Colchicine for prevention and treatment of cardiac diseases: A meta-analysis

DOI: 10.1111/1755-5922.12226 ORIGINAL RESEARCH ARTICLE Colchicine for prevention and treatment of cardiac diseases: A meta-analysis Nikolaos Papageorgiou 1,2, Alexandros Briasoulis 3, George Lazaros 2 Massimo Imazio 4,5 Dimitris Tousoulis 2 1 Barts Heart Centre, St Bartholomew s Hospital, London, UK 2 First Cardiology Department, University of Athens Medical School, Hippokration General Hospital, Athens, Greece 3 Cardiovascular Institute, Wayne State University, Detroit, MI, USA 4 Cardiology Department, Maria Vittoria Hospital, Torino, Italy 5 Department of Public Health and Pediatrics, University of Torino, Torino, Italy Correspondence Alexandros Briasoulis, MD PhD, Cardiovascular Institute, Wayne State University, Detroit, MI, USA. Email: alexbriasoulis@gmail.com Funding No funding received for this work. Summary Aims: Colchicine has been suggested to be beneficial in preventing recurrent pericarditis. The goal of this study was to review all randomized controlled trials that assess the use of colchicine for the prevention and treatment of cardiac diseases. Methods: We performed a meta- analysis of the effects of colchicine on pericarditis, postpericardiotomy syndrome and postprocedural atrial fibrillation recurrence, instent restenosis, gastrointestinal adverse effects, and treatment discontinuation rates. We conducted an EMBASE and MEDLINE search for prospective controlled trials. Results: We identified 17 prospective controlled randomized studies with 2082 patients that received colchicine and 1982 controls with an average follow- up duration of 12 months. Treatment with colchicine is associated with reduced risk of pericarditis recurrence/postpericardiotomy syndrome (OR: 0.37; 95% CI: 0.29-0.47; P<0.001) and lower recurrence of atrial fibrillation rates after cardiac surgery and ablation procedures. However, gastrointestinal side effects were more common in patients treated with colchicine (OR: 2.6; 95% CI: 1.82-3.72; P<0.001) in all subgroups except for those treated for prevention of recurrent pericarditis. The higher rates of side effects resulted in higher incidence of treatment discontinuation in patients treated with colchicine. Conclusion: Colchicine appears to be efficacious and well tolerated for recurrent pericarditis/postpericardiotomy syndrome and recurrence of postprocedural atrial fibrillation. However, its efficacy may be limited by its gastrointestinal adverse events and treatment discontinuation rates particularly in postoperative patients. KEYWORDS Atrial fibrillation, Colchicine, Coronary artery disease, Gastrointestinal side effects, Pericarditis, Post-pericardiotomy syndrome 1 INTRODUCTION Colchicine was introduced in clinical practice approximately 2 millennia ago for the treatment of acute gout, which still constitutes its official therapeutic indication. 1 Much later, colchicine indications expanded to several extracardiac (mainly inflammatory diseases) and Equally contributed. cardiac conditions. 1 In the specific context of the latter conditions, the greatest experience concerns randomized colchicine use on top of the conventional treatment in acute and recurrent pericarditis (either first or multiple recurrences) due to viral, idiopathic, postcardiac injury syndrome and connective tissue disease etiology. 1,2 Additional cardiac conditions where colchicine efficacy has been tested or is being tested include coronary artery disease (including stable coronary disease, acute coronary syndromes, and percutaneous coronary interventions) 10 2016 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/cdr Cardiovascular Therapeutics 2017; 35: 10 18

