<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.1 20151215//EN" "https://jats.nlm.nih.gov/publishing/1.1/JATS-journalpublishing1.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="research-article" dtd-version="1.1" specific-use="sps-1.8" xml:lang="en">
  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">ijcs</journal-id>
      <journal-title-group>
        <journal-title>International Journal of Cardiovascular Sciences</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Int. J. Cardiovasc. Sci.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">2359-4802</issn>
      <issn pub-type="epub">2359-5647</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">FyY3Bbd9TNSSZMd5ppNKtzb</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S2359-56472018000600562</article-id>
      <article-id pub-id-type="publisher-id" specific-use="previous-pid">S2359-56472018005009105</article-id>
      <article-id pub-id-type="doi">10.5935/2359-4802.20180066</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original Articles</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Option for the Radial <italic>versus</italic> Femoral Access in Coronary Intervention in Acute Coronary Syndromes: A Risk-Treatment Paradox</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Lacerda</surname>
            <given-names>Yasmin Falcon</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>S&#225;</surname>
            <given-names>Nicole Cruz de</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Suerdieck</surname>
            <given-names>Jessica Gonzalez</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Fonseca</surname>
            <given-names>Let&#237;cia</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lopes</surname>
            <given-names>Fernanda</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Sodr&#233;</surname>
            <given-names>Gabriella Sant'Ana</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Viana</surname>
            <given-names>Mateus dos Santos</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rabelo</surname>
            <given-names>Marcia Maria Noya</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Correia</surname>
            <given-names>Luis Claudio Lemos</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution content-type="orgname">Escola Bahiana de Medicina e Sa&#250;de P&#250;blica</institution>
        <addr-line>
          <city>Salvador</city>
          <state>BA</state>
        </addr-line>
        <country country="BR">Brazil</country>
        <institution content-type="original">Escola Bahiana de Medicina e Sa&#250;de P&#250;blica, Salvador, BA - Brazil</institution>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution content-type="orgname">Hospital S&#227;o Rafael</institution>
        <institution content-type="orgdiv1">Funda&#231;&#227;o Monte Tabor</institution>
        <addr-line>
          <city>Salvador</city>
          <state>BA</state>
        </addr-line>
        <country country="BR">Brazil</country>
        <institution content-type="original">Hospital S&#227;o Rafael, Funda&#231;&#227;o Monte Tabor, Salvador, BA - Brazil</institution>
      </aff>
      <author-notes>
        <corresp id="c1"><bold>Mailing Address: Lu&#237;s Cl&#225;udio Lemos Correia</bold> Av. Princesa Leopoldina, 19/402. Postal Code: 40150-080, Gra&#231;a, Salvador, BA - Brazil. E-mail: <email>lccorreia@cardiol.br</email>, <email>lccorreia@terra.com.br</email>
				</corresp>
        <fn fn-type="con">
          <p>
            <bold>Author contributions</bold>
          </p>
          <p>Conception and design of the research: Lacerda YF, S&#225; NC, Suerdieck JG, Viana MS, Fonseca L, Lopes F, Rabelo MMN, Correia LCL. Acquisition of data: Lacerda YF, S&#225; NC, Suerdieck JG, Sodr&#233; GS. Analysis and interpretation of the data: Lacerda YF, Suerdieck JG, Viana MS, Sodr&#233; GS, Fonseca L, Rabelo MMN, Correia LCL. Statistical analysis: Suerdieck JG, Viana MS, Sodr&#233; GS, Fonseca L, Lopes F, Correia LCL. Obtaining financing: Lacerda YF. Writing of the manuscript: Lacerda YF, Suerdieck JG, Fonseca L. Critical revision of the manuscript for intellectual content: Lacerda YF, S&#225; NC, Lopes F, Rabelo MMN, Correia LCL. Supervision / as the major investigador: Lacerda YF, S&#225; NC, Rabelo MMN, Correia LCL.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potential Conflict of Interest</bold>
          </p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub">
        <day>27</day>
        <month>08</month>
        <year>2018</year>
      </pub-date>
      <pub-date pub-type="collection">
        <season>Nov-Dec</season>
        <year>2018</year>
      </pub-date>
      <volume>31</volume>
      <issue>6</issue>
      <fpage>562</fpage>
      <lpage>568</lpage>
      <history>
        <date date-type="received">
          <day>07</day>
          <month>11</month>
          <year>2017</year>
        </date>
        <date date-type="rev-recd">
          <day>26</day>
          <month>04</month>
          <year>2018</year>
        </date>
        <date date-type="accepted">
          <day>03</day>
          <month>05</month>
          <year>2018</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/" xml:lang="en">
          <license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>Abstract</title>
        <sec>
          <title>Background:</title>
          <p>In coronary procedures, although the radial approach protects patients from hemorrhagic complications, it is technically more complex than the femoral approach.</p>
        </sec>
        <sec>
          <title>Objectives:</title>
          <p>To test the hypothesis that the radial approach is the procedure of choice in ACS patients due to the high risk of bleeding; and to identify independent predictors of the choice for radial access.</p>
        </sec>
        <sec>
          <title>Methods:</title>
          <p>Patients admitted for ACS who underwent invasive coronary procedure were included. We registered the type of access (femoral or radial) chosen by the physician for the first angiography; the investigators did not interfere with this choosing process. Student&#8217;s t-test was used for comparisons between the CRUSADE and ACUITY scores. Predictors of radial access were compared between the groups. Statistical significance was defined by p &lt; 0,05.</p>
          <p>Results: Radial access was chosen in 67% of 347 consecutive patients. Patients who underwent radial approach had lower risk of bleeding determined by CRUSADE (30 &#177; 14 vs. 37 &#177; 15; p &lt; 0.001) as compared with femoral access. In multivariate analysis, four variables were identified as independent predictors negatively associated with radial access - age (OR = 0.98; 95%CI = 0.96 - 0.99), creatinine (OR = 0.54; 95%CI = 0.3 - 0.98), signs of left ventricular failure (OR = 0.45; 95% CI = 0.22 - 0.92) and previous CABG (OR = 0.022; 95%CI = 0.003 - 0.166).</p>
        </sec>
        <sec>
          <title>Conclusion:</title>
          <p>The propensity to choose radial over femoral access in coronary intervention was not primarily influenced by patients&#8217; bleeding risk. Predictors of this decision, identified in the study, indicated less complex patients, suggesting that the difficulty in performing the technique was a stronger determinant than its potential antihemorrhagic effect. (Int J Cardiovasc Sci. 2018; [online].ahead print, PP.0-0)</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords:</title>
