, a selective aldosterone blocker, in patients with left ventricular
               dysfunction after myocardial infarction. Eplerenone Post-Acute Myocardial Infarction
               Heart Failure Efficacy and Survival Study Investigators. N Engl J Med.
               2003;348(14):1309-21.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Pitt</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Remme</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Zannad</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Neaton</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Martinez</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Roniker</surname>
              <given-names>B</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Eplerenone, a selective aldosterone blocker, in patients
                  with left ventricular dysfunction after myocardial infarction. Eplerenone
                  Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
                  Investigators</article-title>
          <source>N Engl J Med</source>
          <year>2003</year>
          <volume>348</volume>
          <issue>14</issue>
          <fpage>1309</fpage>
          <lpage>1321</lpage>
        </element-citation>
      </ref>
      <ref id="B206">
        <label>206</label>
        <mixed-citation>206. Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ,
               Verheugt FW, et al. Greater clinical benefit of more intensive oral antiplatelet
               therapy with prasugrel in patients with diabetes mellitus in the trial to assess
               improvement in therapeutic outcomes by optimizing platelet inhibition with
               prasugrel-Thrombolysis in Myocardial Infarction 38. TRITON-TIMI 38 Investigators.
               Circulation. 2008;118(16):1626-36.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wiviott</surname>
              <given-names>SD</given-names>
            </name>
            <name>
              <surname>Braunwald</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Angiolillo</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Meisel</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Dalby</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Verheugt</surname>
              <given-names>FW</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Greater clinical benefit of more intensive oral
                  antiplatelet therapy with prasugrel in patients with diabetes mellitus in the
                  trial to assess improvement in therapeutic outcomes by optimizing platelet
                  inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38</article-title>
          <collab>TRITON-TIMI 38 Investigators</collab>
          <source>Circulation</source>
          <year>2008</year>
          <volume>118</volume>
          <issue>16</issue>
          <fpage>1626</fpage>
          <lpage>1636</lpage>
        </element-citation>
      </ref>
      <ref id="B207">
        <label>207</label>
        <mixed-citation>207. James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F,
               et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and
               diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial.
               PLATO Study Group. Eur Heart J. 2010;31(24):3006-16.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>James</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Angiolillo</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Cornel</surname>
              <given-names>JH</given-names>
            </name>
            <name>
              <surname>Erlinge</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Husted</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Kontny</surname>
              <given-names>F</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Ticagrelor vs. clopidogrel in patients with acute
                  coronary syndromes and diabetes: a substudy from the PLATelet inhibition and
                  patient Outcomes (PLATO) trial</article-title>
          <collab>PLATO Study Group</collab>
          <source>Eur Heart J</source>
          <year>2010</year>
          <volume>31</volume>
          <issue>24</issue>
          <fpage>3006</fpage>
          <lpage>3016</lpage>
        </element-citation>
      </ref>
      <ref id="B208">
        <label>208</label>
        <mixed-citation>208. Roffi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Heeschen C, et
               al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients
               with non-ST-segment-elevation acute coronary syndromes. Circulation.
               2001;104(23):2767-71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Roffi</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Chew</surname>
              <given-names>DP</given-names>
            </name>
            <name>
              <surname>Mukherjee</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Bhatt</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Heeschen</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Platelet glycoprotein IIb/IIIa inhibitors reduce
                  mortality in diabetic patients with non-ST-segment-elevation acute coronary
                  syndromes</article-title>
          <source>Circulation</source>
          <year>2001</year>
          <volume>104</volume>
          <issue>23</issue>
          <fpage>2767</fpage>
          <lpage>2771</lpage>
        </element-citation>
      </ref>
      <ref id="B209">
        <label>209</label>
        <mixed-citation>209. Giugliano RP, White JA, Bode C, Armstrong PW, Montalescot G, Lewis
               BS, et al. Early versus delayed, provisional eptifibatide in acute coronary
               syndromes. EARLY ACS Investigators. N Engl J Med.
               2009;360(21):2176-90.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Giugliano</surname>
              <given-names>RP</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Bode</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Armstrong</surname>
              <given-names>PW</given-names>
            </name>
            <name>
              <surname>Montalescot</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Lewis</surname>
              <given-names>BS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Early versus delayed, provisional eptifibatide in acute
                  coronary syndromes</article-title>
          <collab>EARLY ACS Investigators</collab>
          <source>N Engl J Med</source>
          <year>2009</year>
          <volume>360</volume>
          <issue>21</issue>
          <fpage>2176</fpage>
          <lpage>2190</lpage>
        </element-citation>
      </ref>
      <ref id="B210">
        <label>210</label>
        <mixed-citation>210. Mehilli J, Kastrati A, Sch&#252;hlen H, Dibra A, Dotzer F, von Beckerath
               N,et al. Randomized clinical trial of abciximab in diabetic patients undergoing
               elective percutaneous coronary interventions after treatment with a high loading dose
               of clopidogrel. Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a
               Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study
               Investigators. Circulation. 2004;110(24):3627-35.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mehilli</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Kastrati</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Sch&#252;hlen</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Dibra</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Dotzer</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>von Beckerath</surname>
              <given-names>N</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Randomized clinical trial of abciximab in diabetic
                  patients undergoing elective percutaneous coronary interventions after treatment
                  with a high loading dose of clopidogrel. Intracoronary Stenting and Antithrombotic
                  Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in
                  Diabetics (ISAR-SWEET) Study Investigators</article-title>
          <source>Circulation</source>
          <year>2004</year>
          <volume>110</volume>
          <issue>24</issue>
          <fpage>3627</fpage>
          <lpage>3635</lpage>
        </element-citation>
      </ref>
      <ref id="B211">
        <label>211</label>
        <mixed-citation>211. Steg PG, James SK, Atar D, Badano LP, Bl&#246;mstrom-Lundqvist C, Borger
               MA, et al. ESC Guidelines for the management of acute myocardial infarction in
               patients presenting with ST-segment elevation. Task Force on the management of
               ST-segment elevation acute myocardial infarction of the European Society of
               Cardiology (ESC). Eur Heart J. 2012;33(20):2569-619.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Steg</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>James</surname>
              <given-names>SK</given-names>
            </name>
            <name>
              <surname>Atar</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Badano</surname>
              <given-names>LP</given-names>
            </name>
            <name>
              <surname>Bl&#246;mstrom-Lundqvist</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Borger</surname>
              <given-names>MA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ESC Guidelines for the management of acute myocardial
                  infarction in patients presenting with ST-segment elevation. Task Force on the
                  management of ST-segment elevation acute myocardial infarction of the European
                  Society of Cardiology (ESC)</article-title>
          <source>Eur Heart J</source>
          <year>2012</year>
          <volume>33</volume>
          <issue>20</issue>
          <fpage>2569</fpage>
          <lpage>2619</lpage>
        </element-citation>
      </ref>
      <ref id="B212">
        <label>212</label>
        <mixed-citation>212. Mahaffey KW, Cohen M, Garg J, Antman E, Kleiman NS, Goodman SG, et
               al. High-risk patients with acute coronary syndromes treated with
               low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in
               the SYNERGY trial. SYNERGY Trial Investigators. JAMA.
               2005;294(20):2594-600.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mahaffey</surname>
              <given-names>KW</given-names>
            </name>
            <name>
              <surname>Cohen</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Garg</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Antman</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Kleiman</surname>
              <given-names>NS</given-names>
            </name>
            <name>
              <surname>Goodman</surname>
              <given-names>SG</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">High-risk patients with acute coronary syndromes treated
                  with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1
                  year in the SYNERGY trial</article-title>
          <collab>SYNERGY Trial Investigators</collab>
          <source>JAMA</source>
          <year>2005</year>
          <volume>294</volume>
          <issue>20</issue>
          <fpage>2594</fpage>
          <lpage>2600</lpage>
        </element-citation>
      </ref>
      <ref id="B213">
        <label>213</label>
        <mixed-citation>213. Blazing MA, de Lemos JA, White HD, Fox KA, Verheugt FW, Ardissino
               D, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients
               with non-ST-segment elevation acute coronary syndromes who receive tirofiban and
               aspirin: a randomized controlled trial. 'A to Z' Investigators. JAMA.
               2004;292(1):55-64.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Blazing</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>de Lemos</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>HD</given-names>
            </name>
            <name>
              <surname>Fox</surname>
              <given-names>KA</given-names>
            </name>
            <name>
              <surname>Verheugt</surname>
              <given-names>FW</given-names>
            </name>
            <name>
              <surname>Ardissino</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Safety and efficacy of enoxaparin vs unfractionated
                  heparin in patients with non-ST-segment elevation acute coronary syndromes who
                  receive tirofiban and aspirin: a randomized controlled trial. 'A to Z'
                  Investigators</article-title>
          <source>JAMA</source>
          <year>2004</year>
          <volume>292</volume>
          <issue>1</issue>
          <fpage>55</fpage>
          <lpage>64</lpage>
        </element-citation>
      </ref>
      <ref id="B214">
        <label>214</label>
        <mixed-citation>214. Chaitman BR, Hardison RM, Adler D, Gebhart S, Grogan M, Ocampo S,
               et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized
               trial of different treatment strategies in type 2 diabetes mellitus with stable
               ischemic heart disease: impact of treatment strategy on cardiac mortality and
               myocardial infarction. Bypass Angioplasty Revascularization Investigation 2 Diabetes
               (BARI 2D) Study Group. Circulation. 2009;120(25):2529-40.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chaitman</surname>
              <given-names>BR</given-names>
            </name>
            <name>
              <surname>Hardison</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>Adler</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Gebhart</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Grogan</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Ocampo</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">The Bypass Angioplasty Revascularization Investigation 2
                  Diabetes randomized trial of different treatment strategies in type 2 diabetes
                  mellitus with stable ischemic heart disease: impact of treatment strategy on
                  cardiac mortality and myocardial infarction. Bypass Angioplasty Revascularization
                  Investigation 2 Diabetes (BARI 2D) Study Group</article-title>
          <source>Circulation</source>
          <year>2009</year>
          <volume>120</volume>
          <issue>25</issue>
          <fpage>2529</fpage>
          <lpage>2540</lpage>
        </element-citation>
      </ref>
      <ref id="B215">
        <label>215</label>
        <mixed-citation>215. Kosiborod M, Inzucchi SE, Krumholz HM, Xiao L, Jones PG, Fiske S,
               et al. Glucometrics in patients hospitalized with acute myocardial infarction:
               defining the optimal outcomes-based measure of risk. Circulation.
               2008;117(8):1018-27.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kosiborod</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Inzucchi</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Krumholz</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Xiao</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Jones</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Fiske</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Glucometrics in patients hospitalized with acute
                  myocardial infarction: defining the optimal outcomes-based measure of
                  risk</article-title>
          <source>Circulation</source>
          <year>2008</year>
          <volume>117</volume>
          <issue>8</issue>
          <fpage>1018</fpage>
          <lpage>1027</lpage>
        </element-citation>
      </ref>
      <ref id="B216">
        <label>216</label>
        <mixed-citation>216. Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD, et
               al. Prognostic significance of the change in glucose level in the first 24 h after
               acute myocardial infarction: results from the CARDINAL study. Eur Heart J.