11 and postprocedural atrial fibrillation onset (either after coronary artery bypass surgery). 2 Apart from the indisputable efficacy of colchicine in various clinical settings, it should be emphasized that colchicine has a relatively narrow therapeutic range, which is traduced in frequent side effects and toxicity. 1,2 Thus, concerns often rise among clinicians regarding colchicine therapy, in particular when colchicine administration is scheduled for several months. Meta- analysis with their ability to integrate data from similar studies constitutes a valuable tool in the estimation of an overall drug profile. On that basis, by performing a meta- analysis we sought to assess the efficacy and safety of colchicine in prevention and treatment of various cardiac conditions. 2 METHODS 2.1 Search strategy We systematically searched the electronic databases, MEDLINE, PubMed, EMBASE, and the Cochrane Library for Central Register of Clinical Trials, using the MeSH terms, colchicine and pericarditis, recurrent pericarditis, post- pericardiotomy syndrome, postcardiac surgery atrial fibrillation, post ablation atrial fibrillation, acute coronary syndromes, percutaneous coronary intervention, cardiovascular events. We limited our search to studies in human subjects and English language in peer- reviewed journals published until September 2015. A total of 17 studies have been identified by two reviewers after the independent electronic search. There were no disagreements in literature search between the reviewers. Subsequently, we manually searched the references listed in the 17 studies identified by electronic search. Manual search did not reveal any new studies apart from the ones identified by electronic search. 2.2 Study selection We included all randomized controlled studies published as original articles in peer- reviewed scientific journals in English. Studies were selected based on inclusion criteria: patient population group of patients with pericarditis, or postpericardiotomy, or atrial fibrillation treated with radiofrequency ablation, or acute coronary syndromes, or stable ischemic heart disease that received colchicine in addition to standard medical therapy, and a control group of patients that received placebo treatment. We excluded those trials that did not report any of the following variables or outcomes: number of events in both the intervention and reference groups, length of study, description of the main relevant features of the study population, including gender, age, and dose of colchicine. We did not restrict eligibility according to outcomes. were resolved by discussion with a third reviewer, and consensus was reached after discussion. We extracted study characteristics such as study design, sample size, baseline demographics, and cardiovascular risk factors, inclusion criteria and exclusion criteria, primary and secondary outcomes, follow- up duration, and patient demographical characteristics. 2.4 Outcomes assessed The primary outcomes assessed were (1) pericarditis recurrence and postpericardiotomy syndrome for studies enrolling patients with pericarditis or postpericardiotomy, (2) recurrence of atrial fibrillation in patients who underwent radiofrequency ablation or cardiac surgery, (3) in- stent restenosis for the studies including patients after percutaneous coronary interventions, (4) cardiovascular events in studies that were adequately powered to assess that outcome, (5) gastrointestinal effects, and (6) discontinuation of treatment. We did not include allcause mortality as one of the outcomes as none of the included trial was designed to study that outcome. Also, other less frequent side effects of colchicine such as myelotoxicity and neuromuscular complications were very rare in the included studies and consequently excluded as well. 2.5 Risk of bias Cochrane s risk of bias tool has been utilized to assess the individual risk of bias of each study. 