        <kwd>Angioplasty</kwd>
        <kwd>Catheterism</kwd>
        <kwd>Coronary Artery Disease</kwd>
        <kwd>Percutaneous Coronary Intervention</kwd>
        <kwd>Radial Artery</kwd>
        <kwd>Femoral Artery</kwd>
        <kwd>Stents</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introduction</title>
      <p>Percutaneous coronary intervention (PCI) is the main revascularization procedure performed in acute coronary syndromes (ACS) due to its efficacy in preventing recurrent coronary events and less invasiveness as compared with surgical procedures.<xref ref-type="bibr" rid="B1">1</xref> However, PCI is not free of complications, with access site bleeding as the most common adverse effect.<xref ref-type="bibr" rid="B2">2</xref>
			</p>
      <p>Femoral access has been the predominant site for PCI for decades, due to its relative feasibility to perform. Radial access, in turn, has shown to be efficient in preventing bleeding and therefore has become the preferred procedure in the last years.<xref ref-type="bibr" rid="B2">2</xref><sup>-</sup><xref ref-type="bibr" rid="B5">5</xref> The radial approach, however, is a more complex technique, requiring greater technical ability and experience.<xref ref-type="bibr" rid="B6">6</xref> Thus, considering the higher feasibility and reproducibility of the femoral access and the lower risk of bleeding of the radial access, both techniques are available for PCI.</p>
      <p>Efficacy is the intrinsic property of the treatment, described in the ideal world of clinical trials, in which intervention occurs in a random fashion, excluding the effect of medical decision making. Effectiveness represents the performance of the therapy in the real world, in which allocation depends on the medical decision making. Effectiveness is then optimized when allocation of treatment prioritizes patients at high risk for the outcome expected to be prevented by the intervention in question. Radial access would be more effective for patients at higher risk of bleeding who are allocated to this intervention. In a recent study, Wimmer et al.,<xref ref-type="bibr" rid="B7">7</xref> reported a risk-treatment paradox, in which the radial approach was less frequent in patients at higher bleeding risk than in those at lower risk.</p>
      <p>The present study aimed to explore this phenomenon. Using the Prospective Registry of ACS, we tested whether the radial access was the first choice for PCI in patients at high risk of bleeding, which was evaluated by the CRUSADE<xref ref-type="bibr" rid="B8">8</xref> and the ACUITY<xref ref-type="bibr" rid="B9">9</xref> scores. Also, we identified predictors of radial access and developed a propensity score of representative, predicting factors of medical decision making.</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <sec>
        <title>Sample selection</title>
        <p>We included in the study patients consecutively admitted to the coronary unit of a tertiary hospital between December 2011 and January 2016 with diagnosis of ACS (unstable angina or myocardial infarction) with previous diagnostic or therapeutic invasive cardiac procedures. ACS was defined as precordial discomfort in the 48 hours prior to admission, associated with at least one of the following criteria: 1) myocardial necrosis markers, defined as troponin T &#8805; 0.01 ug/L or troponin I &gt; 0.034 g/L, corresponding to values above the 99<sup>th</sup> percentile;<xref ref-type="bibr" rid="B10">10</xref> 2) ischemic electrocardiographic changes, consisting of T-wave inversion (&#8805; 0.1 mV) or ST-segment changes (&#8805; 0.05 mV); 3) previous coronary artery disease, defined as previous Q-wave myocardial infarction or coronary obstruction &#8805; 70% confirmed by angiography. Patients who declined to participate were excluded from the study. The study protocol was in accordance with the Helsinki declaration and approved by the local ethics committee. All patients signed the informed consent form.</p>
      </sec>
      <sec>
        <title>Study protocol</title>
        <p>This is a registry of ACS, composed by collection of prospective data. Variables of these data were used for calculation of bleeding scores. Access site for the first arterial puncture in the first (diagnostic or therapeutic) coronary procedure was systematically registered on data collection form. Major bleeding was defined as BARC (Bleeding Academic Research Consortium) type 3 or type 5.<xref ref-type="bibr" rid="B11">11</xref> The criteria for type 3 bleeding were as follow - decrease in hemoglobin of 3-5 g/dL or need for transfusion (type 3a); hemoglobin drop &#8805; 5 g/dL, cardiac tamponade, requirement of surgical intervention or hemodynamic instability for control (type 3b); and intracranial or intraocular bleed (type 3c). Type 5 bleeding is a definite fatal bleeding (direct causal relationship, type 5a) or a probable fatal bleeding (indirect causal relationship, type 5b). Minor bleeding (type 1 or type 2) or cardiac surgery-related bleeding (type 4) were not included in the analysis.</p>
      </sec>
      <sec>
        <title>Bleeding risk scores</title>
        <p>The CRUSADE score was used to evaluate the baseline risk of bleeding. This instrument is composed of eight variables - four categorical variables (female sex, signs of heart failure, diabetes and peripheral arterial disease) and four numerical variables (baseline hematocrit, creatinine clearance, heart rate, and systolic blood pressure). The point scores were calculated based on the value of each variable; the sum of all variables indicated pre-determined levels (low, intermediate and high).<xref ref-type="bibr" rid="B8">8</xref> Bleeding risk was also confirmed by the ACUITY score, composed of seven variables - four categorical variables (female sex, anemia, bivalirudin therapy and type of ACS) and three numerical variables (age, creatinine clearance, white blood cell count).<xref ref-type="bibr" rid="B9">9</xref>
				</p>
      </sec>
      <sec>
        <title>Statistical analysis</title>
        <p>Although the collection of the variables included in the primary analysis was predetermined, the association between bleeding score and the access route was a posteriori exploratory analysis. Nevertheless, we estimated that a minimum of 100 patients with radial or femoral access would allow the insertion of 10 covariables into the propensity model, based on the logistic regression principle, which establishes the need of at least 10 patients with the outcome in question for each covariable.<xref ref-type="bibr" rid="B12">12</xref>
				</p>
        <p>Numerical variables were described as mean and standard deviation or median and interquartile range, as appropriate. Normality of numerical variables was verified by the Shapiro-Wilk test. Categorical variables were described as absolute and relative frequencies. The CRUDADE and ACUITY scores were compared between radial and femoral groups by the unpaired Student&#8217;s t test. Predictors of the radial access were compared between both groups by the chi-square test or the unpaired Student&#8217;s t test. Variables with p &lt; 0.10 in the univariate analysis were inserted into the logistic regression, with radial access as dependent variable; the odds ratio of each predictor was determined. A p &lt; 0.05 was set as statistically significant in all tests. The analysis was performed using the SPSS software version 21.</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Sample description</title>