               2006;27(11):1289-97.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Goyal</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Mahaffey</surname>
              <given-names>KW</given-names>
            </name>
            <name>
              <surname>Garg</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Nicolau</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Hochman</surname>
              <given-names>JS</given-names>
            </name>
            <name>
              <surname>Weaver</surname>
              <given-names>WD</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prognostic significance of the change in glucose level
                  in the first 24 h after acute myocardial infarction: results from the CARDINAL
                  study</article-title>
          <source>Eur Heart J</source>
          <year>2006</year>
          <volume>27</volume>
          <issue>11</issue>
          <fpage>1289</fpage>
          <lpage>1297</lpage>
        </element-citation>
      </ref>
      <ref id="B217">
        <label>217</label>
        <mixed-citation>217. Malmberg K. Prospective randomised study of intensive insulin
               treatment on long term survival after acute myocardial infarction in patients with
               diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute
               Myocardial Infarction) Study Group. BMJ. 1997;314(7093):1512-5.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Malmberg</surname>
              <given-names>K</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Prospective randomised study of intensive insulin
                  treatment on long term survival after acute myocardial infarction in patients with
                  diabetes mellitus</article-title>
          <collab>DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial
                  Infarction) Study Group</collab>
          <source>BMJ</source>
          <year>1997</year>
          <volume>314</volume>
          <issue>7093</issue>
          <fpage>1512</fpage>
          <lpage>1515</lpage>
        </element-citation>
      </ref>
      <ref id="B218">
        <label>218</label>
        <mixed-citation>218. Malmberg K, Ryd&#233;n L, Wedel H, Birkeland K, Bootsma A, Dickstein K,
               et al. Intense metabolic control by means of insulin in patients with diabetes
               mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and
               morbidity. DIGAMI 2 Investigators. Eur Heart J. 2005;26(7):650-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Malmberg</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Ryd&#233;n</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Wedel</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Birkeland</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Bootsma</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Dickstein</surname>
              <given-names>K</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Intense metabolic control by means of insulin in
                  patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2):
                  effects on mortality and morbidity</article-title>
          <collab>DIGAMI 2 Investigators</collab>
          <source>Eur Heart J</source>
          <year>2005</year>
          <volume>26</volume>
          <issue>7</issue>
          <fpage>650</fpage>
          <lpage>661</lpage>
        </element-citation>
      </ref>
      <ref id="B219">
        <label>219</label>
        <mixed-citation>219. Cheung NW, Wong VW, McLean M. The Hyperglycemia: Intensive Insulin
               Infusion in Infarction (HI-5) study: a randomized controlled trial of insulin
               infusion therapy for myocardial infarction. Diabetes Care.
               2006;29(4):765-70.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cheung</surname>
              <given-names>NW</given-names>
            </name>
            <name>
              <surname>Wong</surname>
              <given-names>VW</given-names>
            </name>
            <name>
              <surname>McLean</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The Hyperglycemia: Intensive Insulin Infusion in
                  Infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy
                  for myocardial infarction</article-title>
          <source>Diabetes Care</source>
          <year>2006</year>
          <volume>29</volume>
          <issue>4</issue>
          <fpage>765</fpage>
          <lpage>770</lpage>
        </element-citation>
      </ref>
      <ref id="B220">
        <label>220</label>
        <mixed-citation>220. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski
               P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treatment of acute
               and chronic heart failure 2008: the Task Force for the diagnosis and treatment of
               acute and chronic heart failure 2008 of the European Society of Cardiology. Developed
               in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by
               the European Society of Intensive Care Medicine (ESICM). ESC Committee for Practice
               Guidelines (CPG). Eur J Heart Fail. 2008;10(10):933-89.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Dickstein</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Cohen-Solal</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Filippatos</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>McMurray</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Ponikowski</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Poole-Wilson</surname>
              <given-names>PA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">ESC guidelines for the diagnosis and treatment of acute
                  and chronic heart failure 2008: the Task Force for the diagnosis and treatment of
                  acute and chronic heart failure 2008 of the European Society of Cardiology.
                  Developed in collaboration with the Heart Failure Association of the ESC (HFA) and
                  endorsed by the European Society of Intensive Care Medicine
                  (ESICM)</article-title>
          <collab>ESC Committee for Practice Guidelines (CPG)</collab>
          <source>Eur J Heart Fail</source>
          <year>2008</year>
          <volume>10</volume>
          <issue>10</issue>
          <fpage>933</fpage>
          <lpage>989</lpage>
        </element-citation>
      </ref>
      <ref id="B221">
        <label>221</label>
        <mixed-citation>221. Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D,
               Rodrigues De A, et al. [Updating of the Brazilian guideline for chronic heart failure
               - 2012]. Arq Bras Cardiol. 2012;98(1 Suppl 1):1-33.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bocchi</surname>
              <given-names>EA</given-names>
            </name>
            <name>
              <surname>Marcondes-Braga</surname>
              <given-names>FG</given-names>
            </name>
            <name>
              <surname>Bacal</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Ferraz</surname>
              <given-names>AS</given-names>
            </name>
            <name>
              <surname>Albuquerque</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Rodrigues De</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <trans-title xml:lang="en">Updating of the Brazilian guideline for chronic heart
                  failure - 2012</trans-title>
          <source>Arq Bras Cardiol</source>
          <year>2012</year>
          <volume>98</volume>
          <issue>1</issue>
          <supplement>Suppl 1</supplement>
          <fpage>1</fpage>
          <lpage>33</lpage>
        </element-citation>
      </ref>
      <ref id="B222">
        <label>222</label>
        <mixed-citation>222. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC.
               Heart failure prevalence, incidence, and mortality in the elderly with diabetes.
               Diabetes Care. 2004;27(3):699-703.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bertoni</surname>
              <given-names>AG</given-names>
            </name>
            <name>
              <surname>Hundley</surname>
              <given-names>WG</given-names>
            </name>
            <name>
              <surname>Massing</surname>
              <given-names>MW</given-names>
            </name>
            <name>
              <surname>Bonds</surname>
              <given-names>DE</given-names>
            </name>
            <name>
              <surname>Burke</surname>
              <given-names>GL</given-names>
            </name>
            <name>
              <surname>Goff</surname>
              <given-names>DC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Heart failure prevalence, incidence, and mortality in
                  the elderly with diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2004</year>
          <volume>27</volume>
          <issue>3</issue>
          <fpage>699</fpage>
          <lpage>703</lpage>
        </element-citation>
      </ref>
      <ref id="B223">
        <label>223</label>
        <mixed-citation>223. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart
               failure: the Framingham Study. J Am Coll Cardiol.1993;22(4 Suppl
               A):6A-13A.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ho</surname>
              <given-names>KK</given-names>
            </name>
            <name>
              <surname>Pinsky</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Kannel</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>Levy</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The epidemiology of heart failure: the Framingham
                  Study</article-title>
          <source>J Am Coll Cardiol</source>
          <year>1993</year>
          <volume>22</volume>
          <issue>4</issue>
          <supplement>Suppl A</supplement>
          <fpage>6A</fpage>
          <lpage>13A</lpage>
        </element-citation>
      </ref>
      <ref id="B224">
        <label>224</label>
        <mixed-citation>224. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive
               heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kannel</surname>
              <given-names>WB</given-names>
            </name>
            <name>
              <surname>Hjortland</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Castelli</surname>
              <given-names>WP</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Role of diabetes in congestive heart failure: the
                  Framingham study</article-title>
          <source>Am J Cardiol</source>
          <year>1974</year>
          <volume>34</volume>
          <issue>1</issue>
          <fpage>29</fpage>
          <lpage>34</lpage>
        </element-citation>
      </ref>
      <ref id="B225">
        <label>225</label>
        <mixed-citation>225. Fonarow GC. Approach to the management of diabetic patients with
               heart failure: role of thiazolidinediones. Am Heart
               J.2004;148(4):551-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fonarow</surname>
              <given-names>GC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Approach to the management of diabetic patients with
                  heart failure: role of thiazolidinediones</article-title>
          <source>Am Heart J</source>
          <year>2004</year>
          <volume>148</volume>
          <issue>4</issue>
          <fpage>551</fpage>
          <lpage>558</lpage>
        </element-citation>
      </ref>
      <ref id="B226">
        <label>226</label>
        <mixed-citation>226. Hamby RI, Zoneraich S, Sherman L. Diabetic cardiomyopathy. JAMA.
               1974;229(13):1749-54.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hamby</surname>
              <given-names>RI</given-names>
            </name>
            <name>
              <surname>Zoneraich</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Sherman</surname>
              <given-names>L</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic cardiomyopathy</article-title>
          <source>JAMA</source>
          <year>1974</year>
          <volume>229</volume>
          <issue>13</issue>
          <fpage>1749</fpage>
          <lpage>1754</lpage>
        </element-citation>
      </ref>
      <ref id="B227">
        <label>227</label>
        <mixed-citation>227. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer
               S, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction
               in type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52(22):1793-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rijzewijk</surname>
              <given-names>LJ</given-names>
            </name>
            <name>
              <surname>van der Meer</surname>
              <given-names>RW</given-names>
            </name>
            <name>
              <surname>Smit</surname>
              <given-names>JW</given-names>
            </name>
            <name>
              <surname>Diamant</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Bax</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Hammer</surname>
              <given-names>S</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Myocardial steatosis is an independent predictor of
                  diastolic dysfunction in type 2 diabetes mellitus</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2008</year>
          <volume>52</volume>
          <issue>22</issue>
          <fpage>1793</fpage>
          <lpage>1799</lpage>
        </element-citation>
      </ref>
      <ref id="B228">
        <label>228</label>
        <mixed-citation>228. Adatya S, Mandel L, Schwarz K, Soucier R. The Effect of
               Hyperglycemia in Patients Hospitalized for Acute Decompensated Heart Failure. J
               Cardiac Fail. 2007;13(6 Suppl 2): S90.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Adatya</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Mandel</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Schwarz</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Soucier</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The Effect of Hyperglycemia in Patients Hospitalized for
                  Acute Decompensated Heart Failure</article-title>
          <source>J Cardiac Fail</source>
          <year>2007</year>
          <volume>13</volume>
          <issue>6</issue>
          <supplement>Suppl 2</supplement>
          <fpage>S90</fpage>
          <lpage>S90</lpage>
        </element-citation>
      </ref>
      <ref id="B229">
        <label>229</label>
        <mixed-citation>229. Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M.
               Increased plasma inactive renin in diabetes mellitus: a marker of microvascular
               complications. N Engl J Med. 1985;312(22):1412-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Luetscher</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Kraemer</surname>
              <given-names>FB</given-names>
            </name>
            <name>
              <surname>Wilson</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Schwartz</surname>
              <given-names>HC</given-names>
            </name>
            <name>
              <surname>Bryer-Ash</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Increased plasma inactive renin in diabetes mellitus: a
                  marker of microvascular complications</article-title>
          <source>N Engl J Med</source>
          <year>1985</year>
          <volume>312</volume>
          <issue>22</issue>
          <fpage>1412</fpage>
          <lpage>1417</lpage>
        </element-citation>
      </ref>
      <ref id="B230">
        <label>230</label>
        <mixed-citation>230. Debono M, Cachia E. The impact of cardiovascular autonomic
               neuropathy in diabetes: is it associated with left ventricular dysfunction? Auton
               Neurosci. 2007;132(1-2):1-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Debono</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Cachia</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The impact of cardiovascular autonomic neuropathy in
                  diabetes: is it associated with left ventricular dysfunction?</article-title>
          <source>Auton Neurosci</source>
          <year>2007</year>
          <volume>132</volume>
          <issue>1-2</issue>
          <fpage>1</fpage>
          <lpage>7</lpage>
        </element-citation>
      </ref>
      <ref id="B231">
        <label>231</label>
        <mixed-citation>231. Zoneiraich S, Silverman G. Primary myocardial disease, diabetes
               mellitus, and small vessel disease. Am Heart J. 1980;5(5):754-5.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zoneiraich</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Silverman</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Primary myocardial disease, diabetes mellitus, and small
                  vessel disease</article-title>
          <source>Am Heart J</source>
          <year>1980</year>
          <volume>5</volume>
          <issue>5</issue>
          <fpage>754</fpage>
          <lpage>755</lpage>
        </element-citation>
      </ref>
      <ref id="B232">
        <label>232</label>
        <mixed-citation>232. Brooks BA, Franjic B, Ban CR, Swaraj K, Yue DK, Celermajer DS, et
               al. Diastolic dysfunction and abnormalities of the microcirculation in type 2
               diabetes. Diabetes Obes Metab. 2008;10(9):739-46.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Brooks</surname>
              <given-names>BA</given-names>
            </name>
            <name>
              <surname>Franjic</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Ban</surname>
              <given-names>CR</given-names>
            </name>
            <name>
              <surname>Swaraj</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Yue</surname>
              <given-names>DK</given-names>
            </name>
            <name>
              <surname>Celermajer</surname>
              <given-names>DS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Diastolic dysfunction and abnormalities of the
                  microcirculation in type 2 diabetes</article-title>
          <source>Diabetes Obes Metab</source>
          <year>2008</year>
          <volume>10</volume>
          <issue>9</issue>
          <fpage>739</fpage>
          <lpage>746</lpage>
        </element-citation>
      </ref>
      <ref id="B233">
        <label>233</label>
        <mixed-citation>233. Teupe C, Rosak C. Diabetic cardiomyopathy and diastolic heart
               failure -- difficulties with relaxation. Diabetes Res Clin Pract.
