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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq Bras Cardiol</journal-id>
      <journal-id journal-id-type="publisher-id">abc</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 - SBC</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">7yxJMMtvFnGLKtJH9xht3yd</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2016004000004</article-id>
      <article-id pub-id-type="publisher-id" specific-use="previous-pid">S0066-782X2016005015103</article-id>
      <article-id pub-id-type="doi">10.5935/abc.20160082</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original Articles</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Colchicine to Reduce Atrial Fibrillation in the Postoperative Period of Myocardial Revascularization</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Zarpelon</surname>
            <given-names>Camila Stuchi</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Netto</surname>
            <given-names>Miguel Chomiski</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jorge</surname>
            <given-names>Jos&#233; Carlos Moura</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Fabris</surname>
            <given-names>C&#225;tia Carolina</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Desengrini</surname>
            <given-names>Dieli</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jardim</surname>
            <given-names>Mariana da Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Silva</surname>
            <given-names>Diego Guedes da</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <aff id="aff1">
          <institution content-type="orgname">Santa Casa de Miseric&#243;rdia de Curitiba</institution>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Irmandade da Santa Casa de Miseric&#243;rdia de Curitiba, Curitiba, PR - Brazil</institution>
          <institution content-type="normalized">Santa Casa de Miseric&#243;rdia de Curitiba</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c1"><bold>Mailing Address: Camila Stuchi Zarpelon,</bold> Hospital Santa Casa de Curitiba. Jeremias Maciel Perretto, Campo Comprido. Postal Code 81210-310, Curitiba, PR - Brazil. E-mail: <email>camilastuchi@cardiol.br</email>, <email>camilastuchi@yahoo.com.br</email>
				</corresp>
        <fn fn-type="con">
          <p>
            <bold>Author contributions</bold>
          </p>
          <p>Conception and design of the research, Analysis and interpretation of the data and Statistical analysis: Zarpelon CS, Chomiski Netto M, Jorge JCM; Acquisition of data: Zarpelon CS, Chomiski Netto M, Fabris CC, Desengrini D, Jardim MS, Silva DG; Writing of the manuscript: Zarpelon CS; Critical revision of the manuscript for intellectual content: Zarpelon CS, Jorge JCM,.</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>24</day>
        <month>05</month>
        <year>2016</year>
      </pub-date>
      <pub-date pub-type="collection">
        <month>07</month>
        <year>2016</year>
      </pub-date>
      <volume>107</volume>
      <issue>1</issue>
      <fpage>4</fpage>
      <lpage>9</lpage>
      <history>
        <date date-type="received">
          <day>11</day>
          <month>07</month>
          <year>2015</year>
        </date>
        <date date-type="rev-recd">
          <day>05</day>
          <month>10</month>
          <year>2015</year>
        </date>
        <date date-type="accepted">
          <day>27</day>
          <month>10</month>
          <year>2015</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="http://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>The high prevalence of atrial fibrillation (AF) in the postoperative period of myocardial revascularization surgery increases morbidity and mortality.</p>
        </sec>
        <sec>
          <title>Objective:</title>
          <p>To assess the efficacy of colchicine to prevent AF in the postoperative period of myocardial revascularization surgery, the impact of AF on hospital length of stay and death, and to identify its risk factors.</p>
        </sec>
        <sec>
          <title>Methods:</title>
          <p>Between May 2012 and November 2013, 140 patients submitted to myocardial revascularization surgery were randomized, 69 to the control group and 71 to the colchicine group. Colchicine was used at the dose of 1 mg orally, twice daily, preoperatively, and of 0.5 mg, twice daily, until hospital discharge. A single dose of 1 mg was administered to those admitted 12 hours or less before surgery.</p>
        </sec>
        <sec>
          <title>Results:</title>
          <p>The primary endpoint was AF rate in the postoperative period of myocardial revascularization surgery. Colchicine group patients showed no reduction in AF incidence as compared to control group patients (7.04% versus 13.04%, respectively; p = 0.271). There was no statistically significant difference between the groups regarding death from any cause rate (5.6% versus 10.1%; p = 0,363) and hospital length of stay (14.5 &#177; 11.5 versus 13.3 &#177; 9.4 days; p = 0.490). However, colchicine group patients had a higher infection rate (26.8% versus 8.7%; p = 0.007).</p>
        </sec>
        <sec>
          <title>Conclusion:</title>
          <p>The use of colchicine to prevent AF after myocardial revascularization surgery was not effective in the present study. Brazilian Registry of Clinical Trials number RBR-556dhr. </p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords:</title>
        <kwd>Colchicine/therapeutic use</kwd>
        <kwd>Atrial Fibrillation/mortality</kwd>
        <kwd>Myocardial Revascularization</kwd>
        <kwd>Postoperative Period</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introduction</title>
      <p>Atrial fibrillation in the postoperative period of myocardial revascularization surgery (AF-POMR) occurs in 10% to 65% of patients,<xref ref-type="bibr" rid="B1">1</xref><sup>-</sup><xref ref-type="bibr" rid="B5">5</xref> increasing morbidity and mortality after surgery.<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B7">7</xref> It is associated with an increase in hospital length of stay, and, thus, in costs,<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B8">8</xref><sup>,</sup><xref ref-type="bibr" rid="B9">9</xref> and can cause serious clinical complications, such as hypotension, heart failure, stroke and other thromboembolic disorders.<xref ref-type="bibr" rid="B10">10</xref>
			</p>
      <p>Although not completely understood, the electrophysiological mechanism of AF-POMR is believed to be reentry. Some complications inherent in the postoperative period can be the trigger in patients predisposed to AF. Perioperative atrial trauma, pericardial inflammatory process secondary to surgical manipulation, autonomic disorder and plasma volume changes are some predisposing factors.<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B11">11</xref>
			</p>
      <p>Colchicine is the classic drug to treat gout, in addition to being part of the management of Mediterranean fever and Behcet's disease. It is usually classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid metabolic pathway. Colchicine binds to non-polymerized tubulin, forming a stable complex that effectively inhibits the dynamic of microtubules, depolymerizing them. Thus, any process requiring changes in the cell cytoskeleton, such as cellular mitosis, exocytosis and neutrophil motility, is affected.<xref ref-type="bibr" rid="B12">12</xref> In addition, colchicine has an important effect on atrial myocytes, changing the atrial response to autonomic effects (reducing the sympathetic activity and increasing the parasympathetic one).<xref ref-type="bibr" rid="B13">13</xref><sup>,</sup><xref ref-type="bibr" rid="B14">14</xref>
			</p>
      <p>A COPPS substudy, published by Imazio et al.,<xref ref-type="bibr" rid="B6">6</xref> has assessed the use of colchicine to prevent atrial fibrillation (AF) in the postoperative period of cardiac surgery. A reduction from 22% to 12% was observed in the AF rate as compared to the control group (p = 0.021), in addition to a reduction in hospital length of stay (p = 0.04) and rehabilitation time (p = 0.009)<sub>.</sub> However, in that study, colchicine was initiated only on the third postoperative day; however, the highest AF incidence occurs on the first 2 to 3 days after cardiac intervention.<xref ref-type="bibr" rid="B15">15</xref>
