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Colchicine for the Heart

Alyssa Keating Vora, PharmD, BCPS, Clinical Pharmacist, Duke University HospitalKristen Bova

Campbell, PharmD, CPP, BCPS (AQ-Cardiology), Clinical Pharmacist, Duke University Hospital,Senior Research Associate, Division of Electrophysiology

Topic:

Results from multiple trials suggest a role for colchicine in the prevention and management of post-operativeatrial fibrillation (POAF).

Background:

Colchicine is FDA-approved for treatment of familial Mediterranean fever and acute gout and for prophylaxis

against gouty arthritis.1 Colchicine exhibits both antiproliferative and anti-inflammatory actions, primarily viainhibition of microtubule self-assembly through the formation of tubulin-colchicine complexes. This inhibitsmovement of intercellular granules and secretion of inflammatory substances. Colchicine also impairsneutrophil adhesion to vascular endothelium. Importantly, colchicine shows a preferential concentration for leukocytes, decreasing leukocyte motility and blunting the inflammatory response. Peak concentrations inleukocytes may be more than 10 times that seen in plasma; therefore, a therapeutic effect can be seen at

relatively low oral doses.2

POAF is the most common complication after cardiac surgery; it is reported in 10% to 65% of cases depending

on the type and complexity of surgery performed.2 The incidence of POAF appears to be increasing due to theescalating number of cardiac surgeries being performed in elderly patients with multiple risk factors andcomorbidities. Development of POAF is likely multifactorial, involving pericardial inflammation, autonomicimbalance, excessive production of catecholamines, and fluid shifts. A substudy of the Colchicine for thePrevention of the Postpericardiotomy Syndrome (COPPS) trial demonstrated a significant decrease in the

incidence of POAF as well as a shorter in-hospital stay in patients who received colchicine postoperatively.3

New Information:

The Colchicine for the Prevention of Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation(COPPS-2) trial sought to evaluate the incremental efficacy of colchicine prophylaxis initiated in the

preoperative period. This double-blind, placebo-controlled, randomized trial evaluated 360 cardiac surgery patients who received colchicine or placebo starting between 48 and 72 hours before surgery and continued for 1 month after surgery. Colchicine was dosed at 0.5 mg twice daily in patients weighing 70 kg or more or 0.5mg once daily in patients weighing less than 70 kg. The primary endpoint of postpericardiotomy syndrome(PPS) within 3 months was significantly reduced in the colchicine group (19.4% vs. 29.4%; 95% CI, 1.1% to18.7%; NNT 10). There was no significant difference in the secondary endpoint of POAF (33.9% vs. 41.7%;95% CI, -2.2% to 17.6%). The reduction in POAF was significant in the pre-specified on-treatment analysis of

patients who tolerated colchicine (27% vs. 41.2%; 95% CI 3.3% to 24.7%). Adverse effects were morefrequent in the colchicine group (20% vs. 11.7%; 95% CI, 0.76% to 15.9%), but discontinuation rates weresimilar (21.7% vs. 17.8%; 95% CI, 1.4% to 14.3%). Adverse effects and discontinuation increased two-foldcompared to the COPPS trial; this is thought to be due to patient vulnerability during the perioperative phase.

The authors concluded that routine preoperative colchicine treatment is not warranted at this time.4

Interpretation and Application:

Data for prevention of POAF in cardiac surgery remain inconclusive; further large-scale studies with a primary

endpoint of POAF are warranted. Consideration should be given to dose-limiting factors such as side effectsand drug-drug interactions. Gastrointestinal side effects of colchicine are common, and some patients may not

be willing to continue therapy if they occur. Furthermore, drugs that inhibit CYP3A4 may increase colchicineconcentrations (and side effects) because it is a substrate of the same metabolic pathway. Common CYP3A4inhibitors include diltiazem, verapamil, azithromycin, and ketoconazole.

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Perhaps the biggest hurdle in expanding colchicine use relates to its cost. Even though the FDA recently

granted approval of generic colchicine to compete with Colcrys®, the price is still about $4.00 (U.S.) per tablet. The impact of wider generic drug distribution is yet to be determined; however, costs are expected todecrease. Providers should consider this cost when prescribing colchicine for off-label indications.

1. Kesselheim AS, Solomon DH. Incentives for drug development – the curious case of colchicine. N Engl J

Med 2010;362:2045-2047. [PubMed: 20393164]2. Deftereos S, Giannopoulo G, Papoutsidakis N, et al. Colchicine and the heart. J Am Coll Cardiol2013;62:1817-1825. [PubMed: 24036026]3. Imazio M, Brucato A, Ferrazzi P et al. Colchicine reduces postoperative atrial fibrillation. Circulation2011;124:2290-2295. [PubMed: 22090167]4. Imazio M, Brucato A, Ferrazzi P et al. Colchicine for prevention of postpericardiotomy syndrome and

postoperative atrial fibrillation: the COPPS-2 randomized clinical trial. JAMA 2014;312:1016-1023.[PubMed: 25172965]5. Fay, Matthew. Generic colchicine: victory in one battle on drug prices. Rheumatology Network. Web. 20 Jan2015.

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