               2012;97(2):185-94.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Teupe</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Rosak</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic cardiomyopathy and diastolic heart failure --
                  difficulties with relaxation</article-title>
          <source>Diabetes Res Clin Pract</source>
          <year>2012</year>
          <volume>97</volume>
          <issue>2</issue>
          <fpage>185</fpage>
          <lpage>194</lpage>
        </element-citation>
      </ref>
      <ref id="B234">
        <label>234</label>
        <mixed-citation>234. Zile MR, Baicu CF, Gaasch WH. Diastolic heart
               failure--abnormalities in active relaxation and passive stiffness of the left
               ventricle. N Engl J Med. 2004;350(19):1953-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zile</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Baicu</surname>
              <given-names>CF</given-names>
            </name>
            <name>
              <surname>Gaasch</surname>
              <given-names>WH</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diastolic heart failure--abnormalities in active
                  relaxation and passive stiffness of the left ventricle</article-title>
          <source>N Engl J Med</source>
          <year>2004</year>
          <volume>350</volume>
          <issue>19</issue>
          <fpage>1953</fpage>
          <lpage>1959</lpage>
        </element-citation>
      </ref>
      <ref id="B235">
        <label>235</label>
        <mixed-citation>235. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside.
               Heart Fail Clin. 2012;8(4):619-31.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Schilling</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Mann</surname>
              <given-names>DL</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic cardiomyopathy: bench to
                  bedside</article-title>
          <source>Heart Fail Clin</source>
          <year>2012</year>
          <volume>8</volume>
          <issue>4</issue>
          <fpage>619</fpage>
          <lpage>631</lpage>
        </element-citation>
      </ref>
      <ref id="B236">
        <label>236</label>
        <mixed-citation>236. Bocchi E, Marcondes-Braga F, Ayub-Ferreira S, Rohde L, Oliveira W,
               Almeida D; Sociedade Brasileira de Cardiologia. III Diretriz brasileira de
               insufici&#234;ncia card&#237;aca cr&#244;nica. Arq Bras Cardiol. 2009;93(1 supl
               1):1-71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bocchi</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Marcondes-Braga</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Ayub-Ferreira</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Rohde</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Oliveira</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Almeida</surname>
              <given-names>D</given-names>
            </name>
            <collab>Sociedade Brasileira de Cardiologia</collab>
          </person-group>
          <article-title xml:lang="pt">III Diretriz brasileira de insufici&#234;ncia card&#237;aca
                  cr&#244;nica</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2009</year>
          <volume>93</volume>
          <issue>1</issue>
          <supplement>supl 1</supplement>
          <fpage>1</fpage>
          <lpage>71</lpage>
        </element-citation>
      </ref>
      <ref id="B237">
        <label>237</label>
        <mixed-citation>237. Kato M, Matsumoto N, Nakano Y, Suzuki Y, Yoda S, Sato Y, et al.
               Combined assessment of myocardial perfusion and function by ECG-gated myocardial
               perfusion single-photon emission computed tomography for the prediction of future
               cardiac events in patients with type 2 diabetes mellitus. Circ J.
               2011;75(2):376-82.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kato</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Matsumoto</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Nakano</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Suzuki</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Yoda</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Sato</surname>
              <given-names>Y</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Combined assessment of myocardial perfusion and function
                  by ECG-gated myocardial perfusion single-photon emission computed tomography for
                  the prediction of future cardiac events in patients with type 2 diabetes
                  mellitus</article-title>
          <source>Circ J</source>
          <year>2011</year>
          <volume>75</volume>
          <issue>2</issue>
          <fpage>376</fpage>
          <lpage>382</lpage>
        </element-citation>
      </ref>
      <ref id="B238">
        <label>238</label>
        <mixed-citation>238. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P,
               et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of
               heart failure. Breathing Not Properly Multinational Study Investigators. N Engl J
               Med. 2002;347(3):161-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Maisel</surname>
              <given-names>AS</given-names>
            </name>
            <name>
              <surname>Krishnaswamy</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Nowak</surname>
              <given-names>RM</given-names>
            </name>
            <name>
              <surname>McCord</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Hollander</surname>
              <given-names>JE</given-names>
            </name>
            <name>
              <surname>Duc</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Rapid measurement of B-type natriuretic peptide in the
                  emergency diagnosis of heart failure. Breathing Not Properly Multinational Study
                  Investigators</article-title>
          <source>N Engl J Med</source>
          <year>2002</year>
          <volume>347</volume>
          <issue>3</issue>
          <fpage>161</fpage>
          <lpage>167</lpage>
        </element-citation>
      </ref>
      <ref id="B239">
        <label>239</label>
        <mixed-citation>239. Fonarow GC, Peacock WF, Phillips CO, Givertz MM, Lopatin M.
               Admission B-type natriuretic peptide levels and in-hospital mortality in acute
               decompensated heart failure. ADHERE Scientific Advisory Committee and Investigators.
               J Am Coll Cardiol. 2007;49(19):1943-50.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Fonarow</surname>
              <given-names>GC</given-names>
            </name>
            <name>
              <surname>Peacock</surname>
              <given-names>WF</given-names>
            </name>
            <name>
              <surname>Phillips</surname>
              <given-names>CO</given-names>
            </name>
            <name>
              <surname>Givertz</surname>
              <given-names>MM</given-names>
            </name>
            <name>
              <surname>Lopatin</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Admission B-type natriuretic peptide levels and
                  in-hospital mortality in acute decompensated heart failure</article-title>
          <collab>ADHERE Scientific Advisory Committee and Investigators</collab>
          <source>J Am Coll Cardiol</source>
          <year>2007</year>
          <volume>49</volume>
          <issue>19</issue>
          <fpage>1943</fpage>
          <lpage>1950</lpage>
        </element-citation>
      </ref>
      <ref id="B240">
        <label>240</label>
        <mixed-citation>240. Kroon MH, van den Hurk K, Alssema M, Kamp O, Stehouwer CD, Henry
               RM, et al. Prospective associations of B-type natriuretic peptide with markers of
               left ventricular function in individuals with and without type 2 diabetes: an 8-year
               follow-up of the Hoorn Study. Diabetes Care. 2012;35(12):2510-4.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kroon</surname>
              <given-names>MH</given-names>
            </name>
            <name>
              <surname>van den Hurk</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Alssema</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Kamp</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Stehouwer</surname>
              <given-names>CD</given-names>
            </name>
            <name>
              <surname>Henry</surname>
              <given-names>RM</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prospective associations of B-type natriuretic peptide
                  with markers of left ventricular function in individuals with and without type 2
                  diabetes: an 8-year follow-up of the Hoorn Study</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>12</issue>
          <fpage>2510</fpage>
          <lpage>2514</lpage>
        </element-citation>
      </ref>
      <ref id="B241">
        <label>241</label>
        <mixed-citation>241. Onodera M, Nakamura M, Tanaka F, Takahashi T, Makita S, Ishisone T,
               et al. Plasma B-type natriuretic peptide is useful for cardiovascular risk assessment
               in community-based diabetes subjects: comparison with albuminuria. Int Heart J.
               2012;53(3):176-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Onodera</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Nakamura</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Tanaka</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Takahashi</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Makita</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Ishisone</surname>
              <given-names>T</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Plasma B-type natriuretic peptide is useful for
                  cardiovascular risk assessment in community-based diabetes subjects: comparison
                  with albuminuria</article-title>
          <source>Int Heart J</source>
          <year>2012</year>
          <volume>53</volume>
          <issue>3</issue>
          <fpage>176</fpage>
          <lpage>181</lpage>
        </element-citation>
      </ref>
      <ref id="B242">
        <label>242</label>
        <mixed-citation>242. Peng Q, Hu W, Su H, Yang Q, Cheng X. B-type natriuretic peptide in
               chronic heart failure patients with and without diabetes mellitus. Exper Therap Med.
               2013;5(1):229-32.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Peng</surname>
              <given-names>Q</given-names>
            </name>
            <name>
              <surname>Hu</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Su</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Yang</surname>
              <given-names>Q</given-names>
            </name>
            <name>
              <surname>Cheng</surname>
              <given-names>X</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">B-type natriuretic peptide in chronic heart failure
                  patients with and without diabetes mellitus</article-title>
          <source>Exper Therap Med</source>
          <year>2013</year>
          <volume>5</volume>
          <issue>1</issue>
          <fpage>229</fpage>
          <lpage>232</lpage>
        </element-citation>
      </ref>
      <ref id="B243">
        <label>243</label>
        <mixed-citation>243. Romano S, Mauro M, Fratini S, Guarracini L, Guarracini F, Poccia G.
               Early diagnosis of left ventricular diastolic dysfunction in diabetic patients: a
               possible role for natriuretic peptides. Cardiovasc Diabetes.
               2010;9:89.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Romano</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Mauro</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Fratini</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Guarracini</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Guarracini</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Poccia</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Early diagnosis of left ventricular diastolic
                  dysfunction in diabetic patients: a possible role for natriuretic
                  peptides</article-title>
          <source>Cardiovasc Diabetes</source>
          <year>2010</year>
          <volume>9</volume>
          <fpage>89</fpage>
          <lpage>89</lpage>
        </element-citation>
      </ref>
      <ref id="B244">
        <label>244</label>
        <mixed-citation>244. Righettoni M, Tricoli A, Pratsinis SE. Si:WO(3) Sensors for highly
               selective detection of acetone for easy diagnosis of diabetes by breath analysis.
               Anal Chem. 2010;82(9):3581-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Righettoni</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Tricoli</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Pratsinis</surname>
              <given-names>SE</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Si:WO(3) Sensors for highly selective detection of
                  acetone for easy diagnosis of diabetes by breath analysis</article-title>
          <source>Anal Chem</source>
          <year>2010</year>
          <volume>82</volume>
          <issue>9</issue>
          <fpage>3581</fpage>
          <lpage>3587</lpage>
        </element-citation>
      </ref>
      <ref id="B245">
        <label>245</label>
        <mixed-citation>245. Marcondes-Braga FG, Gutz IG, Batista GL, Saldiva PH, Ayub-Ferreira
               SM, Issa VS, et al. Exhaled acetone as a new biomaker of heart failure severity.
               Chest. 2012;142:457-66.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Marcondes-Braga</surname>
              <given-names>FG</given-names>
            </name>
            <name>
              <surname>Gutz</surname>
              <given-names>IG</given-names>
            </name>
            <name>
              <surname>Batista</surname>
              <given-names>GL</given-names>
            </name>
            <name>
              <surname>Saldiva</surname>
              <given-names>PH</given-names>
            </name>
            <name>
              <surname>Ayub-Ferreira</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Issa</surname>
              <given-names>VS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Exhaled acetone as a new biomaker of heart failure
                  severity</article-title>
          <source>Chest</source>
          <year>2012</year>
          <volume>142</volume>
          <fpage>457</fpage>
          <lpage>466</lpage>
        </element-citation>
      </ref>
      <ref id="B246">
        <label>246</label>
        <mixed-citation>246. Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT,
               Varney J, et al. Benefits and harms of antidiabetic agents in patients with diabetes
               and heart failure: systematic review. BMJ. 2007;335(7618):497.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Eurich</surname>
              <given-names>DT</given-names>
            </name>
            <name>
              <surname>McAlister</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Blackburn</surname>
              <given-names>DF</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Tsuyuki</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Varney</surname>
              <given-names>J</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Benefits and harms of antidiabetic agents in patients
                  with diabetes and heart failures: ystematic review</article-title>
          <source>BMJ</source>
          <year>2007</year>
          <volume>335</volume>
          <issue>7618</issue>
          <fpage>497</fpage>
          <lpage>497</lpage>
        </element-citation>
      </ref>
      <ref id="B247">
        <label>247</label>
        <mixed-citation>247. Nasir S, Aguilar D. Congestive heart failure and diabetes mellitus:
               balancing glycemic control with heart failure improvement. Am J Cardiol.