2.6 Data analysis and synthesis Data analysis was performed in accordance with the Cochrane Collaboration, Meta- analysis Of Observational Studies in Epidemiology (MOOSE), and the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) Statement. Meta- analyses was performed using the Review Manager (RevMan) 5.3. Chi- square test of heterogeneity and I 2 statistic of inconsistency were used to assess heterogeneity between studies. I 2 values of 25%, 50%, and 75% indicate low, moderate, and high heterogeneity, respectively. A significant heterogeneity was considered if the P<0.05 or an I 2 statistic greater than 75%. In the absence of heterogeneity, pooled estimates of odds ratio (ORs) with their 95% confidence intervals (CIs) were calculated using the Mantel- Haenszel method. Reported values are two- tailed, and hypothesis- testing results were considered statistically significant at P<0.05. The small study effect, including publication bias, was tested using funnel plot and the Egger test. 3 RESULTS 2.3 Data extraction and quality The data were independently extracted by two authors (A. B. and N. P.) using standardized protocol and reporting form. Disagreements 3.1 Study selection Our search strategy is outlined in Figure 1. Literature search resulted in total of 452 studies. Titles and abstracts were reviewed. Studies

12 FIGURE 1 Fixed- effect meta- analysis for pericarditis recurrence. The figure presents number of events, number of patients in treatment and control groups, odds ratio (OR), and 95% confidence interval (CI) for each trial, overall OR estimate with 95% CI and P value for association test, P value for heterogeneity test, and between- trial inconsistency (I 2 ) measures were selected based on inclusion criteria finally resulting in 17 studies. We excluded studies presented as abstracts in conferences, review articles, and case control studies. We were not able to identify any new studies after hand search. A total of 16 studies were finally included in the meta- analysis. 3-20 All of them were reported between 1992 and 2015. 3.2 Study characteristics The total number of patients in the colchicine group was 2082 and in the control group was 1982. The average follow- up duration was 11.3 months. Mean age of the study population is 60 years. The baseline characteristics of the included studies are represented in Table 1. Eight RCTs enrolled patients who received colchicine for treatment/prevention of either acute pericarditis, or recurrent pericarditis, or postpericardiotomy syndrome, or postcardiac surgery pericardial effusion. 3-11 Four RCTs enrolled patients who received colchicine for prevention of recurrent atrial fibrillation postcardiac surgery or radiofrequency ablation, 10,12,14,16 two studies included patients postcoronary intervention, 13,15 two studies enrolled patients with acute coronary syndromes, 18,19 one study included patients with heart failure with reduced ejection fraction, 17 and finally, one study assessed the effects of colchicine on cardiovascular outcomes in patients with stable ischemic heart disease. 20 Most studies used colchicine at a daily dose of 1 mg and adjusted the dose to 0.5 mg/day in patients with signs of medication intolerance or body weight <70 kg, except for Finkelstein et al. who used 1.5 mg/day postoperatively and Nidorf et al. who used 0.5 mg daily for secondary prevention of cardiovascular events. 3.3 Quality assessment On the basis of quality assessment, 15 studies 3-7,9-11,13-20 were deemed as high quality and two study of medium quality. 8,12 No lowquality studies were included. 3.4 Pericarditis and postpericardiotomy syndrome The incidence of recurrent pericarditis was 18.4% in the colchicine group versus 42% in the control group. Postpericardiotomy syndrome was seen in 13.8% of patients on colchicine and 24.8% in controls. Colchicine significantly decreased the rates of pericarditis/postpericardiotomy syndrome (OR: 0.37, 95% CI: 0.29-0.47; P=0.001; Figure 1), without significant heterogeneity between trials (I 2 0%, P=0.49).