        <p>A total of 347 patients were included; mean age was 63 &#177; 14 years, 63% were men, 27% of them were hospitalized for ST-segment elevation myocardial infarction (the others had ASC with non-ST-segment elevation myocardial infarction). Invasive coronary angiography showed that 38% of patients had three-vessel disease or left coronary artery occlusion. Mean GRACE score was 119 &#177; 37, compatible with an intermediate risk of cardiovascular events. Mean CRUSADE score was 32 &#177; 15 and mean ACUITY score was 14 &#177; 7, both corresponding to moderate risk of bleeding according to validation studies.<xref ref-type="bibr" rid="B8">8</xref><sup>,</sup><xref ref-type="bibr" rid="B9">9</xref> Bleeding occurred in 64 patients (18%) and major bleeding in 12 (3.5%). The CRUSADE score was higher in patients with major bleeding (47 &#177; 17 <italic>versus</italic> 32 &#177; 15; p = 0.01), confirming its predictive value. The same was observed with the ACUITY score (20 &#177; 9 <italic>versus</italic> 14 &#177; 7; p = 0.02). Patients treated with the radial approach showed a higher incidence of major bleeding as compared with those treated with femoral access (1% <italic>versus</italic> 8%; p &lt; 0.01).</p>
      </sec>
      <sec>
        <title>Risk of bleeding and the choice for the radial access</title>
        <p>The radial artery was chosen as the primary vascular access in 64% of patients, whereas the femoral access was chosen for the others. The mean CRUSADE score showed that patients treated with the radial access showed a lower risk of bleeding (30 &#177; 14) compared with those treated with femoral access (37 &#177; 15; p &lt; 0.001) (<xref ref-type="fig" rid="f1">Figure 1</xref>). According to the literature, these values corresponded to a bleeding risk of 5.5% and 8.6%, respectively.<xref ref-type="bibr" rid="B8">8</xref>
				</p>
        <p>
          <fig id="f1">
            <label>Figure 1</label>
            <caption>
              <title>Box-plot comparing the CRUSADE score (Graph A) with the ACUITY score (Graph B) values between radial access and femoral access groups.</title>
            </caption>
            <graphic xlink:href="2359-5647-ijcs-31-06-0562-80066-gf01.jpg"/></fig>
        </p>
        <p>Analysis of the ACUITY score corroborated the fact that patients treated with radial access had a higher risk of bleeding than patients treated with femoral access (13 &#177; 6 <italic>versus</italic> 15 &#177; 7; p = 0.002). These values correspond to a bleeding risk of 3.3% and 6.9%, respectively.<xref ref-type="bibr" rid="B9">9</xref>
				</p>
      </sec>
      <sec>
        <title>Propensity to choose the radial access</title>
        <p>With respect to general characteristics of patients, those with a radial access were younger (61 &#177; 13 years), compared with patients with femoral access (66 &#177; 14 years; p &lt; 0.001). Sex, self-reported race, weight, height, body mass index and body surface were not different between the groups (<xref ref-type="table" rid="t1">Table 1</xref>).</p>
        <table-wrap id="t1">
          <label>Table 1</label>
          <caption>
            <title>Comparison of clinical characteristics of the radial and femoral access groups</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" style="background-color:#C5C6C8">Variables</th>
                <th align="center" style="background-color:#C5C6C8">Radial<break/>(n = 223)</th>
                <th align="center" style="background-color:#C5C6C8">Femoral<break/>(n = 124)</th>
                <th align="center" style="background-color:#C5C6C8">p-value</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Female sex</td>
                <td align="center">85 (38%)</td>
                <td align="center">38 (31%)</td>
                <td align="center">0.62<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Age</td>
                <td align="center">61 &#177; 13</td>
                <td align="center">66 &#177; 14</td>
                <td align="center">0.001<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Weight</td>
                <td align="center">78 &#177; 13</td>
                <td align="center">76 &#177; 18</td>
                <td align="center">0.27<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Height</td>
                <td align="center">1.67 &#177; 0.1</td>
                <td align="center">1.65 &#177; 0.9</td>
                <td align="center">0.12<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Body mass index (kg/m<sup>2</sup>)</td>
                <td align="center">27.9 &#177; 4.5</td>
                <td align="center">27.6 &#177; 5.9</td>
                <td align="center">0.57<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Body surface (m<sup>2</sup>)</td>
                <td align="center">1.89 &#177; 0.2</td>
                <td align="center">1.86 &#177; 0.2</td>
                <td align="center">0.25<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Black/pardo race</td>
                <td align="center">132 (63%)</td>
                <td align="center">72 (62%)</td>
                <td align="center">0.88<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">ST-segment elevation myocardial infarction</td>
                <td align="center">63 (29%)</td>
                <td align="center">32 (26%)</td>
                <td align="center">0.62<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Positive troponin</td>
                <td align="center">171 (77%)</td>
                <td align="center">95 (77%)</td>
                <td align="center">0.98<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Ischemic electrocardiography</td>
                <td align="center">88 (40%)</td>
                <td align="center">50 (40%)</td>
                <td align="center">0.87<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Three-vessel disease or left coronary trunk</td>
                <td align="center">42 (19%)</td>
                <td align="center">28 (23%)</td>
                <td align="center">0.1<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Signs of left ventricular failure</td>
                <td align="center">18 (8%)</td>
                <td align="center">23 (19%)</td>
                <td align="center">0.003<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Heart rate (bpm)</td>
                <td align="center">79 &#177; 16</td>
                <td align="center">82 &#177; 19</td>
                <td align="center">0.13<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Systolic arterial pressure (mmHg)</td>
                <td align="center">153 &#177; 30</td>
                <td align="center">154 &#177; 34</td>
                <td align="center">0.7<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Creatinine</td>
                <td align="center">1.0 &#177; 0.3</td>
                <td align="center">1.2 &#177; 1.1</td>
                <td align="center">0.001<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">GRACE score</td>
                <td align="center">113.9 &#177; 33.5</td>
                <td align="center">128.1 &#177; 41</td>
                <td align="center">0.001<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Hemoglobin</td>
                <td align="center">14.0 &#177; 1.8</td>