               2012;110(9Suppl):50B-57B.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nasir</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Aguilar</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Congestive heart failure and diabetes mellitus:
                  balancing glycemic control with heart failure improvement</article-title>
          <source>Am J Cardiol</source>
          <year>2012</year>
          <volume>110</volume>
          <issue>9</issue>
          <supplement>Suppl</supplement>
          <fpage>50B</fpage>
          <lpage>57B</lpage>
        </element-citation>
      </ref>
      <ref id="B248">
        <label>248</label>
        <mixed-citation>248. Tang WH. A critical review of anti-adrenergic therapy in patients
               with heart failure and diabetes mellitus. Vasc Health Risk Manag.
               2007;3(5):639-45.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tang</surname>
              <given-names>WH</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">A critical review of anti-adrenergic therapy in patients
                  with heart failure and diabetes mellitus</article-title>
          <source>Vasc Health Risk Manag</source>
          <year>2007</year>
          <volume>3</volume>
          <issue>5</issue>
          <fpage>639</fpage>
          <lpage>645</lpage>
        </element-citation>
      </ref>
      <ref id="B249">
        <label>249</label>
        <mixed-citation>249. Torp-Pedersen C, Metra M, Charlesworth A, Spark P, Lukas MA,
               Poole-Wilson PA, et al. Effects of metoprolol and carvedilol on pre-existing and new
               onset diabetes in patients with chronic heart failure: data from the Carvedilol Or
               Metoprolol European Trial (COMET). COMET investigators. Heart.
               2007;93(8):968-73.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Torp-Pedersen</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Metra</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Charlesworth</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Spark</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Lukas</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Poole-Wilson</surname>
              <given-names>PA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of metoprolol and carvedilol on pre-existing and
                  new onset diabetes in patients with chronic heart failure: data from the
                  Carvedilol Or Metoprolol European Trial (COMET)</article-title>
          <collab>COMET investigators</collab>
          <source>Heart</source>
          <year>2007</year>
          <volume>93</volume>
          <issue>8</issue>
          <fpage>968</fpage>
          <lpage>973</lpage>
        </element-citation>
      </ref>
      <ref id="B250">
        <label>250</label>
        <mixed-citation>250. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol
               CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
               Lancet.1999;353(8875):2001-7.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title xml:lang="en">Effect of metoprolol CR/XL in chronic heart failure:
                  Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure
                  (MERIT-HF)</article-title>
          <source>Lancet</source>
          <year>1999</year>
          <volume>353</volume>
          <issue>8875</issue>
          <fpage>2001</fpage>
          <lpage>2007</lpage>
        </element-citation>
      </ref>
      <ref id="B251">
        <label>251</label>
        <mixed-citation>251. Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, et
               al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the
               management of left ventricular systolic dysfunction according to race, gender, and
               diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol.
               2003;41(9):1529-38.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Shekelle</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Rich</surname>
              <given-names>MW</given-names>
            </name>
            <name>
              <surname>Morton</surname>
              <given-names>SC</given-names>
            </name>
            <name>
              <surname>Atkinson</surname>
              <given-names>CS</given-names>
            </name>
            <name>
              <surname>Tu</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Maglione</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Efficacy of angiotensin-converting enzyme inhibitors and
                  beta-blockers in the management of left ventricular systolic dysfunction according
                  to race, gender, and diabetic status: a meta-analysis of major clinical
                  trials</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2003</year>
          <volume>41</volume>
          <issue>9</issue>
          <fpage>1529</fpage>
          <lpage>1538</lpage>
        </element-citation>
      </ref>
      <ref id="B252">
        <label>252</label>
        <mixed-citation>252. Al-Mallah M, Khawaja O, Sinno M, Alzohaili O, Samra AB. Do
               angiotensin converting enzyme inhibitors or angiotensin receptor blockers prevent
               diabetes mellitus? A meta-analysis. Cardiol J. 2010;17(5):448-56.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Al-Mallah</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Khawaja</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Sinno</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Alzohaili</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Samra</surname>
              <given-names>AB</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Do angiotensin converting enzyme inhibitors or
                  angiotensin receptor blockers prevent diabetes mellitus? A
                  meta-analysis</article-title>
          <source>Cardiol J</source>
          <year>2010</year>
          <volume>17</volume>
          <issue>5</issue>
          <fpage>448</fpage>
          <lpage>456</lpage>
        </element-citation>
      </ref>
      <ref id="B253">
        <label>253</label>
        <mixed-citation>253. Geng DF, Jin DM, Wu W, Xu Y, Wang JF. Angiotensin receptor blockers
               for prevention of new-onset type 2 diabetes: a meta-analysis of 59,862 patients. Int
               J Cardiol. 2012;155(8):236-42.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Geng</surname>
              <given-names>DF</given-names>
            </name>
            <name>
              <surname>Jin</surname>
              <given-names>DM</given-names>
            </name>
            <name>
              <surname>Wu</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Xu</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Wang</surname>
              <given-names>JF</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Angiotensin receptor blockers for prevention of
                  new-onset type 2 diabetes: a meta-analysis of 59,862 patients</article-title>
          <source>Int J Cardiol</source>
          <year>2012</year>
          <volume>155</volume>
          <issue>8</issue>
          <fpage>236</fpage>
          <lpage>242</lpage>
        </element-citation>
      </ref>
      <ref id="B254">
        <label>254</label>
        <mixed-citation>254. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi
               H, et al. Eplerenone in patients with systolic heart failure and mild symptoms.
               EMPHASIS-HF Study Group. N Engl J Med. 2011;364(1):11-21.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Zannad</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>McMurray</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Krum</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>van Veldhuisen</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Swedberg</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Shi</surname>
              <given-names>H</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Eplerenone in patients with systolic heart failure and
                  mild symptoms</article-title>
          <collab>EMPHASIS-HF Study Group</collab>
          <source>N Engl J Med</source>
          <year>2011</year>
          <volume>364</volume>
          <issue>1</issue>
          <fpage>11</fpage>
          <lpage>21</lpage>
        </element-citation>
      </ref>
      <ref id="B255">
        <label>255</label>
        <mixed-citation>255. Swaminathan K, Davies J, George J, Rajendra NS, Morris AD,
               Struthers AD. Spironolactone for poorly controlled hypertension in type 2 diabetes:
               conflicting effects on blood pressure, endothelial function, glycaemic control and
               hormonal profiles. Diabetologia. 2008;51(5):762-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Swaminathan</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Davies</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>George</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Rajendra</surname>
              <given-names>NS</given-names>
            </name>
            <name>
              <surname>Morris</surname>
              <given-names>AD</given-names>
            </name>
            <name>
              <surname>Struthers</surname>
              <given-names>AD</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Spironolactone for poorly controlled hypertension in
                  type 2 diabetes: conflicting effects on blood pressure, endothelial function,
                  glycaemic control and hormonal profiles</article-title>
          <source>Diabetologia</source>
          <year>2008</year>
          <volume>51</volume>
          <issue>5</issue>
          <fpage>762</fpage>
          <lpage>768</lpage>
        </element-citation>
      </ref>
      <ref id="B256">
        <label>256</label>
        <mixed-citation>256. Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii
               M,et al. Effect of eplerenone versus spironolactone on cortisol and hemoglobin A1(c)
               levels in patients with chronic heart failure. Am Heart J.
               2010;160(5):915-21.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Yamaji</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Tsutamoto</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Kawahara</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Nishiyama</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Yamamoto</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Fujii</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effect of eplerenone versus spironolactone on cortisol
                  and hemoglobin A1(c) levels in patients with chronic heart failure</article-title>
          <source>Am Heart J</source>
          <year>2010</year>
          <volume>160</volume>
          <issue>5</issue>
          <fpage>915</fpage>
          <lpage>921</lpage>
        </element-citation>
      </ref>
      <ref id="B257">
        <label>257</label>
        <mixed-citation>257. Preiss D, van Veldhuisen DJ, Sattar N, Krum H, Swedberg K, Shi H,
               et al. Eplerenone and new-onset diabetes in patients with mild heart failure: results
               from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart
               Failure (EMPHASIS-HF). Eur J Heart Fail. 2012;14(8):909-15.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Preiss</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>van Veldhuisen</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Sattar</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Krum</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Swedberg</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Shi</surname>
              <given-names>H</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Eplerenone and new-onset diabetes in patients with mild
                  heart failureresults from the Eplerenone in Mild Patients Hospitalization and
                  Survival Study in Heart Failure (EMPHASIS-HF) </article-title>
          <source>Eur J Heart Fail</source>
          <year>2012</year>
          <volume>14</volume>
          <issue>8</issue>
          <fpage>909</fpage>
          <lpage>915</lpage>
        </element-citation>
      </ref>
      <ref id="B258">
        <label>258</label>
        <mixed-citation>258. Misbin RI. The phantom of lactic acidosis due to metformin in
               patients with diabetes. Diabetes Care. 2004;27(7):1791-3.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Misbin</surname>
              <given-names>RI</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The phantom of lactic acidosis due to metformin in
                  patients with diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2004</year>
          <volume>27</volume>
          <issue>7</issue>
          <fpage>1791</fpage>
          <lpage>1793</lpage>
        </element-citation>
      </ref>
      <ref id="B259">
        <label>259</label>
        <mixed-citation>259. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold
               L, et al. Comparative safety and effectiveness of metformin in patients with diabetes
               mellitus and heart failure: systematic review of observational studies involving
               34,000 patients. Circ Heart Fail. 2013;6(3):395-402.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Eurich</surname>
              <given-names>DT</given-names>
            </name>
            <name>
              <surname>Weir</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Tsuyuki</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Johnson</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Tjosvold</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Comparative safety and effectiveness of metformin in
                  patients with diabetes mellitus and heart failures: ystematic review of
                  observational studies involving 34,000 patients</article-title>
          <source>Circ Heart Fail</source>
          <year>2013</year>
          <volume>6</volume>
          <issue>3</issue>
          <fpage>395</fpage>
          <lpage>402</lpage>
        </element-citation>
      </ref>
      <ref id="B260">
        <label>260</label>
        <mixed-citation>260. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA.
               Improved clinical outcomes associated with metformin in patients with diabetes and
               heart failure. Diabetes Care. 2005;28(10):2345-51.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Eurich</surname>
              <given-names>DT</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>McAlister</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Tsuyuki</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Johnson</surname>
              <given-names>JA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Improved clinical outcomes associated with metformin in
                  patients with diabetes and heart failure</article-title>
          <source>Diabetes Care</source>
          <year>2005</year>
          <volume>28</volume>
          <issue>10</issue>
          <fpage>2345</fpage>
          <lpage>2351</lpage>
        </element-citation>
      </ref>
      <ref id="B261">
        <label>261</label>
        <mixed-citation>261. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA.
               Levels of evidence needed for changing indications, contraindications, and Food and
               Drug Administration labeling: the case of metformin. Arch Intern Med.