13 TABLE 1 Characteristics of individual studies included in the analysis Study Year Design Mean age Population No of patients Colchicine Placebo Intervention Deftereos 2013 RCT 64 DM for PCI 196 100 96 Colchicine Deftereos 2014 RCT 67 Heart failure 279 139 140 Colchicine Deftereos 2014 RCT 62 PAF 206 103 103 Colchicine Deftereos 2015 RCT 58 STEMI 151 77 74 Colchicine Loading: 2 mg Finkelstein 2002 RCT 64 PPS 111 47 64 Colchicine 0.5 mg TDS O Keefe 1992 RCT 61 Elective PCI 197 130 67 Colchicine Meurin 2015 RCT 64 Pericardial effusion postcardiac surgery 197 98 99 Colchicine 1 mg OD Nidorf 2013 RCT 67 Stable CAD 532 282 250 Colchicine 0.5 mg OD Raju 2011 RCT 57 ACS or ischemic stroke 80 40 40 Colchicine 1 mg OD Imazio 2005 RCT 57 Acute pericarditis 120 60 60 Colchicine Imazio 2005 RCT 53 Recurrent pericarditis 84 42 42 Colchicine Duration (mo) Follow- up (mo) Primary endpoint Secondary endpoint 6 Angio- ISR & IVUS- ISR Late lumen loss Lumen area loss Percentage of neointima Volume normalized Neointima volume 6 Improvement in NYHA Composite of death and hospital stay for CHF, Change in left ventricular end-diastolic diameter, Change in left ventricular ejection fraction, Change in treadmill exercise time 3 15 AF recurrence Differences in physical and psychological health-related quality of life 5 days 5 days Area under the curve of CK-MB concentration Absolute myocardial infarct volume Myocardial infarct volume Relative infarct size 1 3 Postpericardiotomy syndrome 6 6 Angiographic restenosis 14 14 Mean change from baseline in grade of size of pericardial effusion Frequency of cardiac tamponade Number of patients in whom the individual effusion grade decreased Evolution of mean effusion Occurrence of atrial fibrillation. Frequency of pericardial drainage 1 36 Composite of ACS, fatal or nonfatal out- of- hospital cardiac arrest, or noncardioembolic ischemic stroke. Individual components of the primary outcome and the components of ACS unrelated to stent disease. 1 1 hs- CRP at 30 days Platelet function Occurrence of death, myocardial infarction, or stroke at 30 days. 3 18 Recurrence rate Rate of symptom persistence at 72 h from treatment onset. 6 18 Recurrence rate Symptom persistence 72 h after treatment onset. (continues)

14 TABLE 1 (continued) Study Year Design Mean age Population No of patients Colchicine Placebo Intervention Duration (mo) Follow- up (mo) Primary endpoint Secondary endpoint Imazio 2010 RCT 66 PPS 360 180 180 Colchicine 1 12 PPS Fever beyond first postoperative week Pleuritic chest pain Friction rub Pleural effusion New or worsening pericardial effusion Recurrence Cardiac tamponade Constrictive pericarditis PPS-related hospitalization Imazio 2011 RCT 66 Postoperative AF 336 169 167 Colchicine 1 1 Postoperative AF Cardiac surgery stay Rehabilitation stay Overall hospital stay Death or stroke Imazio 2011 RCT 47 Recurrent pericarditis 120 60 60 Colchicine 6 18 Recurrence rate Symptom persistence at 72 h Median recurrences Median time to first recurrence Disease-related hospitalization, Cardiac tamponade Constrictive pericarditis Imazio 2013 RCT 52 Recurrent pericarditis 240 120 120 Colchicine 3 18 Incessant or recurrent pericarditis Symptom persistence at 72 h Remission within 1 week Number of recurrences Time to first recurrence Disease-related hospitalization Cardiac tamponade and constrictive pericarditis Imazio 2014 RCT 68 PPS Postoperative AF Postoperative pericardial or pleural effusions 360 180 180 Colchicine 1 3 Incidence of postpericardiotomy syndrome Postoperative AF and postoperative effusions Incidence of cardiac tamponade Need for pericardiocentesis or thoracentesis Recurrences of postpericardiotomy syndrome Disease-related readmissions Stroke Overall mortality Imazio 2014 RCT 49 Recurrent pericarditis 240 120 120 Colchicine 6 18 Recurrent pericarditis Persistence of symptoms at 72 h after onset of symptoms Remission within 1 week Number of recurrences Time to first subsequent recurrence Disease-related admission to hospital, cardiac tamponade, and constrictive pericarditis. RCT, randomized controlled trial; DM, diabetes mellitus; PCI, percutaneous coronary intervention; PAF, paroxysmal atrial fibrillation; STEMI, ST- segment elevation myocardial infarction; CAD, coronary artery disease; ACS, acute coronary syndromes; PPS, postpericardiotomy syndrome.