			</p>
      <p>This study aimed at assessing colchicine to prevent AF in patients undergoing myocardial revascularization surgery.</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <sec>
        <title>Study Design and Participants</title>
        <p>This is a prospective, randomized, open, single-center clinical assay, whose 140 participants were recruited from the Hospital Santa Casa de Miseric&#243;rdia de Curitiba.</p>
        <p>This study followed the Declaration of Helsinki, which provides recommendations to biomedical research involving human beings, and was submitted to the Committee of Ethics in Research with Human Beings of the Pontif&#237;cia Universidade Cat&#243;lica do Paran&#225; (PUC-PR) (protocol 50883).</p>
      </sec>
      <sec>
        <title>Inclusion Criteria</title>
        <p>Patients willing and able to provide informed consent term were recruited. The inclusion criteria were as follows: minimum age of 18 years; indication for elective myocardial revascularization surgery; and sinus rhythm on the day prior to surgery. Mean ages were 60.3 &#177; 8.1 years and 61.5 &#177; 10.3 years in the control and colchicine groups (p = 0.44), respectively, and 45 participants were of the female sex, and 95, of the male sex.</p>
      </sec>
      <sec>
        <title>Exclusion Criteria</title>
        <p>The exclusion criteria were: contraindication to the study medication; previously diagnosed AF or atrial flutter; need for heart valve surgery associated; severe liver disease (aminotransferase levels increased more than 1.5-fold the normal value); renal failure (creatinine &gt; 2 mg/dL); known gastrointestinal diseases; current colchicine treatment; cardiogenic shock; severe arrhythmias; neoplasms; non-communicative patients; simultaneous use of antiarrhythmic drugs, except for digoxin, beta-blockers and calcium channel blockers.</p>
      </sec>
      <sec>
        <title>Intervention</title>
        <p>From May 2012 to November 2013, 140 patients submitted to myocardial revascularization surgery were randomized into two groups: control group, not receiving the study medication; and therapeutic group, medicated with colchicine. The therapeutic group received oral colchicine at the dose of 1 mg, twice daily, in the preoperative period (initiated 24 hours before surgery), followed by 0.5 mg, orally or nasogastrically, twice daily, until hospital discharge. If the patient was admitted only 12 hours before surgery, colchicine was administered orally, at a single dose of 1 mg, the night before surgery. Clinical management and medications routinely used in both groups were not changed.</p>
        <p>The cardiac rhythm was defined as AF when no P wave was detected before the QRS complex, and the heart rate was irregular. To be considered in this study, AF episodes should last at least 5 minutes or, if shorter, they should have caused hemodynamic instability. Atrial fibrillation was identified via electrocardiography by using continuous cardiac monitoring and 12-lead electrocardiogram (ECG) during intensive care unit (ICU) stay. After ICU discharge, only daily record of 12-lead ECG.</p>
      </sec>
      <sec>
        <title>Endpoints</title>
        <p>The primary study endpoint was the AF-POMR rate in the colchicine and control groups. Additional analyses included death from any cause, hospital length of stay and postoperative infection.</p>
      </sec>
      <sec>
        <title>Randomization</title>
        <p>Patients were randomly assigned to the groups by use of a computer program (link: <ext-link ext-link-type="uri" xlink:href="http://stattrek.com/statistics/random-number-generator.aspx">http://stattrek.com/statistics/random-number-generator.aspx</ext-link>). Both participants and researchers were instructed on the treatment. Data were collected by use of notification forms, manually completed by study researchers.</p>
      </sec>
      <sec>
        <title>Statistical Analysis</title>
        <p>This study required 140 patients (69 in the control group and 71 in the intervention group) to detect AF rates of 20% and 6%, respectively, with an 80% power and p = 0.05 in both groups. The AF rate was estimated for both groups based on the results of a randomized, placebo-controlled study, in which the AF rate was significantly lower in the colchicine group than in the placebo group (12% versus 22%, respectively, p = 0.021).<xref ref-type="bibr" rid="B6">6</xref>
				</p>
        <p>Quantitative variables were described as means, medians, minimum and maximum values, and standard deviations. Qualitative variables were described as frequencies and percentages. To compare the two groups regarding quantitative variables, Student <italic>t</italic> test or nonparametric Mann-Whitney test was used for independent samples. Regarding qualitative variables, the groups were compared by using Fisher exact test or chi-square test. To compare the two groups regarding time free from AF, log-rank test was used. Values of p &lt; 0.05 indicated statistical significance. Data were assessed by using the Statistica software, v.8.0.</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Patients' Characteristics</title>
        <p>The patients' baseline characteristics were similar in both groups and are shown in <xref ref-type="table" rid="t1">Table 1</xref>.</p>
        <table-wrap id="t1">
          <label>Table 1</label>
          <caption>
            <title>Baseline characteristics of the patients of this study</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup width="25%">
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead>
              <tr>
                <th align="left">Characteristic</th>
                <th align="center">Colchicine (n = 71)</th>
                <th align="center">Control (n = 69)</th>
                <th align="center">p</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Mean age (mean &#177; SD), years</td>
                <td align="center">61.5 &#177; 10.3</td>
                <td align="center">60.3 &#177; 8.1</td>
                <td align="center">0.44</td>
              </tr>
              <tr>
                <td align="left">Age &lt; 65 years (n = 96), n (%)</td>
                <td align="center">43 (60.6)</td>
                <td align="center">53 (76.8)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Age &gt; 65 years (n = 44), n (%)</td>
                <td align="center">28 (39.4)</td>
                <td align="center">16 (23.2)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Female sex (n = 45), n (%)</td>
                <td align="center">22 (30.9)</td>
                <td align="center">23 (33.3)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Male sex (n = 95), n (%)</td>
                <td align="center">49 (69.0)</td>
                <td align="center">46 (66.7)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left" colspan="4">
                  <bold>Previous pathologies, n (%)</bold>
                </td>
              </tr>
              <tr>
                <td align="left">SA (n = 10)</td>
                <td align="center">3 (4.2)</td>
                <td align="center">7 (10.1)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">UA (n = 63)</td>
                <td align="center">32 (45.1)</td>
                <td align="center">31 (44.9)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">CAD (n = 35)</td>
                <td align="center">21 (29.6)</td>
                <td align="center">14 (20.3)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">AMI (n = 32)</td>
                <td align="center">15 (21.1)</td>
                <td align="center">17 (24.6)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">SAH (n = 16)</td>
                <td align="center">63 (88.7)</td>
                <td align="center">61 (88.4)</td>
                <td align="center">1.00</td>
              </tr>
              <tr>
                <td align="left">Smoking habit (n = 57)</td>