               2011;171(11):1042-3.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Eurich</surname>
              <given-names>DT</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>McAlister</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Tsuyuki</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Johnson</surname>
              <given-names>JA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Levels of evidence needed for changing indications,
                  contraindications, and Food and Drug Administration labeling: the case of
                  metformin</article-title>
          <source>Arch Intern Med</source>
          <year>2011</year>
          <volume>171</volume>
          <issue>11</issue>
          <fpage>1042</fpage>
          <lpage>1043</lpage>
        </element-citation>
      </ref>
      <ref id="B262">
        <label>262</label>
        <mixed-citation>262. Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use
               and mortality in ambulatory patients with diabetes and heart failure. Circ Heart
               Fail. 2011;4(1):53-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Aguilar</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Chan</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Bozkurt</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Ramasubbu</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Deswal</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Metformin use and mortality in ambulatory patients with
                  diabetes and heart failure</article-title>
          <source>Circ Heart Fail</source>
          <year>2011</year>
          <volume>4</volume>
          <issue>1</issue>
          <fpage>53</fpage>
          <lpage>58</lpage>
        </element-citation>
      </ref>
      <ref id="B263">
        <label>263</label>
        <mixed-citation>263. MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund
               PS, et al. Treatment of type 2 diabetes and outcomes in patients with heart failure:
               a nested case-control study from the U.K. General Practice Research Database.
               Diabetes Care. 2010;33(6):1213-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>MacDonald</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Eurich</surname>
              <given-names>DT</given-names>
            </name>
            <name>
              <surname>Majumdar</surname>
              <given-names>SR</given-names>
            </name>
            <name>
              <surname>Lewsey</surname>
              <given-names>JD</given-names>
            </name>
            <name>
              <surname>Bhagra</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Jhund</surname>
              <given-names>PS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Treatment of type 2 diabetes and outcomes in patients
                  with heart failure: a nested case-control study from the U.K. General Practice
                  Research Database</article-title>
          <source>Diabetes Care</source>
          <year>2010</year>
          <volume>33</volume>
          <issue>6</issue>
          <fpage>1213</fpage>
          <lpage>1218</lpage>
        </element-citation>
      </ref>
      <ref id="B264">
        <label>264</label>
        <mixed-citation>264. Andersson C, Gislason GH, J&#248;rgensen CH, Hansen PR, Vaag A, S&#248;rensen
               R, et al. Comparable long-term mortality risk associated with individual
               sulfonylureas in diabetes patients with heart failure. Diabetes Res Clin Pract.
               2011;94(1):119-25.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Andersson</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Gislason</surname>
              <given-names>GH</given-names>
            </name>
            <name>
              <surname>J&#248;rgensen</surname>
              <given-names>CH</given-names>
            </name>
            <name>
              <surname>Hansen</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Vaag</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>S&#248;rensen</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Comparable long-term mortality risk associated with
                  individual sulfonylureas in diabetes patients with heart failure</article-title>
          <source>Diabetes Res Clin Pract</source>
          <year>2011</year>
          <volume>94</volume>
          <issue>1</issue>
          <fpage>119</fpage>
          <lpage>125</lpage>
        </element-citation>
      </ref>
      <ref id="B265">
        <label>265</label>
        <mixed-citation>265. Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, et
               al. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled
               evaluation of glimepiride and glibenclamide. Eur Heart J.
               1999;20(6):439-46.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Klepzig</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Kober</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Matter</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Luus</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Schneider</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Boedeker</surname>
              <given-names>KH</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Sulfonylureas and ischaemic preconditioning; a
                  double-blind, placebo-controlled evaluation of glimepiride and
                  glibenclamide</article-title>
          <source>Eur Heart J</source>
          <year>1999</year>
          <volume>20</volume>
          <issue>6</issue>
          <fpage>439</fpage>
          <lpage>446</lpage>
        </element-citation>
      </ref>
      <ref id="B266">
        <label>266</label>
        <mixed-citation>266. Riddle MC. Sulfonylureas differ in effects on ischemic
               preconditioning--is it time to retire glyburide? J Clin Endocrinol Metab.
               2003;88(2):528-30.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Riddle</surname>
              <given-names>MC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Sulfonylureas differ in effects on ischemic
                  preconditioning--is it time to retire glyburide?</article-title>
          <source>J Clin Endocrinol Metab</source>
          <year>2003</year>
          <volume>88</volume>
          <issue>2</issue>
          <fpage>528</fpage>
          <lpage>530</lpage>
        </element-citation>
      </ref>
      <ref id="B267">
        <label>267</label>
        <mixed-citation>267. Rendell M. The role of sulphonylureas in the management of type 2
               diabetes mellitus. Drugs. 2004;64(12):1339-58.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rendell</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The role of sulphonylureas in the management of type 2
                  diabetes mellitus</article-title>
          <source>Drugs</source>
          <year>2004</year>
          <volume>64</volume>
          <issue>12</issue>
          <fpage>1339</fpage>
          <lpage>1358</lpage>
        </element-citation>
      </ref>
      <ref id="B268">
        <label>268</label>
        <mixed-citation>268. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and
               cardiovascular events. Diabetes Care. 2010;33(6):1389-94.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Desouza</surname>
              <given-names>CV</given-names>
            </name>
            <name>
              <surname>Bolli</surname>
              <given-names>GB</given-names>
            </name>
            <name>
              <surname>Fonseca</surname>
              <given-names>V</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Hypoglycemia, diabetes, and cardiovascular
                  events</article-title>
          <source>Diabetes Care</source>
          <year>2010</year>
          <volume>33</volume>
          <issue>6</issue>
          <fpage>1389</fpage>
          <lpage>1394</lpage>
        </element-citation>
      </ref>
      <ref id="B269">
        <label>269</label>
        <mixed-citation>269. Riddle MC. More reasons to say goodbye to glyburide. J Clin
               Endocrinol Metab. 2010;95(11):4867-70.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Riddle</surname>
              <given-names>MC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">More reasons to say goodbye to glyburide</article-title>
          <source>J Clin Endocrinol Metab</source>
          <year>2010</year>
          <volume>95</volume>
          <issue>11</issue>
          <fpage>4867</fpage>
          <lpage>4870</lpage>
        </element-citation>
      </ref>
      <ref id="B270">
        <label>270</label>
        <mixed-citation>270. Tenenbaum A, Fisman EZ. Impaired glucose metabolism in patients
               with heart failure: pathophysiology and possible treatment strategies. Am J
               Cardiovasc Drugs. 2004;4(5):269-80.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tenenbaum</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Fisman</surname>
              <given-names>EZ</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Impaired glucose metabolism in patients with heart
                  failure: pathophysiology and possible treatment strategies</article-title>
          <source>Am J Cardiovasc Drugs</source>
          <year>2004</year>
          <volume>4</volume>
          <issue>5</issue>
          <fpage>269</fpage>
          <lpage>280</lpage>
        </element-citation>
      </ref>
      <ref id="B271">
        <label>271</label>
        <mixed-citation>271. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al.
               Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus
               statement from the American Heart Association and American Diabetes Association.
               Diabetes Care. 2004;27(7):256-63.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nesto</surname>
              <given-names>RW</given-names>
            </name>
            <name>
              <surname>Bell</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Bonow</surname>
              <given-names>RO</given-names>
            </name>
            <name>
              <surname>Fonseca</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Grundy</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Horton</surname>
              <given-names>ES</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Thiazolidinedione use, fluid retention, and congestive
                  heart failure: a consensus statement from the American Heart Association and
                  American Diabetes Association</article-title>
          <source>Diabetes Care</source>
          <year>2004</year>
          <volume>27</volume>
          <issue>7</issue>
          <fpage>256</fpage>
          <lpage>263</lpage>
        </element-citation>
      </ref>
      <ref id="B272">
        <label>272</label>
        <mixed-citation>272. Kaul S, Bolger AF, Herrington D, Giugliano RP, Eckel RH.
               Thiazolidinedione drugs and cardiovascular risks: a science advisory from the
               American Heart Association and American College Of Cardiology Foundation. American
               Heart Association American College Of Cardiology Foundation. J Am Coll Cardiol.
               2010;55(17):1885-94.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kaul</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Bolger</surname>
              <given-names>AF</given-names>
            </name>
            <name>
              <surname>Herrington</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Giugliano</surname>
              <given-names>RP</given-names>
            </name>
            <name>
              <surname>Eckel</surname>
              <given-names>RH</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Thiazolidinedione drugs and cardiovascular risks: a
                  science advisory from the American Heart Association and American College Of
                  Cardiology Foundation. American Heart Association American College Of Cardiology
                  Foundation</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>55</volume>
          <issue>17</issue>
          <fpage>1885</fpage>
          <lpage>1894</lpage>
        </element-citation>
      </ref>
      <ref id="B273">
        <label>273</label>
        <mixed-citation>273. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy
               in type 2 diabetes: systematic review and meta-analysis. JAMA.
               2007;298(2):194-206.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Amori</surname>
              <given-names>RE</given-names>
            </name>
            <name>
              <surname>Lau</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Pittas</surname>
              <given-names>AG</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Efficacy and safety of incretin therapy in type 2
                  diabetes: systematic review and meta-analysis</article-title>
          <source>JAMA</source>
          <year>2007</year>
          <volume>298</volume>
          <issue>2</issue>
          <fpage>194</fpage>
          <lpage>206</lpage>
        </element-citation>
      </ref>
      <ref id="B274">
        <label>274</label>
        <mixed-citation>274. Todd JF, Bloom SR. Incretins and other peptides in the treatment of
               diabetes. Diabet Med. 2007;24(3):223-32.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Todd</surname>
              <given-names>JF</given-names>
            </name>
            <name>
              <surname>Bloom</surname>
              <given-names>SR</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Incretins and other peptides in the treatment of
                  diabetes</article-title>
          <source>Diabet Med</source>
          <year>2007</year>
          <volume>24</volume>
          <issue>3</issue>
          <fpage>223</fpage>
          <lpage>232</lpage>
        </element-citation>
      </ref>
      <ref id="B275">
        <label>275</label>
        <mixed-citation>275. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2
               diabetes treated with exenatide or sitagliptin: a retrospective observational
               pharmacy claims analysis. Diabetes Care.2010;33(11):2349-54.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Garg</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Pendergrass</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Acute pancreatitis in type 2 diabetes treated with
                  exenatide or sitagliptin: a retrospective observational pharmacy claims
                  analysis</article-title>
          <source>Diabetes Care</source>
          <year>2010</year>
          <volume>33</volume>
          <issue>11</issue>
          <fpage>2349</fpage>
          <lpage>2354</lpage>
        </element-citation>
      </ref>
      <ref id="B276">
        <label>276</label>
        <mixed-citation>276. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC.
               Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based
               therapies. Gastroenterology. 2011;141(1):150-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Elashoff</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Matveyenko</surname>
              <given-names>AV</given-names>
            </name>
            <name>
              <surname>Gier</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Elashoff</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Butler</surname>
              <given-names>PC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Pancreatitis, pancreatic, and thyroid cancer with
                  glucagon-like peptide-1-based therapies</article-title>
          <source>Gastroenterology</source>
          <year>2011</year>
          <volume>141</volume>
          <issue>1</issue>
          <fpage>150</fpage>
          <lpage>156</lpage>
        </element-citation>
      </ref>
      <ref id="B277">
        <label>277</label>
        <mixed-citation>277. Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen YT, et
               al. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP
               kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated
               cardiomyopathy. Circ Heart Fail. 2010;3(4):512-21.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bhashyam</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Fields</surname>
              <given-names>AV</given-names>
            </name>
            <name>
              <surname>Patterson</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Testani</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Shen</surname>
              <given-names>YT</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Glucagon-like peptide-1 increases myocardial glucose
                  uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in
                  conscious dogs with dilated cardiomyopathy</article-title>
          <source>Circ Heart Fail</source>
          <year>2010</year>
          <volume>3</volume>
          <issue>4</issue>
          <fpage>512</fpage>
          <lpage>521</lpage>
        </element-citation>
      </ref>
      <ref id="B278">
        <label>278</label>
        <mixed-citation>278. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al.
               Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and
               left ventricular dysfunction after successful reperfusion. Circulation.
