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COPPS-2 curtails colchicine enthusiasm in cardiac surgery




Patients undergoing cardiac surgery who took colchicine had significantly less postpericardiotomy syndrome than did those on placebo, but this protective effect did not extend to postoperative atrial fibrillation and pericardial or pleural effusions in the double-blind COPPS-2 trial.

The failure of colchicine to prevent postoperative atrial fibrillation (AF) was probably due to more frequent adverse events (36 vs. 21 with placebo), especially gastrointestinal intolerance (26 vs. 12), and drug discontinuation (39 vs. 32), since a prespecified on-treatment analysis showed a significant reduction in AF in patients tolerating the drug, Dr. Massimo Imazio reported at the annual congress of the European Society of Cardiology.

Dr. Massimo Imazio

"The high rate of adverse effects is a reason for concern and suggests that colchicine should be considered only in well-selected patients," Dr. Imazio and his associates wrote in an article on COPPS-2 simultaneously published online (JAMA 2014 [doi:10.1001/jama.2014.11026]).

Colchicine has been a promising strategy for postpericardiotomy syndrome prevention, besting methylprednisolone and aspirin in a large meta-analysis (Am. J. Cardiol. 2011;108:575-9).

In the largest trial, COPPS (Colchicine for the Prevention of the Postpericardiotomy Syndrome), Dr. Imazio reported that colchicine significantly reduced the incidence of postpericardiotomy syndrome (8.9% vs. 21.1%), postoperative pericardial effusions (relative risk reduction, 43.9%), and pleural effusions (RRR, 52.3%) at 12 months, compared with placebo (Am. Heart J. 2011;162:527-32 and Eur. Heart J. 2010;31:2749-54). Colchicine was given for 1 month, beginning on the third postoperative day with a 1-mg twice-daily loading dose.

In COPPS-2, the 360 consecutive candidates for cardiac surgery also were given colchicine or placebo for 1 month, but treatment was started 48-72 hours before surgery to pretreat patients and improve colchicine’s ability to prevent postoperative systemic inflammation and its complications.

Colchicine also was administered using weight-based dosing (0.5 mg twice daily in patients weighing at least 70 kg or 0.5 mg once daily in those under 70 kg), and they avoided the loading dose in an effort to improve adherence.

"However, we observed a 2-fold increase of adverse effects and study drug discontinuations compared with those reported in the COPPS trial, likely due to significant vulnerability of patients in the perioperative phase, when the use of antibiotics and proton pump inhibitors is common and also increases the risk of gastrointestinal effects (e.g., diarrhea)," explained Dr. Imazio of Maria Vittoria Hospital and the University of Torino (Italy).

Still, colchicine provided significant protection in the COPPS-2 primary outcome of postpericardiotomy syndrome, compared with placebo (19.4% vs. 29.4%; 95% confidence interval, 1.1%-18.7%). The number needed to treat was 10.

The outcome did not differ significantly among predetermined subgroups based on age, sex, and presence or absence of pericardial effusion, although colchicine was especially efficacious in the setting of systemic inflammation with elevated C-reactive protein, the authors noted.

The intention-to-treat analysis revealed no significant differences between the colchicine and placebo groups for postoperative AF (33.9% vs. 41.7%; 95% CI, –2.2%-17.6%) or postoperative pericardial/pleural effusion (57.2% vs. 58.9%; 95% CI, –8.5%-11.7%).

The prespecified on-treatment analysis, however, showed a 14.2% absolute difference in postoperative AF, favoring colchicine over placebo (27% vs. 41.2%; 95% CI, 3.3%-24.7%).

"While the efficacy of colchicine for postpericardiotomy syndrome prevention is confirmed, the extent of efficacy for postoperative AF needs to be further investigated in future trials," Dr. Imazio stated.

Ongoing studies also will better clarify the potential of colchicine using lower doses that may be better tolerated.

The 360 patients were evenly randomized from 11 centers in Italy between March 2012 and March 2014. Their mean age was 67.5 years, 69% were men, and 36% had planned valvular surgery. Key exclusion criteria were absence of sinus rhythm at enrollment, urgent cardiac surgery, cardiac transplantation, and contraindications to colchicine.

COPPS-2 was supported by the Italian National Health Service and FARGIM. Acarpia provided the study drug. Dr. Imazio reported no conflicts of interest. A coauthor reported consultancy for Servier, serving on an advisory board for Boehringer Ingelheim, and lecturer fees from Abbott, AstraZeneca, Merck, Serono, Richter Gedeon, and Teva.

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