                <td align="center">23 (32.4)</td>
                <td align="center">34 (49.3)</td>
                <td align="center">0.06</td>
              </tr>
              <tr>
                <td align="left">Dyslipidemia (n = 88)</td>
                <td align="center">44 (61.9)</td>
                <td align="center">44 (63.8)</td>
                <td align="center">0.86</td>
              </tr>
              <tr>
                <td align="left">DM (n = 72)</td>
                <td align="center">42 (59.2)</td>
                <td align="center">30 (43.5)</td>
                <td align="center">0.09</td>
              </tr>
              <tr>
                <td align="left">Previous AMI (n = 31)</td>
                <td align="center">17 (23.9)</td>
                <td align="center">14 (20.3)</td>
                <td align="center">0.69</td>
              </tr>
              <tr>
                <td align="left">Previous PCI (n = 20)</td>
                <td align="center">11 (15.5)</td>
                <td align="center">9 (13.1)</td>
                <td align="center">0.81</td>
              </tr>
              <tr>
                <td align="left">Previous MR (n = 5)</td>
                <td align="center">3 (4.2)</td>
                <td align="center">2 (2.9)</td>
                <td align="center">1.00</td>
              </tr>
              <tr>
                <td align="left">FH-CAD (n = 50)</td>
                <td align="center">23 (32.4)</td>
                <td align="center">27 (39.1)</td>
                <td align="center">0.48</td>
              </tr>
              <tr>
                <td align="left">Beta-blocker (n = 72)</td>
                <td align="center">35 (50.0)</td>
                <td align="center">37 (53.6)</td>
                <td align="center">0.74</td>
              </tr>
              <tr>
                <td align="left">ACEI (n = 63)</td>
                <td align="center">33 (46.5)</td>
                <td align="center">30 (43.5)</td>
                <td align="center">0.74</td>
              </tr>
              <tr>
                <td align="left">ARB (n = 22)</td>
                <td align="center">12 (16.9)</td>
                <td align="center">10 (14.5)</td>
                <td align="center">0.82</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN01">
              <p>SA: stable angina; UA: unstable angina; CAD: coronary artery disease; AMI: acute myocardial infarction; SAH: systemic arterial hypertension; DM: diabetes mellitus; PCI: percutaneous coronary intervention; MR: myocardial revascularization; FH: family history; ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin-receptor-blocker.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
      <sec>
        <title>Final Result</title>
        <p>To assess the primary endpoint (AF-POMR in the colchicine and control groups), AF-POMR episodes from the first postoperative day onward were considered. The colchicine group showed no statistically significant reduction in AF incidence as compared to the control group (7.0% versus 13.0%; p = 0.271; colchicine and control, respectively). After beginning the intervention, the numbers of AF-POMR events in the colchicine and control groups were 5 of 71 versus 9 of 69, respectively (<xref ref-type="table" rid="t2">Tabele 2</xref>).</p>
        <table-wrap id="t2">
          <label>Table 2</label>
          <caption>
            <title>Endpoints of this study according to the colchicine and control groups</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup width="20%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" rowspan="2">Event</th>
                <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">Colchicine</th>
                <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">Control</th>
                <th align="center" rowspan="2">p</th>
                <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">RRR, %</th>
              </tr>
              <tr>
                <th align="center">(n = 71)</th>
                <th align="center">(n = 69)</th>
                <th align="center">(95% CI)</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left" colspan="5">
                  <bold>Primary endpoint</bold>
                </td>
              </tr>
              <tr>
                <td align="left">AF-POMR, %<xref ref-type="table-fn" rid="TFN03">*</xref>
								</td>
                <td align="center">7.0</td>
                <td align="center">13.0</td>
                <td align="center">0.271</td>
                <td align="center">46 (-53 a 81)</td>
              </tr>
              <tr>
                <td align="left" colspan="5">
                  <bold>Additional analyses</bold>
                </td>
              </tr>
              <tr>
                <td align="left">Death from any cause, n (%)</td>
                <td align="center">4 (5.6)</td>
                <td align="center">7 (10.1)</td>
                <td align="center">0.363</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Hospital length of stay, days</td>
                <td align="center">14.5 &#177; 11.5</td>
                <td align="center">13.3 &#177; 9.4</td>
                <td align="center">0.490</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Postoperative infection, n (%)</td>
                <td align="center">19 (26.8)</td>
                <td align="center">6 (8.7)</td>
                <td align="center">0.007</td>
                <td align="center">
								</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN02">
              <p>RRR: reduction in relative risk with colchicine; CI: confidence interval; AF-POMR: atrial fibrillation in the postoperative period of myocardial revascularization surgery.</p>
            </fn>
            <fn id="TFN03">
              <label>*</label>
              <p>Calculated with Fisher exact test.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>The colchicine and control groups showed no statistically significant difference regarding the death from any cause rate (5.6% versus 10.1%, respectively; p = 0.363) and hospital length of stay (14.5 &#177; 11.5 versus 13.3 &#177; 9.4 days, respectively; p = 0,490). The colchicine group, however, had a higher infection rate (26.8% versus 8.7%; p = 0.007) (<xref ref-type="table" rid="t2">Table 2</xref>).</p>
        <p>The following clinical characteristics were identified in patients with AF-POMR in both control and colchicine groups as compared to patients without AF-POMR (<xref ref-type="table" rid="t3">Table 3</xref>): coronary care unit length of stay (7.6 &#177; 9.0 days versus 3.6 &#177; 4.6 days, respectively; p = 0.008); use of extracorporeal circulation (ECC) during surgery (28.6% versus 39.7%, respectively; p = 0.566); postoperative beta-blocker use (100.0% versus 93.7%, respectively; p = 1.000); and use of blood products (21.4% versus 26.2%, respectively; p = 1.000). Patients with AF-POMR had a longer coronary care unit length of stay and no other significantly different characteristic.</p>
        <table-wrap id="t3">
          <label>Table 3</label>
          <caption>
            <title>Comparison of the clinical characteristics between patients with and without atrial fibrillation (AF) in the postoperative period of myocardial revascularization surgery in the control and colchicine groups</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup width="25%">
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" rowspan="2">Characteristics</th>
                <th align="center" colspan="3" style="border-bottom-width:thin;border-bottom-style:solid">AF, n (%)</th>
              </tr>
              <tr>
                <th align="center">No (n = 126)</th>
                <th align="center">Yes (n = 14)</th>
                <th align="center">p</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Mean age, years</td>
                <td align="center">60.4 &#177; 9.2</td>
                <td align="center">65.6&#177;9.1</td>
                <td align="center">0.048</td>
              </tr>
              <tr>
                <td align="left">Age &lt; 65 years (n = 96)</td>
                <td align="center">88 (69.8)</td>