                <td align="center">13.8 &#177; 1.9</td>
                <td align="center">0.29<xref ref-type="table-fn" rid="TFN1">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Diabetes mellitus</td>
                <td align="center">76 (34%)</td>
                <td align="center">48 (39%)</td>
                <td align="center">0.34<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Peripheral arterial occlusive disease</td>
                <td align="center">9 (4%)</td>
                <td align="center">11 (9%)</td>
                <td align="center">0.1<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Previous coronary disease</td>
                <td align="center">53 (24%)</td>
                <td align="center">57 (46%)</td>
                <td align="center">0.001<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Previous revascularization</td>
                <td align="center">1 (0.5%)</td>
                <td align="center">24 (19.5%)</td>
                <td align="center">0.001<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Stroke</td>
                <td align="center">7 (3%)</td>
                <td align="center">11 (9%)</td>
                <td align="center">0.021<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Smoking</td>
                <td align="center">23 (10%)</td>
                <td align="center">8 (6.5%)</td>
                <td align="center">0.23<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Previous heart failure</td>
                <td align="center">7 (3%)</td>
                <td align="center">7 (6%)</td>
                <td align="center">0.25<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
              <tr>
                <td align="left">Previous bleeding</td>
                <td align="center">2 (5%)</td>
                <td align="center">1 (8%)</td>
                <td align="center">0.65<sup><xref ref-type="table-fn" rid="TFN2">&#8224;</xref></sup></td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN1">
              <label>*</label>
              <p>Student's t-test;</p>
            </fn>
            <fn id="TFN2">
              <label>&#8224;</label>
              <p>chi-square test.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>Regarding ACS presentation, compared with patients treated with femoral approach, patients with radial access had a lower mean GRACE score (114 &#177; 34 <italic>versus</italic> 128 &#177; 41; p &lt; 0,001), better renal function according to creatinine levels (1.0 &#177; 0.3 <italic>versus</italic> 1.2 &#177; 1.1; p &lt; 0.001) and lower prevalence of signs of left ventricular failure (Killip &gt; 1: 8% <italic>versus</italic> 19%; p &lt; 0.003). The type of ACS, heart rate, systolic arterial pressure, positive troponin, electrocardiographic ischemia, three-vessel disease, coronary angiography showing involvement of the trunk and hemoglobin levels at admission were not different between the groups (<xref ref-type="table" rid="t1">Table 1</xref>).</p>
        <p>Regarding comorbidities, there was a lower prevalence of previous coronary disease in patients treated with radial access (24% <italic>versus</italic> 46%, p &lt; 0.001). Previous history of stroke (3% <italic>versus</italic> 9%; p &lt; 0.021) and myocardial revascularization surgery (0.5% <italic>versus</italic> 19.5%; p &lt; 0.001) was also different between the groups, whereas no difference was observed in the presence of diabetes mellitus, peripheral artery disease, smoking, previous history of heart failure or bleeding (<xref ref-type="table" rid="t1">Table 1</xref>).</p>
        <p>The variables described above as significant in the univariate analysis were inserted into the logistic regression model, with radial access as dependent variable. In this analysis, the variables with independent association with radial access were age (OR = 0.98; 95%CI = 0.96 - 0.99), creatinine (OR = 0.54; 95%CI = 0.3 - 0.98), signs of left ventricular failure (OR = 0.45; 95%CI = 0.22 - 0.92) and previous myocardial revascularization surgery (OR = 0.022; 95%CI = 0.003 - 0.16), all with a discouraging effect on the use of the radial access (<xref ref-type="table" rid="t2">Table 2</xref>).</p>
        <table-wrap id="t2">
          <label>Table 2</label>
          <caption>
            <title>Multivariate analysis that generated the propensity model of radial access</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" style="background-color:#C5C6C8">
								</th>
                <th align="center" style="background-color:#C5C6C8">Odds ratio</th>
                <th align="center" style="background-color:#C5C6C8">95% CI</th>
                <th align="center" style="background-color:#C5C6C8">p-value</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Creatinine</td>
                <td align="center">0.54</td>
                <td align="center">0.3 - 0.98</td>
                <td align="center">0.041<xref ref-type="table-fn" rid="TFN3">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Age</td>
                <td align="center">0.98</td>
                <td align="center">0.96 - 0.99</td>
                <td align="center">0.037<xref ref-type="table-fn" rid="TFN3">*</xref>
								</td>
              </tr>
              <tr>
                <td align="left">Killip class &gt; 1</td>
                <td align="center">0.45</td>
                <td align="center">0.22 - 0.92</td>
                <td align="center">0.029</td>
              </tr>
              <tr>
                <td align="left">Previous revascularization</td>
                <td align="center">0.022</td>
                <td align="center">0.003 - 0.166</td>
                <td align="center">0.001</td>
              </tr>
              <tr>
                <td align="left">Stroke</td>
                <td align="center">0.366</td>
                <td align="center">0.13 - 1.07</td>
                <td align="center">0.066</td>
              </tr>
              <tr>
                <td align="left">Previous coronary disease</td>
                <td align="center">0.75</td>
                <td align="center">0.43 - 1.31</td>
                <td align="center">0.313</td>
              </tr>
              <tr>
                <td align="left">GRACE score</td>
                <td align="center">1.0</td>
                <td align="center">0.99 - 1.01</td>
                <td align="center">0.543<xref ref-type="table-fn" rid="TFN3">*</xref>
								</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN3">
              <label>*</label>
              <p>Numerical variables.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <p>In the present study, patients treated with radial approach for coronary procedures had lower baseline risk of bleeding as compared with the femoral access group. This finding contrasts with the logical expectation that the access related to lower incidence of bleeding is the one more commonly used in patients at higher risk for this complication, characterizing a risk-treatment paradox.</p>
