Colchicine to Reduce Atrial Fibrillation in the Postoperative Period of Myocardial Revascularization

Background The high prevalence of atrial fibrillation (AF) in the postoperative period of myocardial revascularization surgery increases morbidity and mortality. Objective 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. Methods 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. Results 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 ± 11.5 versus 13.3 ± 9.4 days; p = 0.490). However, colchicine group patients had a higher infection rate (26.8% versus 8.7%; p = 0.007). Conclusion 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.


Introduction
Atrial fibrillation in the postoperative period of myocardial revascularization surgery (AF-POMR) occurs in 10% to 65% of patients, [1][2][3][4][5] increasing morbidity and mortality after surgery. 6,7 It is associated with an increase in hospital length of stay, and, thus, in costs, 6,8,9 and can cause serious clinical complications, such as hypotension, heart failure, stroke and other thromboembolic disorders. 10 A l t h o u g h n o t c o m p l e t e l y u n d e r s t o o d , t h e 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. 6,11 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. 12 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). 13,14 A COPPS substudy, published by Imazio et al., 6 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) . 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. 15 This study aimed at assessing colchicine to prevent AF in patients undergoing myocardial revascularization surgery.

Study Design and Participants
This is a prospective, randomized, open, single-center clinical assay, whose 140 participants were recruited from the Hospital Santa Casa de Misericórdia de Curitiba.
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 Pontifícia Universidade Católica do Paraná (PUC-PR) (protocol 50883).

Inclusion Criteria
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 ± 8.1 years and 61.5 ± 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.

Exclusion Criteria
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 > 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.

Intervention
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.
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.

Endpoints
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.

Randomization
Patients were randomly assigned to the groups by use of a computer program (link: http://stattrek.com/statistics/ random-number-generator.aspx). Both participants and researchers were instructed on the treatment. Data were collected by use of notification forms, manually completed by study researchers.

Statistical Analysis
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). 6 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 t 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 < 0.05 indicated statistical significance. Data were assessed by using the Statistica software, v.8.0.

Patients' Characteristics
The patients' baseline characteristics were similar in both groups and are shown in Table 1.

Final Result
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 (Tabele 2).

Discussion
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). 6 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.
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.
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.
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 ± 3.7 versus 10.3 ± 4.3 days; p = 0.040). 6 Of the 140 patients studied, 54 patients underwent myocardial revascularization surgery with ECC, and 86 patients, without ECC. Hashemzadeh et al., 16 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.
Similarly to the COPPS-POAF substudy, the incidence of death from any cause was not significantly smaller in the colchicine group of this study. 6 Colchicine is a potent anti-inflammatory drug classically used to treat pericarditis. 12 Further studies are required to confirm its real safety and efficacy in preventing AF-POMR.

Conclusion
The use of colchicine to prevent AF-POMR showed no efficacy in the present study.
The authors deny any conflict of interest.