                <td align="center">8 (57.1)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Age &gt; 65 years (n = 44)</td>
                <td align="center">38 (30.2)</td>
                <td align="center">6 (42.9)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Female sex (n = 45)</td>
                <td align="center">41 (32.5)</td>
                <td align="center">4 (28.6)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Male sex (n = 95)</td>
                <td align="center">85 (67.5)</td>
                <td align="center">10 (71.4)</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">SAH (n = 124)</td>
                <td align="center">114 (90.5)</td>
                <td align="center">10 (71.4)</td>
                <td align="center">0.057</td>
              </tr>
              <tr>
                <td align="left">Previous MR (n = 5)</td>
                <td align="center">5 (3.9)</td>
                <td align="center">0 (0.0)</td>
                <td align="center">1.000</td>
              </tr>
              <tr>
                <td align="left">DM (n = 72)</td>
                <td align="center">65 (51.6)</td>
                <td align="center">7 (50.0)</td>
                <td align="center">1.000</td>
              </tr>
              <tr>
                <td align="left">CCU length of stay, days</td>
                <td align="center">3.6 &#177; 4.6</td>
                <td align="center">7.6 &#177; 9.0</td>
                <td align="center">0.008</td>
              </tr>
              <tr>
                <td align="left">ECC (n = 54)</td>
                <td align="center">50 (39.7)</td>
                <td align="center">4 (28.6)</td>
                <td align="center">0.566</td>
              </tr>
              <tr>
                <td align="left">Perioperative beta-blocker (n = 132)</td>
                <td align="center">118 (93.7)</td>
                <td align="center">14 (100.0)</td>
                <td align="center">1.000</td>
              </tr>
              <tr>
                <td align="left">Use of blood products (n = 36)</td>
                <td align="center">33 (26.2)</td>
                <td align="center">3 (21.4)</td>
                <td align="center">1.000</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN04">
              <p>SAH: systemic arterial hypertension; MR: myocardial revascularization surgery; DM: diabetes mellitus; CCU: coronary care unit; ECC: extracorporeal circulation.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <p>The COPPS-POAF substudy has shown colchicine to be safe and effective to prevent pericarditis and AF-POMR, reducing the incidence of AF (p = 0.021).<xref ref-type="bibr" rid="B6">6</xref> The present study showed no statistically significant reduction in the AF-POMR rate, and one cause of that might have been the reduced sample size.</p>
      <p>In addition, the cardiac rhythm recording method (continuous cardiac monitoring and 12-lead ECG) might have missed some AF episodes, because the monitors used did not allow data storage for later analysis. The AF-POMR episodes were recorded only when they caused symptoms or hemodynamic change, or, if asymptomatic, when witnessed by an attending physician.</p>
      <p>The infection rate of the colchicine group was greater than that of the control group. There is neither a randomized study nor a case report confirming the relationship between colchicine use at therapeutic doses and the increase in the number of infection cases. Our finding might have been random and related to the reduced number of patients, which can be assessed in future studies.</p>
      <p>Patients treated with colchicine remain hospitalized longer. That might not be related to the drug itself, but rather to the infection rate, which, as previously stated, was higher in the colchicine group. In addition, the COPPS-POAF substudy, assessing a larger sample, has reported a reduction in the hospital length of stay in the colchicine group as compared to that in the control group (9.4 &#177; 3.7 versus 10.3 &#177; 4.3 days; p = 0.040).<xref ref-type="bibr" rid="B6">6</xref>
			</p>
      <p>Of the 140 patients studied, 54 patients underwent myocardial revascularization surgery with ECC, and 86 patients, without ECC. Hashemzadeh et al.,<xref ref-type="bibr" rid="B16">16</xref> assessing 939 patients submitted to myocardial revascularization surgery, have reported AF-POMR in 38 patients of the non-ECC group and in 93 patients of the ECC group (9.8% versus 16.7%, respectively, p=0.002), showing an increase in the AF-POMR rate of patients undergoing surgery with ECC. In the present study, most surgeries were performed without ECC, which might explain the low AF-POMR rate found.</p>
      <p>Similarly to the COPPS-POAF substudy, the incidence of death from any cause was not significantly smaller in the colchicine group of this study.<xref ref-type="bibr" rid="B6">6</xref>
			</p>
      <p>Colchicine is a potent anti-inflammatory drug classically used to treat pericarditis.<xref ref-type="bibr" rid="B12">12</xref> Further studies are required to confirm its real safety and efficacy in preventing AF-POMR.</p>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclusion</title>
      <p>The use of colchicine to prevent AF-POMR showed no efficacy in the present study.</p>
      <p>The authors deny any conflict of interest.</p>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="supported-by">
        <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 study is not associated with any thesis or dissertation work.</p>
      </fn>
    </fn-group>
    <ack>
      <title>Acknowledgements</title>
      <p>We thank those who made this study possible, especially the Cardiac Surgery team and the Clinical Cardiology teachers of the Hospital Santa Casa de Miseric&#243;rdia de Curitiba.</p>
    </ack>
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              <surname>de Beaumont</surname>
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          <source>Circulation</source>
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              <surname>Dehdilani</surname>
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    </ref-list>
  </back>
  <sub-article article-type="translation" id="s1" xml:lang="pt">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Artigos Originais</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Colchicina para Redu&#231;&#227;o de Fibrila&#231;&#227;o Atrial em P&#243;s-Operat&#243;rio de Revasculariza&#231;&#227;o Mioc&#225;rdica</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Zarpelon</surname>
            <given-names>Camila Stuchi</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
          <xref ref-type="corresp" rid="c2"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Netto</surname>
            <given-names>Miguel Chomiski</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jorge</surname>
            <given-names>Jos&#233; Carlos Moura</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Fabris</surname>
            <given-names>C&#225;tia Carolina</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Desengrini</surname>
            <given-names>Dieli</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jardim</surname>
            <given-names>Mariana da Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Silva</surname>
            <given-names>Diego Guedes da</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">1</xref>
        </contrib>
        <aff id="aff2">
          <label>1</label>
          <institution content-type="original">Irmandade da Santa Casa de Miseric&#243;rdia de Curitiba, Curitiba, PR - Brasil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c2"><bold>Correspond&#234;ncia: Camila Stuchi Zarpelon</bold>, Hospital Santa Casa de Curitiba. Jeremias Maciel Perretto, Campo Comprido. CEP 81210-310, Curitiba, PR - Brasil. E-mail: <email>camilastuchi@cardiol.br</email>, <email>camilastuchi@yahoo.com.br</email></corresp>
        <fn fn-type="con">
          <p>
            <bold>Contribui&#231;&#227;o dos autores</bold>
          </p>