               2004;109(8):962-5.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nikolaidis</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Mankad</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Sokos</surname>
              <given-names>GG</given-names>
            </name>
            <name>
              <surname>Miske</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Shah</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Elahi</surname>
              <given-names>D</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of glucagon-like peptide-1 in patients with
                  acute myocardial infarction and left ventricular dysfunction after successful
                  reperfusion</article-title>
          <source>Circulation</source>
          <year>2004</year>
          <volume>109</volume>
          <issue>8</issue>
          <fpage>962</fpage>
          <lpage>965</lpage>
        </element-citation>
      </ref>
      <ref id="B279">
        <label>279</label>
        <mixed-citation>279. Nathanson D, Ullman B, L&#246;fstr&#246;m U, Hedman A, Frick M, Sj&#246;holm A, et
               al. Effects of intravenous exenatide in type 2 diabetic patients with congestive
               heart failure: a double-blind, randomised controlled clinical trial of efficacy and
               safety. Diabetologia. 2012;55(4):926-35.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Nathanson</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Ullman</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>L&#246;fstr&#246;m</surname>
              <given-names>U</given-names>
            </name>
            <name>
              <surname>Hedman</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Frick</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sj&#246;holm</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of intravenous exenatide in type 2 diabetic
                  patients with congestive heart failure: a double-blind, randomised controlled
                  clinical trial of efficacy and safety</article-title>
          <source>Diabetologia</source>
          <year>2012</year>
          <volume>55</volume>
          <issue>4</issue>
          <fpage>926</fpage>
          <lpage>935</lpage>
        </element-citation>
      </ref>
      <ref id="B280">
        <label>280</label>
        <mixed-citation>280. Halbirk M, N&#248;rrelund H, M&#248;ller N, Holst JJ, Schmitz O, Nielsen R,
               et al. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion
               in compensated chronic patients with heart failure. Am J Physiol Heart Circ Physiol.
               2010;298(3):H1096-102.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Halbirk</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>N&#248;rrelund</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>M&#248;ller</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Holst</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Schmitz</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Nielsen</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Cardiovascular and metabolic effects of 48-h
                  glucagon-like peptide-1 infusion in compensated chronic patients with heart
                  failure</article-title>
          <source>Am J Physiol Heart Circ Physiol</source>
          <year>2010</year>
          <volume>298</volume>
          <issue>3</issue>
          <fpage>H1096</fpage>
          <lpage>H1102</lpage>
        </element-citation>
      </ref>
      <ref id="B281">
        <label>281</label>
        <mixed-citation>281. Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L.
               Cardiovascular safety of exenatide BID: an integrated analysis from controlled
               clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol. 2011 mar
               16;10:22.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ratner</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Han</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Nicewarner</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Yushmanova</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Hoogwerf</surname>
              <given-names>BJ</given-names>
            </name>
            <name>
              <surname>Shen</surname>
              <given-names>L</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Cardiovascular safety of exenatide BID: an integrated
                  analysis from controlled clinical trials in participants with type 2
                  diabetes</article-title>
          <source>Cardiovasc Diabetol</source>
          <day>16</day>
          <month>03</month>
          <year>2011</year>
          <volume>10</volume>
          <fpage>22</fpage>
          <lpage>22</lpage>
        </element-citation>
      </ref>
      <ref id="B282">
        <label>282</label>
        <mixed-citation>282. Monami M, Cremasco F, Lamanna C, Colombi C, Desideri CM, Iacomelli
               I, et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a
               meta-analysis of randomized clinical trials. Exp Diabetes Res.
               2011;21:57-64.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Monami</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Cremasco</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Lamanna</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Colombi</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Desideri</surname>
              <given-names>CM</given-names>
            </name>
            <name>
              <surname>Iacomelli</surname>
              <given-names>I</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Glucagon-like peptide-1 receptor agonists and
                  cardiovascular events: a meta-analysis of randomized clinical
                  trials</article-title>
          <source>Exp Diabetes Res</source>
          <year>2011</year>
          <volume>21</volume>
          <fpage>57</fpage>
          <lpage>64</lpage>
        </element-citation>
      </ref>
      <ref id="B283">
        <label>283</label>
        <mixed-citation>283. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, et
               al. Acarbose treatment and the risk of cardiovascular disease and hypertension in
               patients with impaired glucose tolerance: the STOP-NIDDM trial. STOP-NIDDM Trial
               Research Group. JAMA. 2003;290(4):486-94.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chiasson</surname>
              <given-names>JL</given-names>
            </name>
            <name>
              <surname>Josse</surname>
              <given-names>RG</given-names>
            </name>
            <name>
              <surname>Gomis</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Hanefeld</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Karasik</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Laakso</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
            <collab>STOP-NIDDM Trial Research Group</collab>
          </person-group>
          <article-title xml:lang="en">Acarbose treatment and the risk of cardiovascular
                  disease and hypertension in patients with impaired glucose tolerance: the
                  STOP-NIDDM trial</article-title>
          <source>JAMA</source>
          <year>2003</year>
          <volume>290</volume>
          <issue>4</issue>
          <fpage>486</fpage>
          <lpage>494</lpage>
        </element-citation>
      </ref>
      <ref id="B284">
        <label>284</label>
        <mixed-citation>284. Liao Y, Takashima S, Zhao H, Asano Y, Shintani Y, Minamino T, et
               al. Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative
               stress and slows the progression of heart failure in mice. Cardiovasc Res.
               2006;70(1):107-16.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Liao</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Takashima</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Zhao</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Asano</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Shintani</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Minamino</surname>
              <given-names>T</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Control of plasma glucose with alpha-glucosidase
                  inhibitor attenuates oxidative stress and slows the progression of heart failure
                  in mice</article-title>
          <source>Cardiovasc Res</source>
          <year>2006</year>
          <volume>70</volume>
          <issue>1</issue>
          <fpage>107</fpage>
          <lpage>116</lpage>
        </element-citation>
      </ref>
      <ref id="B285">
        <label>285</label>
        <mixed-citation>285. Ben-Ami H, Krivoy N, Nagachandran P, Roguin A, Edoute Y. An
               interaction between digoxin and acarbose. Diabetes Care.
               1999;22(5):860-1.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ben-Ami</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Krivoy</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Nagachandran</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Roguin</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Edoute</surname>
              <given-names>Y</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">An interaction between digoxin and
                  acarbose</article-title>
          <source>Diabetes Care</source>
          <year>1999</year>
          <volume>22</volume>
          <issue>5</issue>
          <fpage>860</fpage>
          <lpage>861</lpage>
        </element-citation>
      </ref>
      <ref id="B286">
        <label>286</label>
        <mixed-citation>286. Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB,
               et al. Predictors of mortality and morbidity in patients with chronic heart failure.
               Eur Heart J. 2006;27(1):65-75.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Pocock</surname>
              <given-names>SJ</given-names>
            </name>
            <name>
              <surname>Wang</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Pfeffer</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Yusuf</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>McMurray</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Swedberg</surname>
              <given-names>KB</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Predictors of mortality and morbidity in patients with
                  chronic heart failure</article-title>
          <source>Eur Heart J</source>
          <year>2006</year>
          <volume>27</volume>
          <issue>1</issue>
          <fpage>65</fpage>
          <lpage>75</lpage>
        </element-citation>
      </ref>
      <ref id="B287">
        <label>287</label>
        <mixed-citation>287. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz
               HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and
               heart failure: an observational study. Circulation.
               2005;111(5):583-90.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Masoudi</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Inzucchi</surname>
              <given-names>SE</given-names>
            </name>
            <name>
              <surname>Wang</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Havranek</surname>
              <given-names>EP</given-names>
            </name>
            <name>
              <surname>Foody</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Krumholz</surname>
              <given-names>HM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Thiazolidinediones, metformin, and outcomes in older
                  patients with diabetes and heart failure: an observational study</article-title>
          <source>Circulation</source>
          <year>2005</year>
          <volume>111</volume>
          <issue>5</issue>
          <fpage>583</fpage>
          <lpage>590</lpage>
        </element-citation>
      </ref>
      <ref id="B288">
        <label>288</label>
        <mixed-citation>288. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic
               neuropathy. Diabetes Care. 2003;26(:1553-1579.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vinik</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Maser</surname>
              <given-names>RE</given-names>
            </name>
            <name>
              <surname>Mitchell</surname>
              <given-names>BD</given-names>
            </name>
            <name>
              <surname>Freeman</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic autonomic neuropathy</article-title>
          <source>Diabetes Care</source>
          <year>2003</year>
          <volume>26</volume>
          <fpage>1553</fpage>
          <lpage>1579</lpage>
        </element-citation>
      </ref>
      <ref id="B289">
        <label>289</label>
        <mixed-citation>289. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy.
               Circulation. 2007;115(3):387-97.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vinik</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Ziegler</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic cardiovascular autonomic
                  neuropathy</article-title>
          <source>Circulation</source>
          <year>2007</year>
          <volume>115</volume>
          <issue>3</issue>
          <fpage>387</fpage>
          <lpage>397</lpage>
        </element-citation>
      </ref>
      <ref id="B290">
        <label>290</label>
        <mixed-citation>290. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M,
               Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its
               relation to glycaemic control and potential risk factors: the EURODIAB IDDM
               Complications Study. Diabetologia. 1996;39(10):1377-84.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tesfaye</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Stevens</surname>
              <given-names>LK</given-names>
            </name>
            <name>
              <surname>Stephenson</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Fuller</surname>
              <given-names>JH</given-names>
            </name>
            <name>
              <surname>Plater</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Ionescu-Tirgoviste</surname>
              <given-names>C</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Prevalence of diabetic peripheral neuropathy and its
                  relation to glycaemic control and potential risk factors: the EURODIAB IDDM
                  Complications Study</article-title>
          <source>Diabetologia</source>
          <year>1996</year>
          <volume>39</volume>
          <issue>10</issue>
          <fpage>1377</fpage>
          <lpage>1384</lpage>
        </element-citation>
      </ref>
      <ref id="B291">
        <label>291</label>
        <mixed-citation>291. Rolim LC, S&#225; JR, Chacra AR, Dib SA. Diabetic cardiovascular
               autonomic neuropathy: risk factors, clinical impact and early diagnosis. Arq Bras
               Cardiol. 2008;90(4):e24-31.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Rolim</surname>
              <given-names>LC</given-names>
            </name>
            <name>
              <surname>S&#225;</surname>
              <given-names>JR</given-names>
            </name>
            <name>
              <surname>Chacra</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Dib</surname>
              <given-names>SA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Diabetic cardiovascular autonomic neuropathy: risk
                  factors, clinical impact and early diagnosis</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2008</year>
          <volume>90</volume>
          <issue>4</issue>
          <fpage>e24</fpage>
          <lpage>e31</lpage>
        </element-citation>
      </ref>
      <ref id="B292">
        <label>292</label>
        <mixed-citation>292. Balcioglu S, Arslan U, T&#252;rkoglu S, Ozdemir M, Cengel A. Heart rate
               variability and heart rate turbulence in patients with type 2 diabetes mellitus with
               versus without cardiac autonomic neuropathy. Am J
               Cardiol.2007;100(5):890-3.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Balcioglu</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Arslan</surname>
              <given-names>U</given-names>
            </name>
            <name>
              <surname>T&#252;rkoglu</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Ozdemir</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Cengel</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Heart rate variability and heart rate turbulence in
                  patients with type 2 diabetes mellitus with versus without cardiac autonomic
                  neuropathy</article-title>
          <source>Am J Cardiol</source>
          <year>2007</year>
          <volume>100</volume>
          <issue>5</issue>
          <fpage>890</fpage>
          <lpage>893</lpage>
        </element-citation>
      </ref>
      <ref id="B293">
        <label>293</label>
        <mixed-citation>293. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et
               al. Diabetic neuropathies: a statement by the American Diabetes Association. American
               Diabetes Association. Diabetes Care. 2005;28(4):956-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Boulton</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Vinik</surname>
              <given-names>AI</given-names>
            </name>
            <name>
              <surname>Arezzo</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Bril</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Feldman</surname>
              <given-names>EL</given-names>
            </name>
            <name>
              <surname>Freeman</surname>
              <given-names>R</given-names>
            </name>
            <etal>et al</etal>
            <collab>American Diabetes Association</collab>
          </person-group>
          <article-title xml:lang="en">Diabetic neuropathies: a statement by the American
                  Diabetes Association</article-title>
          <source>Diabetes Care</source>
          <year>2005</year>
          <volume>28</volume>
          <issue>4</issue>
          <fpage>956</fpage>
          <lpage>962</lpage>
        </element-citation>
      </ref>
      <ref id="B294">
        <label>294</label>
        <mixed-citation>294. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P,
               et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation
               of severity, and treatments. Toronto Diabetic Neuropathy Expert Group. Diabetes Care.