      <p>This paradoxical result raises the need for discussing potential causes of this phenomenon in a critical perspective of the cognitive process of the medical decision-making process. This, in turn, is presumedly influenced by several factors. One may expect that such decision is based on the main objective of the radial approach, i.e. to prevent bleeding; however, other factors may be determinant in this process. Interventionists have a natural sense of achieving success with their techniques. By intuition, the chance of success is expected to be lower from procedures considered technically more difficult. Hence, the operator tends to avoid the access considered more difficult in attempt to reduce the challenge. Nevertheless, that would be a biased view, since the risk of failure in the radial approach is lower than the risk of increased bleeding in femoral approach (eight times greater in the present study). Besides, a migration from radial to femoral vascular access when needed is also possible. Although the results of this study were exploratory, they suggest that the physician&#8217;s decision may be more strongly influenced by a sense of self-protection rather than a protection of the treated patients. This is quite possible, since while bleeding tends to be seen as a natural complication, failure in the intervention tends to be considered a medical failure. Further studies should explore these potential mechanisms.</p>
      <p>Intuitive estimation of probabilities in conditions of uncertainties is influenced by cognitive biases.<xref ref-type="bibr" rid="B13">13</xref><sup>-</sup><xref ref-type="bibr" rid="B15">15</xref> For example, when we opt to treat less complex patients, we are seeking cognitive comfort; and in search of this, we underestimate the risk of more complex patients, intuitively reducing the magnitude of the benefits that these patients could obtain from the procedure. In consequence, patients with more complex conditions receive less treatment than needed. This generates a risk-treatment paradox, typical of this intuitive process of decision making.</p>
      <p>To understand the mechanisms of this paradox, we built a propensity model to identify potential determinants to the choice for the radial access. In this model, we identified variables that had a negative association with the radial access only, not including variables that may increase the chance for this choice. This propensity score allows us to make interpretations of the decision-making process. It is possible that our interventionist had the radial access as the first-choice option (in fact, this approach was the most frequent in the study) and then used other criteria for secondary options. These criteria were represented in our model by independent predictors of the radial access. Analysis of these predictors showed that all of them concerned more complex patients, with predictors representing each of the domains: patient&#8217;s baseline constitution (age), comorbidities (creatinine), severity of ACS presentation (acute heart failure) and previous history (surgery). These observations suggest that the physician tends to avoid the radial access as the patient&#8217;s condition gets more severe, disregarding patient&#8217;s higher risk of bleeding. On the other hand, we should recognize that this is not a conscious choice.</p>
      <p>The risk-treatment paradox has been described in situations in which the most effective approach is also the most complex. For example, in atrial fibrillation, anticoagulant therapy is more frequently provided to patients with a low risk of embolic events than patients at high risk.<xref ref-type="bibr" rid="B16">16</xref> In the ACS scenario also, there has been no association between risk and the choice for an invasive strategy.<xref ref-type="bibr" rid="B17">17</xref><sup>,</sup><xref ref-type="bibr" rid="B18">18</xref> In PCI, the prospective, observational, multicenter study by Wimmer et al.,<xref ref-type="bibr" rid="B7">7</xref> also reported this phenomenon by showing that patients at higher risk of femoral access site complications were less susceptible of receiving the radial access approach. An additional contribution of our study is the identification of independent predictors involved in the generation of this paradox. Other previous studies<xref ref-type="bibr" rid="B19">19</xref><sup>,</sup><xref ref-type="bibr" rid="B20">20</xref> evaluated the predictors involved in the choice for the radial access, however, in none of them a multivariate analysis was performed to minimize confounding bias.</p>
      <p>Once the presence of the risk-treatment paradox is detected in certain situation, a possible adjustment strategy is the use of probabilistic models to estimate the risk.<xref ref-type="bibr" rid="B21">21</xref><sup>,</sup><xref ref-type="bibr" rid="B22">22</xref> In other words, the use of scores for allocation of more complex resources induces the physician to make decisions based on probability. In case of bleeding in ACS, the best validated models are the CRUSADE<xref ref-type="bibr" rid="B8">8</xref> and the ACUITY scores.<xref ref-type="bibr" rid="B9">9</xref>
			</p>
      <p>Our findings were obtained in a single center, in which five interventional cardiologists were working during the study period. Thus, we must recognize the limited external validation of these findings. Nevertheless, the real aim of this study was not to describe interventionists&#8217; behavior, since in fact it may vary considerably among regions. Actually, the impact of the present study is not the inference of the prevalence of a phenomenon, but rather to call attention to a situation in which the decision-making process may suffer a risk-treatment paradox.</p>
      <p>A natural thought would be to suggest an evaluation of medical practice variation, to verify the uniformity of this phenomenon. However, we avoided this analysis, since in the Registry design, the unit of analysis was the patient who was treated and not the physician himself, whose consent to be observed was not sought. We also believe that individual evaluation of each of the five interventionists involved in the study would not be accurate due to the sample size of the study.</p>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclusion</title>
      <p>In this exploratory study, we observed that the choice for the radial access was not primarily influenced by its potential benefit on bleeding prevention, since baseline bleeding risk was negatively associated with this access, characterizing a risk-treatment paradox. Determinants of the preference for the radial access were variables that connote patients&#8217; clinical status/severity, suggesting that in highly complex patients, the access is primarily chosen for its easiness and not for its antihemorrhagic effect.</p>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="financial-disclosure">
        <p>
          <bold>Sources of Funding</bold>
        </p>
        <p>There were no external funding sources for this study.</p>
      </fn>
      <fn fn-type="other">
        <p>
          <bold>Study Association</bold>
        </p>
        <p>This article is part of the thesis of master submitted by Mateus dos Santos Viana, from Escola Bahiana de Medicina e Sa&#250;de P&#250;blica.</p>
      </fn>
      <fn fn-type="other">
        <p>
          <bold>Ethics approval and consent to participate</bold>
        </p>
        <p>This study was approved by the Ethics Committee of the <italic>Hospital S&#227;o Rafael</italic> under the protocol number 35/11. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.</p>
      </fn>
    </fn-group>
    <ref-list>
      <title>References</title>
      <ref id="B1">
        <label>1</label>