          <p>Concep&#231;&#227;o e desenho da pesquisa, An&#225;lise e interpreta&#231;&#227;o dos dados e An&#225;lise estat&#237;stica: Zarpelon CS, Chomiski Netto M, Jorge JCM; Obten&#231;&#227;o de dados: Zarpelon CS, Chomiski Netto M, Fabris CC, Desengrini D, Jardim MS, Silva DG; Reda&#231;&#227;o do manuscrito: Zarpelon CS; Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante: Zarpelon CS, Jorge JCM.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potencial conflito de interesse</bold>
          </p>
          <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
        </fn>
      </author-notes>
      <abstract>
        <title>Resumo</title>
        <sec>
          <title>Fundamento:</title>
          <p>A alta preval&#234;ncia de fibrila&#231;&#227;o atrial (FA) no p&#243;s-operat&#243;rio de cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica ocasiona maior morbidade e mortalidade. </p>
        </sec>
        <sec>
          <title>Objetivos:</title>
          <p>Avaliar a efic&#225;cia da colchicina como profilaxia para FA no p&#243;s-operat&#243;rio de cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica, o impacto da FA sobre o tempo de interna&#231;&#227;o hospitalar e &#243;bito e identificar fatores de risco para o seu aparecimento.</p>
        </sec>
        <sec>
          <title>M&#233;todos:</title>
          <p>Entre maio de 2012 e novembro de 2013, 140 pacientes submetidos &#224; cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica foram randomizados, 69 no grupo controle e 71 no grupo colchicina. A colchicina foi utilizada na dose de 1 mg via oral, duas vezes ao dia, no pr&#233;-operat&#243;rio, e 0,5 mg, duas vezes ao dia, at&#233; a alta hospitalar. Dose &#250;nica de 1 mg foi administrada aos internados 12 horas ou menos antes da cirurgia.</p>
        </sec>
        <sec>
          <title>Resultados:</title>
          <p>O desfecho prim&#225;rio foi a taxa de FA no p&#243;s-operat&#243;rio de cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica. Os pacientes do grupo colchicina n&#227;o apresentaram redu&#231;&#227;o na incid&#234;ncia de FA em compara&#231;&#227;o aos do grupo controle (7,0% versus 13,0%, respectivamente; p = 0,271). N&#227;o houve diferen&#231;a estatisticamente significativa entre os grupos em rela&#231;&#227;o &#224; taxa de &#243;bito por qualquer causa (5,6% versus 10,1%; p = 0,363) e ao tempo de interna&#231;&#227;o (14,5 &#177; 11,5 versus 13,3 &#177; 9,4 dias; p = 0,490). Por&#233;m, o grupo colchicina apresentou maior taxa de infec&#231;&#227;o (26,8% versus 8,7%; p = 0,007).</p>
        </sec>
        <sec>
          <title>Conclus&#245;es:</title>
          <p>O uso da colchicina para profilaxia da FA no p&#243;s-operat&#243;rio de revasculariza&#231;&#227;o mioc&#225;rdica n&#227;o se mostrou eficaz neste estudo. Registro Brasileiro de Ensaios Cl&#237;nicos n&#250;mero RBR-556dhr.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="pt">
        <title>Palavras-chave:</title>
        <kwd>Colchicina/uso terap&#234;utico</kwd>
        <kwd>Fibrila&#231;&#227;o Atrial/mortalidade</kwd>
        <kwd>Revasculariza&#231;&#227;o Mioc&#225;rdica</kwd>
        <kwd>Per&#237;odo P&#243;s Operat&#243;rio</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <sec sec-type="intro">
        <title>Introdu&#231;&#227;o</title>
        <p>A fibrila&#231;&#227;o atrial no p&#243;s-operat&#243;rio de cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica (FA-PORM) ocorre em 10% a 65% dos pacientes,<xref ref-type="bibr" rid="B1">1</xref><sup>-</sup><xref ref-type="bibr" rid="B5">5</xref> ocasionando maior morbidade e mortalidade ap&#243;s essa cirurgia.<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B7">7</xref> Associa-se a aumento no tempo de perman&#234;ncia hospitalar e, portanto, custos,<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B8">8</xref><sup>,</sup><xref ref-type="bibr" rid="B9">9</xref> podendo ocasionar complica&#231;&#245;es cl&#237;nicas s&#233;rias como hipotens&#227;o, insufici&#234;ncia card&#237;aca, acidente vascular cerebral e outros transtornos tromboemb&#243;licos.<xref ref-type="bibr" rid="B10">10</xref>
				</p>
        <p>Acredita-se que o mecanismo eletrofisiol&#243;gico causador da FA-PORM seja reentrada, entretanto n&#227;o &#233; totalmente conhecido. Algumas complica&#231;&#245;es inerentes ao p&#243;s-operat&#243;rio podem ser o gatilho em pacientes predispostos a essa arritmia. Trauma atrial perioperat&#243;rio, processo inflamat&#243;rio peric&#225;rdico secund&#225;rio a manipula&#231;&#227;o cir&#250;rgica, dist&#250;rbio auton&#244;mico e mudan&#231;as no volume plasm&#225;tico s&#227;o alguns dos fatores predisponentes.<xref ref-type="bibr" rid="B6">6</xref><sup>,</sup><xref ref-type="bibr" rid="B11">11</xref>
				</p>
        <p>A colchicina &#233; o medicamento cl&#225;ssico para o tratamento da gota, e tamb&#233;m faz parte do manejo da febre do Mediterr&#226;neo e doen&#231;a de Behcet. &#201; comumente classificada como um agente anti-inflamat&#243;rio, embora seu mecanismo de a&#231;&#227;o n&#227;o envolva a via metab&#243;lica do &#225;cido araquid&#244;nico. A colchicina liga-se &#224; tubulina n&#227;o polimerizada, formando um complexo est&#225;vel que efetivamente inibe a din&#226;mica dos microt&#250;bulos, despolimerizando-os. Dessa forma, &#233; afetado qualquer processo que exige altera&#231;&#245;es do citoesqueleto celular, incluindo a mitose celular, exocitose e motilidade de neutr&#243;filos.<xref ref-type="bibr" rid="B12">12</xref> Tem efeito importante tamb&#233;m sobre os mi&#243;citos do &#225;trio, alterando a resposta atrial aos efeitos auton&#244;micos (atenua a atividade simp&#225;tica e aumenta a parassimp&#225;tica).<xref ref-type="bibr" rid="B13">13</xref><sup>,</sup><xref ref-type="bibr" rid="B14">14</xref>
				</p>
        <p>Em subestudo do estudo COPPS, publicado por Imazio et al.,<xref ref-type="bibr" rid="B6">6</xref> foi avaliado o uso da colchicina na preven&#231;&#227;o de fibrila&#231;&#227;o atrial (FA) em p&#243;s-operat&#243;rio de cirurgia card&#237;aca. Houve redu&#231;&#227;o de 22% para 12% na taxa de FA em compara&#231;&#227;o com grupo controle (p = 0,021), redu&#231;&#227;o no tempo de interna&#231;&#227;o hospitalar (p = 0,04) e de reabilita&#231;&#227;o (p = 0,009)<sub>.</sub> No entanto, nesse estudo a colchicina foi iniciada somente no terceiro dia de p&#243;s-operat&#243;rio, sendo que a maior incid&#234;ncia de FA ocorre nos primeiros 2 a 3 dias ap&#243;s a interven&#231;&#227;o card&#237;aca.<xref ref-type="bibr" rid="B15">15</xref>
				</p>
        <p>Prop&#245;e-se neste estudo a avalia&#231;&#227;o da colchicina para profilaxia de FA nos pacientes submetidos &#224; cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica.</p>
      </sec>
      <sec sec-type="methods">
        <title>M&#233;todos</title>
        <sec>
          <title>Desenho do Estudo e Participantes</title>
          <p>Realizado ensaio cl&#237;nico prospectivo, randomizado, aberto, em um &#250;nico centro. Os 140 participantes do estudo foram recrutados do Hospital Santa Casa de Miseric&#243;rdia de Curitiba.</p>
          <p>Seguiu-se a Declara&#231;&#227;o de Helsinki, que forneceu recomenda&#231;&#245;es &#224; pesquisa biom&#233;dica envolvendo humanos como objetos de estudo. Este trabalho foi submetido &#224; an&#225;lise e aprova&#231;&#227;o do Comit&#234; de &#201;tica em Pesquisa com Humanos (CEPH) da Pontif&#237;cia Universidade Cat&#243;lica do Paran&#225; (PUC-PR). Parecer n&#250;mero 50883.</p>
        </sec>
        <sec>
          <title>Crit&#233;rios de Inclus&#227;o</title>
          <p>Foram recrutados pacientes dispostos e capazes de fornecer o termo de consentimento livre e esclarecido e que atendessem aos seguintes crit&#233;rios: idade m&#237;nima de 18 anos; indica&#231;&#227;o de revasculariza&#231;&#227;o mioc&#225;rdica eletiva; ritmo sinusal no dia anterior ao da cirurgia. A m&#233;dia de idade foi 60,3 &#177; 8,1 anos no grupo controle e 61,5 &#177; 10,3 anos no grupo colchicina (p = 0,44), sendo 45 participantes do sexo feminino e 95 do sexo masculino.</p>
        </sec>
        <sec>
          <title>Crit&#233;rios de Exclus&#227;o</title>