               2010;33(11):2285-93.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tesfaye</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Boulton</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Dyck</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>Freeman</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Horowitz</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Kempler</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
            <collab>Toronto Diabetic Neuropathy Expert Group</collab>
          </person-group>
          <article-title xml:lang="en">Diabetic neuropathies: update on definitions, diagnostic
                  criteria, estimation of severity, and treatments</article-title>
          <source>Diabetes Care</source>
          <year>2010</year>
          <volume>33</volume>
          <issue>11</issue>
          <fpage>2285</fpage>
          <lpage>2293</lpage>
        </element-citation>
      </ref>
      <ref id="B295">
        <label>295</label>
        <mixed-citation>295. Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT,
               Bray GA, et al. American Association of Clinical Endocrinologists Medical Guidelines
               for Clinical Practice for developing a diabetes mellitus comprehensive care plan.
               AACE Task Force for Developing Diabetes Comprehensive Care Plan. Endocr Pract.
               2011;17(Suppl 2):1-53.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Handelsman</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Mechanick</surname>
              <given-names>JI</given-names>
            </name>
            <name>
              <surname>Blonde</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Grunberger</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Bloomgarden</surname>
              <given-names>ZT</given-names>
            </name>
            <name>
              <surname>Bray</surname>
              <given-names>GA</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">American Association of Clinical Endocrinologists
                  Medical Guidelines for Clinical Practice for developing a diabetes mellitus
                  comprehensive care plan. AACE Task Force for Developing Diabetes Comprehensive
                  Care Plan</article-title>
          <source>Endocr Pract</source>
          <year>2011</year>
          <volume>17</volume>
          <supplement>Suppl 2</supplement>
          <fpage>1</fpage>
          <lpage>53</lpage>
        </element-citation>
      </ref>
      <ref id="B296">
        <label>296</label>
        <mixed-citation>296. Macedo PG, Leite LR, Santos-Neto L, Hachul D. Tilt test--from the
               necessary to the indispensable. Arq Bras Cardiol. 2011;96(3):246-54.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Macedo</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Leite</surname>
              <given-names>LR</given-names>
            </name>
            <name>
              <surname>Santos-Neto</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Hachul</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Tilt test--from the necessary to the
                  indispensable</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2011</year>
          <volume>96</volume>
          <issue>3</issue>
          <fpage>246</fpage>
          <lpage>254</lpage>
        </element-citation>
      </ref>
      <ref id="B297">
        <label>297</label>
        <mixed-citation>297. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de
               Hipertens&#227;o, Sociedade Brasileira de Nefrologia. [VI Brazilian Guidelines on
               Hypertension]. Arq Bras Cardiol. 2010;95(1 Suppl):1-51.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>Sociedade Brasileira de Cardiologia</collab>
            <collab>Sociedade Brasileira de Hipertens&#227;o</collab>
            <collab>Sociedade Brasileira de Nefrologia</collab>
          </person-group>
          <trans-title xml:lang="en">VI Brazilian Guidelines on Hypertension</trans-title>
          <source>Arq Bras Cardiol</source>
          <year>2010</year>
          <volume>95</volume>
          <issue>1</issue>
          <supplement>Suppl</supplement>
          <fpage>1</fpage>
          <lpage>51</lpage>
        </element-citation>
      </ref>
      <ref id="B298">
        <label>298</label>
        <mixed-citation>298. Deedwania PC. Blood pressure control in diabetes mellitus: is lower
               always better, and how low should it go? Circulation.
               2011;123(24):2776-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Deedwania</surname>
              <given-names>PC</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Blood pressure control in diabetes mellitus: is lower
                  always better, and how low should it go?</article-title>
          <source>Circulation</source>
          <year>2011</year>
          <volume>123</volume>
          <issue>24</issue>
          <fpage>2776</fpage>
          <lpage>2778</lpage>
        </element-citation>
      </ref>
      <ref id="B299">
        <label>299</label>
        <mixed-citation>299. Garcia-Touza M, Sowers JR. Evidence-based hypertension treatment in
               patients with diabetes. J Clin Hypertens (Greenwich).
               2012;14(2):97-102.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Garcia-Touza</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sowers</surname>
              <given-names>JR</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Evidence-based hypertension treatment in patients with
                  diabetes</article-title>
          <source>J Clin Hypertens (Greenwich)</source>
          <year>2012</year>
          <volume>14</volume>
          <issue>2</issue>
          <fpage>97</fpage>
          <lpage>102</lpage>
        </element-citation>
      </ref>
      <ref id="B300">
        <label>300</label>
        <mixed-citation>300. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano
               G, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force
               for the Management of Arterial Hypertension of the European Society of Hypertension
               (ESH) and of the European Society of Cardiology (ESC). Eur Heart J.
               2007;28(12):1462-536.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mancia</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>De Backer</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Dominiczak</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Cifkova</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Fagard</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Germano</surname>
              <given-names>G</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2007 Guidelines for the management of arterial
                  hypertension: The Task Force for the Management of Arterial Hypertension of the
                  European Society of Hypertension (ESH) and of the European Society of Cardiology
                  (ESC)</article-title>
          <source>Eur Heart J</source>
          <year>2007</year>
          <volume>28</volume>
          <issue>12</issue>
          <fpage>1462</fpage>
          <lpage>1536</lpage>
        </element-citation>
      </ref>
      <ref id="B301">
        <label>301</label>
        <mixed-citation>301. Van der Zwan LP, Scheffer PG, Dekker JM, Stehouwer CD, Heine RJ,
               Teerlink T. Hyperglycemia and oxidative stress strengthen the association between
               myeloperoxidase and blood pressure. Hypertension.
               2010;55(6):1366-72.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Van der Zwan</surname>
              <given-names>LP</given-names>
            </name>
            <name>
              <surname>Scheffer</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>Dekker</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Stehouwer</surname>
              <given-names>CD</given-names>
            </name>
            <name>
              <surname>Heine</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Teerlink</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Hyperglycemia and oxidative stress strengthen the
                  association between myeloperoxidase and blood pressure</article-title>
          <source>Hypertension</source>
          <year>2010</year>
          <volume>55</volume>
          <issue>6</issue>
          <fpage>1366</fpage>
          <lpage>1372</lpage>
        </element-citation>
      </ref>
      <ref id="B302">
        <label>302</label>
        <mixed-citation>302. National Clinical Guideline Centre (UK). Hypertension: the clinical
               management of primary hypertension in adults: update of clinical guidelines 18 and
               34[Internet]. London: Royal College of Physicians (UK); Aug 2011. (NICE Clinical
               Guidelines, No. 127)</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>National Clinical Guideline Centre (UK)</collab>
          </person-group>
          <source xml:lang="en">Hypertension: the clinical management of primary hypertension
                  in adults: update of clinical guidelines 18 and 34[Internet]</source>
          <publisher-loc>London</publisher-loc>
          <publisher-name>Royal College of Physicians (UK)</publisher-name>
          <month>Aug </month>
          <year>2011</year>
          <comment>NICE Clinical Guidelines, No. 127</comment>
        </element-citation>
      </ref>
      <ref id="B303">
        <label>303</label>
        <mixed-citation>303. Van den Born BJ, Hulsman CA, Hoekstra JB, Schlingemann RO, van
               Montfrans GA. Value of routine funduscopy in patients with hypertension: systematic
               review. BMJ. 2005;331(7508):73.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Van den Born</surname>
              <given-names>BJ</given-names>
            </name>
            <name>
              <surname>Hulsman</surname>
              <given-names>CA</given-names>
            </name>
            <name>
              <surname>Hoekstra</surname>
              <given-names>JB</given-names>
            </name>
            <name>
              <surname>Schlingemann</surname>
              <given-names>RO</given-names>
            </name>
            <name>
              <surname>van Montfrans</surname>
              <given-names>GA</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Value of routine funduscopy in patients with
                  hypertension: systematic review</article-title>
          <source>BMJ</source>
          <year>2005</year>
          <volume>331</volume>
          <issue>7508</issue>
          <fpage>73</fpage>
          <lpage>73</lpage>
        </element-citation>
      </ref>
      <ref id="B304">
        <label>304</label>
        <mixed-citation>304. Hsu CC, Brancati FL, Astor BC, Kao WH, Steffes MW, Folsom AR, et
               al. Blood pressure, atherosclerosis, and albuminuria in 10,113 participants in the
               atherosclerosis risk in communities study. J Hypertens.
               2009;27(2):397-409.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hsu</surname>
              <given-names>CC</given-names>
            </name>
            <name>
              <surname>Brancati</surname>
              <given-names>FL</given-names>
            </name>
            <name>
              <surname>Astor</surname>
              <given-names>BC</given-names>
            </name>
            <name>
              <surname>Kao</surname>
              <given-names>WH</given-names>
            </name>
            <name>
              <surname>Steffes</surname>
              <given-names>MW</given-names>
            </name>
            <name>
              <surname>Folsom</surname>
              <given-names>AR</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Blood pressure, atherosclerosis, and albuminuria in
                  10,113 participants in the atherosclerosis risk in communities
                  study</article-title>
          <source>J Hypertens</source>
          <year>2009</year>
          <volume>27</volume>
          <issue>2</issue>
          <fpage>397</fpage>
          <lpage>409</lpage>
        </element-citation>
      </ref>
      <ref id="B305">
        <label>305</label>
        <mixed-citation>305. Mancia G, Fagard R, Narkiewicz K, Red&#243;n J, Zanchetti A, B&#246;hm M, et
               al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task
               Force for the management of arterial hypertension of the European Society of
               Hypertension (ESH) and of the European Society of Cardiology (ESC). Task Force
               Members. J Hypertens. 2013;31(12):1281-357.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mancia</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Fagard</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Narkiewicz</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Red&#243;n</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Zanchetti</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>B&#246;hm</surname>
              <given-names>M</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">2013 ESH/ESC Guidelines for the management of arterial
                  hypertension: the Task Force for the management of arterial hypertension of the
                  European Society of Hypertension (ESH) and of the European Society of Cardiology
                  (ESC). Task Force Members</article-title>
          <source>J Hypertens</source>
          <year>2013</year>
          <volume>31</volume>
          <issue>12</issue>
          <fpage>1281</fpage>
          <lpage>1357</lpage>
        </element-citation>
      </ref>
      <ref id="B306">
        <label>306</label>
        <mixed-citation>306. Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell'Italia LJ,
               et al. Effects of dietary sodium reduction on blood pressure in subjects with
               resistant hypertension: results from a randomized trial. Hypertension.