        <mixed-citation>1 Godinho RR, Ribeiro HB, Faig S, Spadaro AG, Gabrilaitis C, Sacramento G, et al. Compara&#231;&#227;o das vias radial e femoral nas interven&#231;&#245;es coron&#225;rias percut&#226;neas: Resultados do registro TotalCor. Rev Bras Cardiol Invasiva. 2011;19(3):272-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Godinho</surname>
              <given-names>RR</given-names>
            </name>
            <name>
              <surname>Ribeiro</surname>
              <given-names>HB</given-names>
            </name>
            <name>
              <surname>Faig</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Spadaro</surname>
              <given-names>AG</given-names>
            </name>
            <name>
              <surname>Gabrilaitis</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Sacramento</surname>
              <given-names>G</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Compara&#231;&#227;o das vias radial e femoral nas interven&#231;&#245;es coron&#225;rias percut&#226;neas: Resultados do registro TotalCor</article-title>
          <source>Rev Bras Cardiol Invasiva</source>
          <year>2011</year>
          <volume>19</volume>
          <issue>3</issue>
          <fpage>272</fpage>
          <lpage>278</lpage>
        </element-citation>
      </ref>
      <ref id="B2">
        <label>2</label>
        <mixed-citation>2 Ndrepepa G, Neumann FJ, Richardt G, Schulz S, T&#246;lg R, Stoyanov KM, et al. Prognostic value of access and non-access sites bleeding after percutaneous coronary intervention. Circ Cardiovasc Interv. 2013;6(4):354-61.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ndrepepa</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Neumann</surname>
              <given-names>FJ</given-names>
            </name>
            <name>
              <surname>Richardt</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Schulz</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>T&#246;lg</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Stoyanov</surname>
              <given-names>KM</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Prognostic value of access and non-access sites bleeding after percutaneous coronary intervention</article-title>
          <source>Circ Cardiovasc Interv</source>
          <year>2013</year>
          <volume>6</volume>
          <issue>4</issue>
          <fpage>354</fpage>
          <lpage>361</lpage>
        </element-citation>
      </ref>
      <ref id="B3">
        <label>3</label>
        <mixed-citation>3 Bianchi R, D'Acierno L, Crisci M, Tartaglione D, Cappelli Bigazzi M, Canonico M, et al. From femoral to radial approach in coronary intervention: review of the literature and 6 years single-center experience. Angiology.2017;68(4):281-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bianchi</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>D'Acierno</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Crisci</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Tartaglione</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Bigazzi</surname>
              <given-names>M Cappelli</given-names>
            </name>
            <name>
              <surname>Canonico</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>From femoral to radial approach in coronary intervention: review of the literature and 6 years single-center experience</article-title>
          <source>Angiology</source>
          <year>2017</year>
          <volume>68</volume>
          <issue>4</issue>
          <fpage>281</fpage>
          <lpage>287</lpage>
        </element-citation>
      </ref>
      <ref id="B4">
        <label>4</label>
        <mixed-citation>4 Chase AJ, Fretz EB, Warburton WP, Klinke WP, Carere RG, Pi D, et al. Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart. 2008;94(8):1019-25.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Chase</surname>
              <given-names>AJ</given-names>
            </name>
            <name>
              <surname>Fretz</surname>
              <given-names>EB</given-names>
            </name>
            <name>
              <surname>Warburton</surname>
              <given-names>WP</given-names>
            </name>
            <name>
              <surname>Klinke</surname>
              <given-names>WP</given-names>
            </name>
            <name>
              <surname>Carere</surname>
              <given-names>RG</given-names>
            </name>
            <name>
              <surname>Pi</surname>
              <given-names>D</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg)</article-title>
          <source>Heart</source>
          <year>2008</year>
          <volume>94</volume>
          <issue>8</issue>
          <fpage>1019</fpage>
          <lpage>1025</lpage>
        </element-citation>
      </ref>
      <ref id="B5">
        <label>5</label>
        <mixed-citation>5 Ferrante G, Rao S V, J&#252;ni P, Da Costa BR, Reimers B, Condorelli G, et al. Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease. A meta-analysis of randomized trials. JACC Cardiovasc Interv. 2016;9(14):1419-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Ferrante</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Rao S</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>J&#252;ni</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Costa</surname>
              <given-names>BR Da</given-names>
            </name>
            <name>
              <surname>Reimers</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Condorelli</surname>
              <given-names>G</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease. A meta-analysis of randomized trials</article-title>
          <source>JACC Cardiovasc Interv</source>
          <year>2016</year>
          <volume>9</volume>
          <issue>14</issue>
          <fpage>1419</fpage>
          <lpage>1434</lpage>
        </element-citation>
      </ref>
      <ref id="B6">
        <label>6</label>
        <mixed-citation>6 Hillegass W. The many radial access learning curves. Catheter Cardiovasc Interv. 2017;89(5):865-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hillegass</surname>
              <given-names>W</given-names>
            </name>
          </person-group>
          <article-title>The many radial access learning curves</article-title>
          <source>Catheter Cardiovasc Interv</source>
          <year>2017</year>
          <volume>89</volume>
          <issue>5</issue>
          <fpage>865</fpage>
          <lpage>866</lpage>
        </element-citation>
      </ref>
      <ref id="B7">
        <label>7</label>
        <mixed-citation>7 Wimmer NJ,Resnic F, Mauri L, Matheney ME, Piemonte TC, Pomerantsey E, et al. Risk-treatment paradox in the selection of transradial access for percutaneous coronary intervention. J Am Heart Assoc. 2013;2(3):e000174</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wimmer</surname>
              <given-names>NJ</given-names>
            </name>
            <name>
              <surname>Resnic</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Mauri</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Matheney</surname>
              <given-names>ME</given-names>
            </name>
            <name>
              <surname>Piemonte</surname>
              <given-names>TC</given-names>
            </name>
            <name>
              <surname>Pomerantsey</surname>