          <p>Os crit&#233;rios de exclus&#227;o foram: contraindica&#231;&#227;o para uso da medica&#231;&#227;o do estudo; FA ou <italic>flutter</italic> atrial previamente diagnosticados; necessidade de cirurgia valvar associada; doen&#231;a hep&#225;tica grave (transaminases acima de 1,5 vez o valor normal); insufici&#234;ncia renal (creatinina &gt; 2 mg/dl); doen&#231;as gastrointestinais conhecidas; tratamento atual com colchicina; choque cardiog&#234;nico; arritmias graves; neoplasias; pacientes n&#227;o comunicativos; uso simult&#226;neo de drogas antiarr&#237;tmicas, excluindo digoxina, betabloqueador e bloqueador dos canais de c&#225;lcio.</p>
        </sec>
        <sec>
          <title>Interven&#231;&#227;o</title>
          <p>Entre maio de 2012 e novembro de 2013, 140 pacientes submetidos a cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica foram randomizados para compor dois grupos: o grupo controle, que n&#227;o recebeu a medica&#231;&#227;o do estudo; e o grupo terap&#234;utico, medicado com colchicina. Para os pacientes alocados no grupo terap&#234;utico, a colchicina foi prescrita na dose de 1 mg via oral, duas vezes ao dia, durante o pr&#233;-operat&#243;rio (iniciada 24 horas antes da cirurgia), seguida de 0,5 mg via oral ou via sonda nasog&#225;strica, duas vezes ao dia, at&#233; o momento da alta hospitalar. Caso o paciente fosse internado somente 12 horas antes do procedimento cir&#250;rgico, era administrada colchicina 1 mg via oral em dose &#250;nica na noite anterior &#224; cirurgia. N&#227;o houve nenhuma interfer&#234;ncia na conduta cl&#237;nica e nos medicamentos rotineiramente empregados nos pacientes em ambos os grupos.</p>
          <p>O ritmo foi definido como FA quando n&#227;o se detectava onda P antes do complexo QRS e a frequ&#234;ncia card&#237;aca era irregular. Para serem considerados no estudo, os epis&#243;dios de FA deveriam ter a dura&#231;&#227;o de, no m&#237;nimo, 5 minutos ou, se inferior a esse tempo, ter causado instabilidade hemodin&#226;mica. O reconhecimento da FA foi realizado atrav&#233;s do registro eletrocardiogr&#225;fico por monitores card&#237;acos cont&#237;nuos e do eletrocardiograma (ECG) de 12 deriva&#231;&#245;es, durante a perman&#234;ncia em unidade de terapia intensiva (UTI). Ap&#243;s alta da UTI, somente registro di&#225;rio de ECG de 12 deriva&#231;&#245;es.</p>
        </sec>
        <sec>
          <title>Desfechos</title>
          <p>O desfecho prim&#225;rio do estudo foi a taxa de FA-PORM no grupo em que usou colchicina e no grupo controle. An&#225;lises adicionais inclu&#237;ram &#243;bito por qualquer causa, tempo de interna&#231;&#227;o e presen&#231;a de infec&#231;&#227;o no p&#243;s-operat&#243;rio.</p>
        </sec>
        <sec>
          <title>Randomiza&#231;&#227;o</title>
          <p>Houve distribui&#231;&#227;o aleat&#243;ria dos pacientes aos tratamentos propostos empregando-se m&#233;todo computadorizado (link: <ext-link ext-link-type="uri" xlink:href="http://stattrek.com/statistics/random-number-generator.aspx">http://stattrek.com/statistics/random-number-generator.aspx</ext-link>). Tanto os participantes quanto os investigadores foram informados sobre o tratamento. Os dados foram coletados atrav&#233;s de formul&#225;rios de notifica&#231;&#227;o, preenchidos manualmente pelos investigadores do estudo.</p>
        </sec>
        <sec>
          <title>An&#225;lise Estat&#237;stica</title>
          <p>Para o atual estudo, o total de 140 pacientes, 69 no grupo controle e 71 no grupo interven&#231;&#227;o, foi necess&#225;rio para detectar uma taxa de FA de 20% e 6% (controle e colchicina, respectivamente), com um poder de 80% e usando p = 0,05 nos dois grupos. Determinou-se a taxa estimada de FA para os dois grupos com base nos resultados de um estudo randomizado placebo-controlado em que a taxa de FA era significativamente menor no grupo colchicina do que no grupo placebo (12% versus 22%, respectivamente, p = 0,021).<xref ref-type="bibr" rid="B6">6</xref>
					</p>
          <p>Vari&#225;veis quantitativas foram descritas por m&#233;dias, medianas, valores m&#237;nimos, valores m&#225;ximos e desvios-padr&#227;o. Vari&#225;veis qualitativas foram descritas por frequ&#234;ncias e porcentuais. Para a compara&#231;&#227;o dos dois grupos em rela&#231;&#227;o a vari&#225;veis quantitativas foi considerado o teste <italic>t</italic> de Student para amostras independentes ou o teste n&#227;o param&#233;trico de Mann-Whitney. Em rela&#231;&#227;o a vari&#225;veis qualitativas, os grupos foram comparados usando-se o teste exato de Fisher ou do Qui-quadrado. Para a compara&#231;&#227;o dos dois grupos em rela&#231;&#227;o ao tempo livre de FA foi considerado o teste de Log-rank. Valores de p&lt;0,05 indicaram signific&#226;ncia estat&#237;stica. Os dados foram analisados com o programa computacional Statistica v.8.0.</p>
        </sec>
      </sec>
      <sec sec-type="results">
        <title>Resultados</title>
        <sec>
          <title>Caracter&#237;sticas dos Pacientes</title>
          <p>As caracter&#237;sticas basais dos pacientes foram semelhantes em ambos os grupos do estudo e est&#227;o listadas na <xref ref-type="table" rid="t4">Tabela 1</xref>.</p>
          <table-wrap id="t4">
            <label>Tabela 1</label>
            <caption>
              <title>Caracter&#237;sticas basais dos pacientes do Estudo Colchicina para Redu&#231;&#227;o de Fibrila&#231;&#227;o Atrial em P&#243;s-Operat&#243;rio de Revasculariza&#231;&#227;o Mioc&#225;rdica</title>
            </caption>
            <table frame="hsides" rules="groups">
              <colgroup width="25%">
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead>
                <tr>
                  <th align="left">Caracter&#237;stica</th>
                  <th align="center">Colchicina (n = 71)</th>
                  <th align="center">Controle (n = 69)</th>
                  <th align="center">p</th>
                </tr>
              </thead>
              <tbody>
                <tr>
                  <td align="left">M&#233;dia de idade (m&#233;dia &#177; DP), anos</td>
                  <td align="center">61,5&#177;10,3</td>
                  <td align="center">60,3&#177;8,1</td>
                  <td align="center">0,44</td>
                </tr>
                <tr>
                  <td align="left">Idade &lt; 65 anos (n = 96), n (%)</td>
                  <td align="center">43 (60,6)</td>
                  <td align="center">53 (76,8)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Idade &gt; 65 anos (n = 44), n (%)</td>
                  <td align="center">28 (39,4)</td>
                  <td align="center">16 (23,2)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Sexo feminino (n = 45), n (%)</td>
                  <td align="center">22 (30,9)</td>
                  <td align="center">23 (33,3)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Sexo masculino (n = 95), n (%)</td>
                  <td align="center">49 (69,0)</td>
                  <td align="center">46 (66,7)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left" colspan="4">
                    <bold>Hist&#243;ria m&#243;rbida pregressa, n (%)</bold>
                  </td>
                </tr>
                <tr>
                  <td align="left">AE (n = 10)</td>
                  <td align="center">3 (4,2)</td>
                  <td align="center">7 (10,1)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">AI (n = 63)</td>
                  <td align="center">32 (45,1)</td>
                  <td align="center">31 (44,9)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">DAC (n = 35)</td>
                  <td align="center">21 (29,6)</td>
                  <td align="center">14 (20,3)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">IAM (n = 32)</td>
                  <td align="center">15 (21,1)</td>
                  <td align="center">17 (24,6)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">HAS (n = 16)</td>
                  <td align="center">63 (88,7)</td>
                  <td align="center">61 (88,4)</td>
                  <td align="center">1,00</td>
                </tr>
                <tr>
                  <td align="left">Tabagismo (n = 57)</td>
                  <td align="center">23 (32,4)</td>