15 3.5 Atrial fibrillation Treatment with colchicine reduced the recurrence of atrial fibrillation significantly in patients after cardiac surgery or pulmonary vein isolation (OR: 0.54, 95% CI: 0.41-0.7; P=0.001; Figure 2) without significant heterogeneity between trials (I 2 1%, P=0.39). Sensitivity analysis of studies that enrolled patients postcardiac surgery suggested significantly reduced rates of atrial fibrillation (P<0.001) without significant heterogeneity among studies. 3.6 Cardiac events In- stent restenosis rates were not significantly reduced in patients after percutaneous coronary intervention (OR: 0.61, 95% CI: 0.24-1.57; P=0.31; Figure 3) without significant heterogeneity between studies (P=0.06). Only one study assessed the effects of colchicine on cardiovascular events in stable ischemic heart disease and showed decreased rates of cardiovascular events (OR: 0.29, 95% CI: 0.16-0.55; P=0.001). 3.7 Gastrointestinal adverse events and treatment discontinuation Diarrhea was the main adverse event of colchicine. Other gastrointestinal side effects such as nausea, vomiting, abdominal pain, and hepatotoxicity were rarely encountered. Gastrointestinal side effects may often lead to discontinuation of colchicine. The incidence of gastrointestinal side effects was 13.9% in the colchicine group but significantly less frequent (5%) in controls (OR: 2.60, 95% CI: 1.82-3.72; P=0.003; Figure 4) with significant heterogeneity between trials (I 2 44%, P=0.03). Sensitivity analysis of studies of colchicine administration for prevention of pericarditis showed incidence of adverse events of 8% in the colchicine which was not significantly different from the incidence in the controls (6.5%), P=0.6. However, the incidence of adverse events was 11%, 12.5%, and 22.6% in patients postcardiac surgery, ablation, and percutaneous intervention, respectively, significantly elevated compared with controls and without heterogeneity among studies in these subgroups. These differences are likely attributed to lower age range and overall less comorbidities of patients enrolled in the secondary prevention of pericarditis studies. The treatment discontinuation rates were significantly higher in patients treated with colchicine (12.5%) compared with controls (4.9%) (OR: 2.89, 95% CI: 1.76-4.74; P=0.001; Figure 5) with significant heterogeneity between trials (I 2 49%, P=0.02) which was eliminated after the exclusion of the study by Nidorf et al. that reported treatment discontinuation in 16% of patients treated with colchicine and none in the control group. 3.8 Publication bias The funnel plot did not show asymmetry consistent with publication bias, and the Egger test was not significant for the outcomes studied. 4 DISCUSSION Our analysis was designed to assess outcomes and adverse events in patients receiving with colchicine for prevention and treatment of various cardiac disorders. Although this is not the first meta- analysis dealing with this topic, it is the most recent update which incorporates the most recent data in this context. Previous systematic reviews 21 and meta-analyses 22,23 confirmed the efficacy of treatment with colchicine in prevention of recurrences of acute/recurrent pericarditis. In our analysis, we examined the role of colchicine in treatment of FIGURE 2 Fixed- effect meta- analysis for atrial fibrillation recurrence FIGURE 3 Fixed- effect meta- analysis for in- stent restenosis

16 FIGURE 4 Random- effect meta- analysis for gastrointestinal adverse events

17 FIGURE 5 Random- effect meta- analysis for treatment discontinuation pericarditis and postpericardiotomy syndrome but also in prevention of postoperative atrial fibrillation and cardiovascular events. In addition, we studied the safety profile and discontinuation rates in the respective populations. The salient findings of our study may be summarized as follows: (1) colchicine is associated with reduced risk of pericarditis recurrence/ postpericardiotomy syndrome, with homogenous results across these clinical settings, (2) colchicine was associated with lower recurrence of atrial fibrillation rates after cardiac surgery and ablation procedures, and (3) gastrointestinal side effects were more common in patients treated with colchicine in all subgroups except for those treated for prevention of recurrent pericarditis. The higher rates of side effects resulted in higher incidence of treatment discontinuation in patients treated with colchicine. Although the precise mechanism of action of colchicine is not fully elucidated, it seems that most of the therapeutic effects stem from its ability to concentrate in the leukocytes altering mobility, adhesion as well as cytokine production. 