              <given-names>E</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Risk-treatment paradox in the selection of transradial access for percutaneous coronary intervention</article-title>
          <source>J Am Heart Assoc</source>
          <year>2013</year>
          <volume>2</volume>
          <issue>3</issue>
          <elocation-id>e000174</elocation-id>
        </element-citation>
      </ref>
      <ref id="B8">
        <label>8</label>
        <mixed-citation>8 Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009;119(14):1873-82.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Subherwal</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Bach</surname>
              <given-names>RG</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>AY</given-names>
            </name>
            <name>
              <surname>Gage</surname>
              <given-names>BF</given-names>
            </name>
            <name>
              <surname>Rao</surname>
              <given-names>SV</given-names>
            </name>
            <name>
              <surname>Newby</surname>
              <given-names>LK</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score</article-title>
          <source>Circulation</source>
          <year>2009</year>
          <volume>119</volume>
          <issue>14</issue>
          <fpage>1873</fpage>
          <lpage>1882</lpage>
        </element-citation>
      </ref>
      <ref id="B9">
        <label>9</label>
        <mixed-citation>9 Mehran R, Pocock S, Nikolski E, CClayton T, Dangas GD, Kirtane AJ, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010; 55(23): 2556-66.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mehran</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Pocock</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Nikolski</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>CClayton</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Dangas</surname>
              <given-names>GD</given-names>
            </name>
            <name>
              <surname>Kirtane</surname>
              <given-names>AJ</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>A risk score to predict bleeding in patients with acute coronary syndromes</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>55</volume>
          <issue>23</issue>
          <fpage>2556</fpage>
          <lpage>2566</lpage>
        </element-citation>
      </ref>
      <ref id="B10">
        <label>10</label>
        <mixed-citation>10 Apple FS, Quist HE, Doyle PJ, Otto AP, Murakami MM. Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations. Clin Chem. 2003;49(8):1331-6.</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>Quist</surname>
              <given-names>HE</given-names>
            </name>
            <name>
              <surname>Doyle</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>Otto</surname>
              <given-names>AP</given-names>
            </name>
            <name>
              <surname>Murakami</surname>
              <given-names>MM</given-names>
            </name>
          </person-group>
          <article-title>Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations</article-title>
          <source>Clin Chem</source>
          <year>2003</year>
          <volume>49</volume>
          <issue>8</issue>
          <fpage>1331</fpage>
          <lpage>1336</lpage>
        </element-citation>
      </ref>
      <ref id="B11">
        <label>11</label>
        <mixed-citation>11 Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-47.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mehran</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Rao</surname>
              <given-names>SV</given-names>
            </name>
            <name>
              <surname>Bhatt</surname>
              <given-names>DL</given-names>
            </name>
            <name>
              <surname>Gibson</surname>
              <given-names>CM</given-names>
            </name>
            <name>
              <surname>Caixeta</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Eikelboom</surname>
              <given-names>J</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium</article-title>
          <source>Circulation</source>
          <year>2011</year>
          <volume>123</volume>
          <issue>23</issue>
          <fpage>2736</fpage>
          <lpage>2747</lpage>
        </element-citation>
      </ref>
      <ref id="B12">
        <label>12</label>
        <mixed-citation>12 Demidenko E. Sample size and optimal design for logistic regression with binary interaction. Stat Med. 2008;27(1):36-46.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Demidenko</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>Sample size and optimal design for logistic regression with binary interaction</article-title>
          <source>Stat Med</source>
          <year>2008</year>
          <volume>27</volume>
          <issue>1</issue>
          <fpage>36</fpage>
          <lpage>46</lpage>
        </element-citation>
      </ref>
      <ref id="B13">
        <label>13</label>
        <mixed-citation>13 Bornstein BH, Emler AC. Rationality in medical decision making: a review of the literature on doctors'decision-making biases. J Evaluat Clin Pract. 2001; 7(2): 97-107.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bornstein</surname>
              <given-names>BH</given-names>
            </name>
            <name>
              <surname>Emler</surname>
              <given-names>AC</given-names>
            </name>
          </person-group>
          <article-title>Rationality in medical decision making: a review of the literature on doctors'decision-making biases</article-title>
          <source>J Evaluat Clin Pract</source>
          <year>2001</year>
          <volume>7</volume>
          <issue>2</issue>
          <fpage>97</fpage>
          <lpage>107</lpage>
        </element-citation>
      </ref>
      <ref id="B14">
        <label>14</label>
        <mixed-citation>14 Silva G. O processo de tomada de decis&#227;o na pr&#225;tica cl&#237;nica: a medicina como estado da arte. Rev Bras Clin Med. S&#227;o Paulo, 2013 jan-mar; 11(1): 75-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Silva</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title>O processo de tomada de decis&#227;o na pr&#225;tica cl&#237;nica: a medicina como estado da arte</article-title>
          <source>Rev Bras Clin Med</source>
          <publisher-loc>S&#227;o Paulo</publisher-loc>
          <season>jan-mar</season>
          <year>2013</year>
          <volume>11</volume>
          <issue>1</issue>
          <fpage>75</fpage>
          <lpage>79</lpage>
        </element-citation>
      </ref>
      <ref id="B15">
        <label>15</label>
        <mixed-citation>15 Hall KH. Reviewing intuitive decision-making and uncertainty: the implications for medical education. Med Educ. 2002;36(3):216-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hall</surname>
              <given-names>KH</given-names>
            </name>
          </person-group>
          <article-title>Reviewing intuitive decision-making and uncertainty: the implications for medical education</article-title>
          <source>Med Educ</source>
          <year>2002</year>
          <volume>36</volume>
          <issue>3</issue>
          <fpage>216</fpage>
          <lpage>224</lpage>
        </element-citation>