                  <td align="center">34 (49,3)</td>
                  <td align="center">0,06</td>
                </tr>
                <tr>
                  <td align="left">Dislipidemia (n = 88)</td>
                  <td align="center">44 (61,9)</td>
                  <td align="center">44 (63,8)</td>
                  <td align="center">0,86</td>
                </tr>
                <tr>
                  <td align="left">DM (n = 72)</td>
                  <td align="center">42 (59,2)</td>
                  <td align="center">30 (43,5)</td>
                  <td align="center">0,09</td>
                </tr>
                <tr>
                  <td align="left">IAM Pr&#233;vio (n = 31)</td>
                  <td align="center">17 (23,9)</td>
                  <td align="center">14 (20,3)</td>
                  <td align="center">0,69</td>
                </tr>
                <tr>
                  <td align="left">ATC Pr&#233;via (n = 20)</td>
                  <td align="center">11 (15,5)</td>
                  <td align="center">9 (13,1)</td>
                  <td align="center">0,81</td>
                </tr>
                <tr>
                  <td align="left">RM Pr&#233;via (n = 5)</td>
                  <td align="center">3 (4,2)</td>
                  <td align="center">2 (2,9)</td>
                  <td align="center">1,00</td>
                </tr>
                <tr>
                  <td align="left">HF-DAC (n = 50)</td>
                  <td align="center">23 (32,4)</td>
                  <td align="center">27 (39,1)</td>
                  <td align="center">0,48</td>
                </tr>
                <tr>
                  <td align="left">Betabloq (n = 72)</td>
                  <td align="center">35 (50,0)</td>
                  <td align="center">37 (53,6)</td>
                  <td align="center">0,74</td>
                </tr>
                <tr>
                  <td align="left">IECA (n = 63)</td>
                  <td align="center">33 (46,5)</td>
                  <td align="center">30 (43,5)</td>
                  <td align="center">0,74</td>
                </tr>
                <tr>
                  <td align="left">BRA (n = 22)</td>
                  <td align="center">12 (16,9)</td>
                  <td align="center">10 (14,5)</td>
                  <td align="center">0,82</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN05">
                <p>AE: angina est&#225;vel; AI: angina inst&#225;vel; DAC: doen&#231;a arterial coronariana; IAM: infarto agudo do mioc&#225;rdio; HAS: hipertens&#227;o arterial sist&#234;mica; DM: diabetes mellitus; ATC: angioplastia coronariana; RM: revasculariza&#231;&#227;o mioc&#225;rdica; HF: hist&#243;ria familiar; Betabloq: betabloqueador; IECA: inibidor da enzima conversora de angiotensina; BRA: bloqueador do receptor da angiotensina.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Resultado Final</title>
          <p>Para a avalia&#231;&#227;o do desfecho prim&#225;rio (FA-PORM nos grupos colchicina e controle), foram considerados os epis&#243;dios de FA-PORM a partir do primeiro dia de p&#243;s-operat&#243;rio. Os pacientes do grupo colchicina n&#227;o apresentaram redu&#231;&#227;o estatisticamente significativa na incid&#234;ncia de fibrila&#231;&#227;o atrial em compara&#231;&#227;o ao grupo controle (7,0% versus 13,0%; p = 0,271; colchicina e controle, respectivamente). O n&#250;mero de eventos de FA-PORM ap&#243;s o in&#237;cio da interven&#231;&#227;o (grupo colchicina/controle) foi 5 de 71 versus 9 de 69, respectivamente (<xref ref-type="table" rid="t5">Tabela 2</xref>).</p>
          <p>N&#227;o houve diferen&#231;a estatisticamente significativa entre os grupos colchicina e controle em rela&#231;&#227;o &#224; taxa de &#243;bito por qualquer causa (5,6% versus 10,1%, respectivamente; p = 0,363) e ao tempo de interna&#231;&#227;o (14,5 &#177; 11,5 versus 13,3 &#177; 9,4 dias, respectivamente; p = 0,490). Por&#233;m, os pacientes do grupo colchicina apresentaram maior taxa de infec&#231;&#227;o (26,8% versus 8,7%; p = 0,007) (<xref ref-type="table" rid="t5">Tabela 2</xref>).</p>
          <table-wrap id="t5">
            <label>Tabela 2</label>
            <caption>
              <title>Desfechos do Estudo Colchicina para Redu&#231;&#227;o de Fibrila&#231;&#227;o Atrial em P&#243;s-Operat&#243;rio de Revasculariza&#231;&#227;o Mioc&#225;rdica nos grupos controle e colchicina</title>
            </caption>
            <table frame="hsides" rules="groups">
              <colgroup width="20%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead>
                <tr>
                  <th align="left" rowspan="2">Evento</th>
                  <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">Colchicina</th>
                  <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">Controle</th>
                  <th align="center" rowspan="2">p</th>
                  <th align="center" style="border-bottom-width:thin;border-bottom-style:solid">RRR, %</th>
                </tr>
                <tr>
                  <th align="center">(n = 71)</th>
                  <th align="center">(n = 69)</th>
                  <th align="center">(IC 95%)</th>
                </tr>
              </thead>
              <tbody>
                <tr>
                  <td align="left" colspan="5">
                    <bold>Desfecho prim&#225;rio</bold>
                  </td>
                </tr>
                <tr>
                  <td align="left">FA-PORM, %<xref ref-type="table-fn" rid="TFN07">*</xref>
									</td>
                  <td align="center">7,0</td>
                  <td align="center">13,0</td>
                  <td align="center">0,271</td>
                  <td align="center">46 (-53 a 81)</td>
                </tr>
                <tr>
                  <td align="left" colspan="5">
                    <bold>An&#225;lises adicionais</bold>
                  </td>
                </tr>
                <tr>
                  <td align="left">&#211;bito por qualquer causa, n (%)</td>
                  <td align="center">4 (5,6)</td>
                  <td align="center">7 (10,1)</td>
                  <td align="center">0,363</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Tempo de interna&#231;&#227;o, dias</td>
                  <td align="center">14,5 &#177; 11,5</td>
                  <td align="center">13,3 &#177; 9,4</td>
                  <td align="center">0,490</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Infec&#231;&#227;o no p&#243;s-operat&#243;rio, n (%)</td>
                  <td align="center">19 (26,8)</td>
                  <td align="center">6 (8,7)</td>
                  <td align="center">0,007</td>
                  <td align="center">
									</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN06">
                <p>RRR: redu&#231;&#227;o do risco relativo com colchicina; IC: intervalo do confian&#231;a; FA-PORM: fibrila&#231;&#227;o atrial no p&#243;s operat&#243;rio de revasculariza&#231;&#227;o mioc&#225;rdica.</p>
              </fn>
              <fn id="TFN07">
                <label>*</label>
                <p>Calculado por Teste exato de Fisher.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <p>As caracter&#237;sticas cl&#237;nicas a seguir foram encontradas nos pacientes com FA-PORM tanto no grupo controle quanto no grupo colchicina, em compara&#231;&#227;o aos pacientes que n&#227;o desenvolveram FA-PORM (<xref ref-type="table" rid="t6">Tabela 3</xref>): dias de interna&#231;&#227;o em unidade coronariana (7,6 &#177; 9,0 versus 3,6 &#177; 4,6 dias, respectivamente; p = 0,008), uso de circula&#231;&#227;o extracorp&#243;rea (CEC) durante a cirurgia (28,6% versus 39,7%, respectivamente; p = 0,566), uso de betabloqueador no p&#243;s-operat&#243;rio (100,0% versus 93,7%, respectivamente; p = 1,000) e uso de hemoderivados (21,4% versus 26,2%, respectivamente; p = 1,000). Os pacientes com FA-PORM permaneceram mais dias em unidade coronariana e n&#227;o diferiram significativamente quanto &#224;s outras caracter&#237;sticas.</p>
          <table-wrap id="t6">
            <label>Tabela 3</label>
            <caption>