24 The latter effects can explain the majority of its antiinflammatory effects and accordingly its therapeutic implications. Colchicine differs from other antiinflammatory medications in that its mechanism of action does not involve the arachidonic acid pathway. It binds to unpolymerized tubulin heterodimers, forming a stable complex that causes microtubule depolymerization by inhibiting lateral contacts between protofilaments, thus affecting any process that requires cytoskeletal changes, including cell mitosis, exocytosis, and neutrophil motility. By targeting neutrophils, endothelial cells, and platelets, and inhibiting mitosis, vascular hyperplasia, and fibrosis, colchicine improves outcomes of pericarditis, myocardial ischemia, and coronary interventions. The most common side effects of colchicine include gastrointestinal side effects, namely abdominal pain nausea, vomiting, and diarrhea in 10-15% of cases, and often lead to discontinuation of treatment. 1,24 Use of weight- adjusted doses (0.5 mg as maximum dose for patients <70 kg and 0.5 mg twice daily for 70 kg) and avoidance of attack doses may be useful to reduce gastrointestinal intolerance m maintaining the same efficacy as demonstrated in the last trials without a loading dose. A higher rate of gastrointestinal side effects has been reported in studies with daily doses more than 1.0 mg. In patients above the age of 70, dose should be reduced by 50%. Similarly, in patients with advanced chronic kidney disease with creatinine clearance <30 ml/min, the daily dose should not exceed 0.3 mg daily. 24,25 Less usual side effects reported in less than 10% of patients and treated cases consist of transaminasemia and alopecia. The most serious colchicine side effects, such as myelotoxicity and myopathy, appear in less than 1%. Moreover, the action of antimitotic properties of colchicine is a matter of concern in women of childbearing age. 1,25 Although, side effects and tolerability may limit the use of colchicine in certain subgroups such as in those with postpericardiotomy syndrome, based on the currently available data colchicine appears to be efficacious in the treatment of these patients and is recommended by 2015 European Society of Cardiology guidelines. 25 Careful consideration of potential contraindications, drug interactions, and side effects and use of weight- and creatinine clearance- adjusted doses may be useful for reducing gastrointestinal adverse events in individuals at higher risk for toxicity. Regarding cardiac disorders, the common denominator of its administration relates to the antiinflammatory effects. Inflammation, either clinical as in pericarditis (acute, recurrent, or postpericardiotomy) or subclinical as in coronary artery disease and atrial fibrillation, plays an important role in disease development and progression. 1,24,26 In the setting of coronary artery disease, the suppression of activated neutrophils contained in atheromas ensures plaque stability and accordingly its diversion to unstable status and onset of acute coronary syndromes. 24 Similarly, colchicine has been proved an efficacious treatment option in the prevention of atrial fibrillation recurrence, when administered after catheter ablation for atrial fibrillation. 15 The most plausible explanation is that the procedure per se induces a proinflammatory process which is limited by colchicine, as it is suggested by the colchicine- induced reduction of the circulating proinflammatory biomarkers such as C-reactive protein and IL- 6. 15

18 There are some limitations to the interpretation of our data analysis. First, publication bias may still exist despite our best efforts to conduct a comprehensive search and despite the lack of statistical evidence for the existence of bias. Second, any metaanalysis based on pooling of data from different trials with different inclusion criteria, different designs and populations, variable follow- up duration with differing attrition rates, and not being unified in definition and validation of endpoints in individual trials presents challenges. Conclusively, colchicine appears to be efficacious and well tolerated for recurrent pericarditis/postpericardiotomy syndrome and recurrence of atrial fibrillation after cardiac surgery and atrial fibrillation ablation procedure. However, its efficacy may be limited by its gastrointestinal adverse events and treatment discontinuation rates particularly in postoperative patients. CONFLICTS OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Imazio M, Brucato A, Trinchero R, Spodick D, Adler Y. Colchicine for pericarditis: hype or hope? Eur Heart J. 2009;30:532 539. 2. Imazio M, Brucato A, Belli R, et al. Colchicine for the prevention of pericarditis: what we know and what we do notknow in 2014 systematic review and meta- analysis. J Cardiovasc Med (Hagerstown). 2014;15:840 846. 3. Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2015;112:2012 2016. 4. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369:1522 1528. 5. Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first- choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med. 2005;165:1987 1991. 6. 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