      </ref>
      <ref id="B16">
        <label>16</label>
        <mixed-citation>16 Watanabe E. Risk-treatment paradox of anticoagulation therapy in atrial fibrillation. Circ J. 2014;78(9):2146-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Watanabe</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>Risk-treatment paradox of anticoagulation therapy in atrial fibrillation</article-title>
          <source>Circ J</source>
          <year>2014</year>
          <volume>78</volume>
          <issue>9</issue>
          <fpage>2146</fpage>
          <lpage>2148</lpage>
        </element-citation>
      </ref>
      <ref id="B17">
        <label>17</label>
        <mixed-citation>17 Roe MT, Peterson ED, Newby LK, Chen AY, Pollack C, Brindis RG, et al. The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes. Am Heart J. 2006;151(6):1205-13.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Roe</surname>
              <given-names>MT</given-names>
            </name>
            <name>
              <surname>Peterson</surname>
              <given-names>ED</given-names>
            </name>
            <name>
              <surname>Newby</surname>
              <given-names>LK</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>AY</given-names>
            </name>
            <name>
              <surname>Pollack</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Brindis</surname>
              <given-names>RG</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes</article-title>
          <source>Am Heart J</source>
          <year>2006</year>
          <volume>151</volume>
          <issue>6</issue>
          <fpage>1205</fpage>
          <lpage>1213</lpage>
        </element-citation>
      </ref>
      <ref id="B18">
        <label>18</label>
        <mixed-citation>18 Birkemeyer R, Schneider H, Rillig A, Ebeling J, Akin I, Kische S, et al. Do gender differences in primary PCI mortality represent a different adherence to guideline recommended therapy? a multicenter observation. BMC Cardiovasc Disord. 2014; Jan 2,144:71.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Birkemeyer</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Schneider</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Rillig</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Ebeling</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Akin</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Kische</surname>
              <given-names>S</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Do gender differences in primary PCI mortality represent a different adherence to guideline recommended therapy? a multicenter observation</article-title>
          <source>BMC Cardiovasc Disord</source>
          <day>02</day>
          <month>01</month>
          <year>2014</year>
          <volume>144</volume>
          <fpage>71</fpage>
          <lpage>71</lpage>
        </element-citation>
      </ref>
      <ref id="B19">
        <label>19</label>
        <mixed-citation>19 Lim YH, Lee Y, Shin J, Yoon J, Lee SH, Rha SW, et al. Comparisons of clinical and procedural outcomes between transradial and transfemoral approaches in percutaneous coronary intervention (from the Korean Transradial Intervention Prospective Registry). Am J Cardiol.2016;117(8):1272-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lim</surname>
              <given-names>YH</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Shin</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Yoon</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>SH</given-names>
            </name>
            <name>
              <surname>Rha</surname>
              <given-names>SW</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Comparisons of clinical and procedural outcomes between transradial and transfemoral approaches in percutaneous coronary intervention (from the Korean Transradial Intervention Prospective Registry)</article-title>
          <source>Am J Cardiol</source>
          <year>2016</year>
          <volume>117</volume>
          <issue>8</issue>
          <fpage>1272</fpage>
          <lpage>1281</lpage>
        </element-citation>
      </ref>
      <ref id="B20">
        <label>20</label>
        <mixed-citation>20 Kilic S, Hermanides RS, Ottervanger JP, Kolkman E, Dambrink JHE, Roolvink V, et al. Effects of radial versus femoral artery access in patients with acute myocardial infarction: A large centre prospective registry. Neth Heart J. 2017;25(1):33-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kilic</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Hermanides</surname>
              <given-names>RS</given-names>
            </name>
            <name>
              <surname>Ottervanger</surname>
              <given-names>JP</given-names>
            </name>
            <name>
              <surname>Kolkman</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Dambrink</surname>
              <given-names>JHE</given-names>
            </name>
            <name>
              <surname>Roolvink</surname>
              <given-names>V</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Effects of radial versus femoral artery access in patients with acute myocardial infarction: A large centre prospective registry</article-title>
          <source>Neth Heart J</source>
          <year>2017</year>
          <volume>25</volume>
          <issue>1</issue>
          <fpage>33</fpage>
          <lpage>39</lpage>
        </element-citation>
      </ref>
      <ref id="B21">
        <label>21</label>
        <mixed-citation>21 Yan AT, Yan RT, Tan M, Casanova A, Labinaz M, Sridhar K, et al. Risk scores for risk stratification in acute coronary syndromes: Useful but simpler is not necessarily better. Eur Heart J. 2007;28(9):1072-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Yan</surname>
              <given-names>AT</given-names>
            </name>
            <name>
              <surname>Yan</surname>
              <given-names>RT</given-names>
            </name>
            <name>
              <surname>Tan</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Casanova</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Labinaz</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sridhar</surname>
              <given-names>K</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Risk scores for risk stratification in acute coronary syndromes: Useful but simpler is not necessarily better</article-title>
          <source>Eur Heart J</source>
          <year>2007</year>
          <volume>28</volume>
          <issue>9</issue>
          <fpage>1072</fpage>
          <lpage>1078</lpage>
        </element-citation>
      </ref>
      <ref id="B22">
        <label>22</label>
        <mixed-citation>22 Weintraub WS. Prediction scores after myocardial infarction: Value, limitations, and future directions. Circulation. 2002;106(18):2292-3.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Weintraub</surname>
              <given-names>WS</given-names>
            </name>
          </person-group>
          <article-title>Prediction scores after myocardial infarction: Value, limitations, and future directions</article-title>
          <source>Circulation</source>
          <year>2002</year>
          <volume>106</volume>
          <issue>18</issue>
          <fpage>2292</fpage>
          <lpage>2293</lpage>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>