              <title>Compara&#231;&#227;o das caracter&#237;sticas cl&#237;nicas entre os pacientes com e sem fibrila&#231;&#227;o atrial no p&#243;s operat&#243;rio de revasculariza&#231;&#227;o mioc&#225;rdica nos grupos controle/colchicina</title>
            </caption>
            <table frame="hsides" rules="groups">
              <colgroup width="25%">
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead>
                <tr>
                  <th align="left" rowspan="2">Caracter&#237;sticas</th>
                  <th align="center" colspan="3" style="border-bottom-width:thin;border-bottom-style:solid">FA, n (%)</th>
                </tr>
                <tr>
                  <th align="center">N&#227;o (n = 126)</th>
                  <th align="center">Sim (n = 14)</th>
                  <th align="center">p</th>
                </tr>
              </thead>
              <tbody>
                <tr>
                  <td align="left">M&#233;dia de idade, anos</td>
                  <td align="center">60,4 &#177; 9,2</td>
                  <td align="center">65,6 &#177; 9,1</td>
                  <td align="center">0,048</td>
                </tr>
                <tr>
                  <td align="left">Idade &lt; 65 anos (n = 96)</td>
                  <td align="center">88 (69,8)</td>
                  <td align="center">8 (57,1)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Idade &gt; 65 anos (n = 44)</td>
                  <td align="center">38 (30,2)</td>
                  <td align="center">6 (42,9)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Sexo feminino (n = 45)</td>
                  <td align="center">41 (32,5)</td>
                  <td align="center">4 (28,6)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">Sexo masculino (n = 95)</td>
                  <td align="center">85 (67,5)</td>
                  <td align="center">10 (71,4)</td>
                  <td align="center">
									</td>
                </tr>
                <tr>
                  <td align="left">HAS (n = 124)</td>
                  <td align="center">114 (90,5)</td>
                  <td align="center">10 (71,4)</td>
                  <td align="center">0,057</td>
                </tr>
                <tr>
                  <td align="left">RM pr&#233;via (n = 5)</td>
                  <td align="center">5 (3,9)</td>
                  <td align="center">0 (0,0)</td>
                  <td align="center">1,000</td>
                </tr>
                <tr>
                  <td align="left">DM (n = 72)</td>
                  <td align="center">65 (51,6)</td>
                  <td align="center">7 (50,0)</td>
                  <td align="center">1,000</td>
                </tr>
                <tr>
                  <td align="left">Dias na UCO, d</td>
                  <td align="center">3,6 &#177; 4,6</td>
                  <td align="center">7,6 &#177; 9,0</td>
                  <td align="center">0,008</td>
                </tr>
                <tr>
                  <td align="left">CEC (n = 54)</td>
                  <td align="center">50 (39,7)</td>
                  <td align="center">4 (28,6)</td>
                  <td align="center">0,566</td>
                </tr>
                <tr>
                  <td align="left">Betabloq perioperat&#243;rio (n = 132)</td>
                  <td align="center">118 (93,7)</td>
                  <td align="center">14 (100,0)</td>
                  <td align="center">1,000</td>
                </tr>
                <tr>
                  <td align="left">Uso de hemoderivados (n = 36)</td>
                  <td align="center">33 (26,2)</td>
                  <td align="center">3 (21,4)</td>
                  <td align="center">1,000</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN08">
                <p>HAS: hipertens&#227;o arterial sist&#234;mica; RM: revasculariza&#231;&#227;o mioc&#225;rdica cir&#250;rgica; DM: diabetes mellitus; UCO: unidade coronariana; CEC: circula&#231;&#227;o extracorp&#243;rea; Betabloq: betabloqueador.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
      </sec>
      <sec sec-type="discussion">
        <title>Discuss&#227;o</title>
        <p>O subestudo COPPS-POAF demonstrou que a colchicina foi um medicamento seguro e eficaz na preven&#231;&#227;o de pericardite e de FA-PORM, reduzindo a incid&#234;ncia dessa arritmia (p = 0,021).<xref ref-type="bibr" rid="B6">6</xref> No presente estudo n&#227;o observou-se a redu&#231;&#227;o estatisticamente significativa da taxa de FA-PORM. Uma das causas para esse desfecho pode ter sido o tamanho reduzido da amostra.</p>
        <p>Tamb&#233;m o m&#233;todo de registro do ritmo card&#237;aco (monitores card&#237;acos cont&#237;nuos e ECG de 12 deriva&#231;&#245;es) pode ter omitido alguns epis&#243;dios de FA, j&#225; que os monitores utilizados nos pacientes n&#227;o possibilitavam armazenamento dos dados para an&#225;lise posterior. Os epis&#243;dios de FA-PORM eram registrados somente quando geravam sintomatologia ou altera&#231;&#227;o hemodin&#226;mica ou, se assintom&#225;ticos, quando eram observados pelo m&#233;dico assistente.</p>
        <p>A taxa de infec&#231;&#227;o entre os pacientes submetidos &#224; colchicina foi maior em rela&#231;&#227;o &#224; do grupo controle. N&#227;o h&#225; na literatura m&#233;dica estudo randomizado, t&#227;o pouco relato de caso, que comprove a rela&#231;&#227;o entre o uso da colchicina em dose terap&#234;utica e o aumento de casos de infec&#231;&#227;o. Provavelmente esse dado foi aleat&#243;rio, relacionado ao n&#250;mero reduzido de pacientes. Entretanto, pode ser um dado gerador de hip&#243;tese a ser averiguada em futuros estudos.</p>
        <p>Pacientes tratados com colchicina permaneceram internados por mais tempo. &#201; prov&#225;vel que n&#227;o haja rela&#231;&#227;o com a droga e sim com a taxa de infec&#231;&#227;o que, como dito anteriormente, tamb&#233;m foi maior no grupo colchicina. Ademais, no subestudo COPPS-POAF com amostra maior, houve diminui&#231;&#227;o do tempo de interna&#231;&#227;o no grupo colchicina/controle (9,4 &#177; 3,7 versus 10,3 &#177; 4,3 dias; p = 0,040).<xref ref-type="bibr" rid="B6">6</xref>
				</p>
        <p>Entre os 140 pacientes do estudo, 54 foram submetidos a revasculariza&#231;&#227;o mioc&#225;rdica com CEC e 86, sem CEC. Hashemzadeh et al.,<xref ref-type="bibr" rid="B16">16</xref> avaliando 939 pacientes submetidos a cirurgia de revasculariza&#231;&#227;o mioc&#225;rdica, relataram FA-PORM em 38 pacientes do grupo sem CEC e em 93 pacientes do grupo com CEC (9,8% versus 16,7%, respectivamente, p = 0,002), mostrando que h&#225; aumento da taxa de FA-PORM em pacientes operados com CEC. O fato de a maioria das cirurgias ter sido realizada sem CEC pode ser uma das justificativas para a baixa taxa de FA-PORM no presente estudo.</p>
        <p>Assim como no subestudo COPPS-POAF, a incid&#234;ncia de &#243;bito por qualquer causa n&#227;o foi significativamente menor no grupo colchicina.<xref ref-type="bibr" rid="B6">6</xref>
				</p>
        <p>A colchicina &#233; uma droga com a&#231;&#227;o anti-inflamat&#243;ria potente e tem sido utilizada classicamente para o tratamento de pericardite.<xref ref-type="bibr" rid="B12">12</xref> Novos estudos s&#227;o necess&#225;rios para comprovar sua real seguran&#231;a e efic&#225;cia para a profilaxia de FA-PORM.</p>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="supported-by">
          <p>
            <bold>Fontes de financiamento</bold>
          </p>
          <p>O presente estudo n&#227;o teve fontes de financiamento externas.</p>
        </fn>
        <fn fn-type="other">
          <p>
            <bold>Vincula&#231;&#227;o acad&#234;mica</bold>
          </p>
          <p>N&#227;o h&#225; vincula&#231;&#227;o deste estudo a programas de p&#243;s-gradua&#231;&#227;o.</p>
        </fn>
      </fn-group>
      <ack>
        <title>Agradecimentos</title>
        <p>Agradecemos o suporte dado por todos aqueles que viabilizaram a realiza&#231;&#227;o deste estudo, especialmente aos integrantes das equipes de cirurgia card&#237;aca e aos preceptores da cardiologia cl&#237;nica do Hospital Santa Casa de Miseric&#243;rdia de Curitiba.</p>
      </ack>
    </back>
  </sub-article>
</article>