               2009;54(3):475-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Pimenta</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Gaddam</surname>
              <given-names>KK</given-names>
            </name>
            <name>
              <surname>Oparil</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Aban</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Husain</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Dell'Italia</surname>
              <given-names>LJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Effects of dietary sodium reduction on blood pressure in
                  subjects with resistant hypertension: results from a randomized
                  trial</article-title>
          <source>Hypertension</source>
          <year>2009</year>
          <volume>54</volume>
          <issue>3</issue>
          <fpage>475</fpage>
          <lpage>481</lpage>
        </element-citation>
      </ref>
      <ref id="B307">
        <label>307</label>
        <mixed-citation>307. Murphy MH, Nevill AM, Murtagh EM, Holder RL. The effect of walking
               on fitness, fatness and resting blood pressure: a meta-analysis of randomised,
               controlled trials. Prev Med. 2007;44(20):377-85.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Murphy</surname>
              <given-names>MH</given-names>
            </name>
            <name>
              <surname>Nevill</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Murtagh</surname>
              <given-names>EM</given-names>
            </name>
            <name>
              <surname>Holder</surname>
              <given-names>RL</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">The effect of walking on fitness, fatness and resting
                  blood pressure: a meta-analysis of randomised, controlled trials</article-title>
          <source>Prev Med</source>
          <year>2007</year>
          <volume>44</volume>
          <issue>20</issue>
          <fpage>377</fpage>
          <lpage>385</lpage>
        </element-citation>
      </ref>
      <ref id="B308">
        <label>308</label>
        <mixed-citation>308. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et
               al. Sleep apnea and cardiovascular disease: an American Heart Association/american
               College Of Cardiology Foundation Scientific Statement from the American Heart
               Association Council for High Blood Pressure Research Professional Education
               Committee, Council on Clinical Cardiology, Stroke Council, and Council On
               Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood
               Institute National Center on Sleep Disorders Research (National Institutes of
               Health). Circulation. 2008;118(10):1080-111.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Somers</surname>
              <given-names>VK</given-names>
            </name>
            <name>
              <surname>White</surname>
              <given-names>DP</given-names>
            </name>
            <name>
              <surname>Amin</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Abraham</surname>
              <given-names>WT</given-names>
            </name>
            <name>
              <surname>Costa</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Culebras</surname>
              <given-names>A</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Sleep apnea and cardiovascular disease: an American
                  Heart Association/american College Of Cardiology Foundation Scientific Statement
                  from the American Heart Association Council for High Blood Pressure Research
                  Professional Education Committee, Council on Clinical Cardiology, Stroke Council,
                  and Council On Cardiovascular Nursing. In collaboration with the National Heart,
                  Lung, and Blood Institute National Center on Sleep Disorders Research (National
                  Institutes of Health)</article-title>
          <source>Circulation</source>
          <year>2008</year>
          <volume>118</volume>
          <issue>10</issue>
          <fpage>1080</fpage>
          <lpage>1111</lpage>
        </element-citation>
      </ref>
      <ref id="B309">
        <label>309</label>
        <mixed-citation>309. American Diabates Association. Standards of medical care in
               diabetes--2009. Diabetes Care. 2009;32(Suppl 1):S13-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>American Diabates Association</collab>
          </person-group>
          <article-title xml:lang="en">Standards of medical care in
                  diabetes--2009</article-title>
          <source>Diabetes Care</source>
          <year>2009</year>
          <volume>32</volume>
          <supplement>Suppl 1</supplement>
          <fpage>S13</fpage>
          <lpage>S61</lpage>
        </element-citation>
      </ref>
      <ref id="B310">
        <label>310</label>
        <mixed-citation>310. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et
               al. Effects of different blood pressure-lowering regimens on major cardiovascular
               events in individuals with and without diabetes mellitus: results of prospectively
               designed overviews of randomized trials. Blood Pressure Lowering Treatment Trialists'
               Collaboration. Arch Intern Med. 2005;165(12):1410-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Turnbull</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Neal</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Algert</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Chalmers</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Chapman</surname>
              <given-names>N</given-names>
            </name>
            <name>
              <surname>Cutler</surname>
              <given-names>J</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="pt">Effects of different blood pressure-lowering regimens on
                  major cardiovascular events in individuals with and without diabetes mellitus:
                  results of prospectively designed overviews of randomized trials</article-title>
          <collab>Blood Pressure Lowering Treatment Trialists' Collaboration</collab>
          <source>Arch Intern Med</source>
          <year>2005</year>
          <volume>165</volume>
          <issue>12</issue>
          <fpage>1410</fpage>
          <lpage>1419</lpage>
        </element-citation>
      </ref>
      <ref id="B311">
        <label>311</label>
        <mixed-citation>311. Major outcomes in high-risk hypertensive patients randomized to
               angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The
               Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
               ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The
               Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA.
               2002;288(23):2981-97.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <collab>ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
                     Group</collab>
            <collab>The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
                     Trial</collab>
          </person-group>
          <article-title xml:lang="en">Major outcomes in high-risk hypertensive patients
                  randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker
                  vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
                  Attack Trial (ALLHAT)</article-title>
          <source>JAMA</source>
          <year>2002</year>
          <volume>288</volume>
          <issue>23</issue>
          <fpage>2981</fpage>
          <lpage>2997</lpage>
        </element-citation>
      </ref>
      <ref id="B312">
        <label>312</label>
        <mixed-citation>312. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M,
               Caulfield MJ, et al. Reappraisal of European guidelines on hypertension management: a
               European Society of Hypertension Task Force document. European Society of
               Hypertension. J Hypertens. 2009;27(11):2121-58.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mancia</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Laurent</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Agabiti-Rosei</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Ambrosioni</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Burnier</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Caulfield</surname>
              <given-names>MJ</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Reappraisal of European guidelines on hypertension
                  management: a European Society of Hypertension Task Force document</article-title>
          <collab>European Society of Hypertension</collab>
          <source>J Hypertens</source>
          <year>2009</year>
          <volume>27</volume>
          <issue>11</issue>
          <fpage>2121</fpage>
          <lpage>2158</lpage>
        </element-citation>
      </ref>
      <ref id="B313">
        <label>313</label>
        <mixed-citation>313. Minist&#233;rio da Sa&#250;de. VIGITEL. Brasil 2011. (Vigil&#226;ncia de fatores
               de risco e prote&#231;&#227;o para doen&#231;as cr&#244;nicas por inqu&#233;rito telef&#244;nico). Quase metade da
               popula&#231;&#227;o brasileira est&#225; acima do peso. Brasilia; 2011.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Minist&#233;rio da Sa&#250;de.</collab>
            <collab>VIGITEL</collab>
          </person-group>
          <source xml:lang="pt">Brasil 2011. (Vigil&#226;ncia de fatores de risco e prote&#231;&#227;o para
                  doen&#231;as cr&#244;nicas por inqu&#233;rito telef&#244;nico). Quase metade da popula&#231;&#227;o brasileira
                  est&#225; acima do peso</source>
          <publisher-loc>Brasilia</publisher-loc>
          <year>2011</year>
        </element-citation>
      </ref>
      <ref id="B314">
        <label>314</label>
        <mixed-citation>314. Romeo S, Maglio C, Burza MA, Pirazzi C, Sj&#246;holm K, Jacobson P, et
               al. Cardiovascular events after bariatric surgery in obese subjects with type 2
               diabetes. Diabetes Care. 2012;35(12):2613-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Romeo</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Maglio</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Burza</surname>
              <given-names>MA</given-names>
            </name>
            <name>
              <surname>Pirazzi</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Sj&#246;holm</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Jacobson</surname>
              <given-names>P</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Cardiovascular events after bariatric surgery in obese
                  subjects with type 2 diabetes</article-title>
          <source>Diabetes Care</source>
          <year>2012</year>
          <volume>35</volume>
          <issue>12</issue>
          <fpage>2613</fpage>
          <lpage>2617</lpage>
        </element-citation>
      </ref>
      <ref id="B315">
        <label>315</label>
        <mixed-citation>315. Heneghan HM, Meron-Eldar S, Brethauer SA, Schauer PR, Young JB.
               Effect of bariatric surgery on cardiovascular risk profile. Am J
               Cardiol.2011;108(10):1499-507.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Heneghan</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Meron-Eldar</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Brethauer</surname>
              <given-names>SA</given-names>
            </name>
            <name>
              <surname>Schauer</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Young</surname>
              <given-names>JB</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Effect of bariatric surgery on cardiovascular risk
                  profile</article-title>
          <source>Am J Cardiol</source>
          <year>2011</year>
          <volume>108</volume>
          <issue>10</issue>
          <fpage>1499</fpage>
          <lpage>1507</lpage>
        </element-citation>
      </ref>
      <ref id="B316">
        <label>316</label>
        <mixed-citation>316. Minist&#233;rio da Sa&#250;de. Boletim Informativo. Portal da Sa&#250;de, 2013.
               Doen&#231;as ligadas &#224; obesidade custam R$ 488 milh&#245;es. Brasilia;2013.</mixed-citation>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <collab>Minist&#233;rio da Sa&#250;de</collab>
          </person-group>
          <source xml:lang="pt">Boletim Informativo. Portal da Sa&#250;de, 2013. Doen&#231;as ligadas &#224;
                  obesidade custam R$ 488 milh&#245;es</source>
          <publisher-loc>Brasilia</publisher-loc>
          <year>2013</year>
        </element-citation>
      </ref>
      <ref id="B317">
        <label>317</label>
        <mixed-citation>317. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP.
               Cardiovascular benefits of bariatric surgery in morbidly obese patients. Obes Rev.
               2011;12(7):515-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Athyros</surname>
              <given-names>VG</given-names>
            </name>
            <name>
              <surname>Tziomalos</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Karagiannis</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Mikhailidis</surname>
              <given-names>DP</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Cardiovascular benefits of bariatric surgery in morbidly
                  obese patients</article-title>
          <source>Obes Rev</source>
          <year>2011</year>
          <volume>12</volume>
          <issue>7</issue>
          <fpage>515</fpage>
          <lpage>524</lpage>
        </element-citation>
      </ref>
      <ref id="B318">
        <label>318</label>
        <mixed-citation>318. Vest AR, Heneghan HM, Agarwal S, Schauer PR, Young JB. Bariatric
               surgery and cardiovascular outcomes: a systematic review. Heart.
               2012;98(24):1763-77.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vest</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Heneghan</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Agarwal</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Schauer</surname>
              <given-names>PR</given-names>
            </name>
            <name>
              <surname>Young</surname>
              <given-names>JB</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Bariatric surgery and cardiovascular outcomes: a
                  systematic review</article-title>
          <source>Heart</source>
          <year>2012</year>
          <volume>98</volume>
          <issue>24</issue>
          <fpage>1763</fpage>
          <lpage>1777</lpage>
        </element-citation>
      </ref>
      <ref id="B319">
        <label>319</label>
        <mixed-citation>319. Vogel JA, Franklin BA, Zalesin KC, Trivax JE, Krause KR, Chengelis
               DL , et al. Reduction in predicted coronary heart disease risk after substantial
               weight reduction after bariatric surgery. Am J Cardiol.
               2007;99(2):222-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vogel</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Franklin</surname>
              <given-names>BA</given-names>
            </name>
            <name>
              <surname>Zalesin</surname>
              <given-names>KC</given-names>
            </name>
            <name>
              <surname>Trivax</surname>
              <given-names>JE</given-names>
            </name>
            <name>
              <surname>Krause</surname>
              <given-names>KR</given-names>
            </name>
            <name>
              <surname>Chengelis</surname>
              <given-names>DL</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Reduction in predicted coronary heart disease risk after
                  substantial weight reduction after bariatric surgery</article-title>
          <source>Am J Cardiol</source>
          <year>2007</year>
          <volume>99</volume>
          <issue>2</issue>
          <fpage>222</fpage>
          <lpage>226</lpage>
        </element-citation>
      </ref>
      <ref id="B320">
        <label>320</label>
        <mixed-citation>320. Courcoulas AP, Christian NJ, Belle SH, Berk PD, Flum DR, Garcia L,
               et al., Consortium LAoBSL. Weight change and health outcomes at 3 years after
               bariatric surgery among individuals with severe obesity. JAMA.
               2013;310(22):2416-25.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Courcoulas</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Christian</surname>
              <given-names>NJ</given-names>
            </name>
            <name>
              <surname>Belle</surname>
              <given-names>SH</given-names>
            </name>
            <name>
              <surname>Berk</surname>
              <given-names>PD</given-names>
            </name>
            <name>
              <surname>Flum</surname>
              <given-names>DR</given-names>
            </name>
            <name>
              <surname>Garcia</surname>
              <given-names>L</given-names>
            </name>
            <etal>et al</etal>
            <collab>Consortium LAoBSL</collab>
          </person-group>
          <article-title xml:lang="en">Weight change and health outcomes at 3 years after
                  bariatric surgery among individuals with severe obesity</article-title>
          <source>JAMA</source>
          <year>2013</year>
          <volume>310</volume>
          <issue>22</issue>
          <fpage>2416</fpage>
          <lpage>2425</lpage>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>
