Trends were seen with reductions in events, but these did not reach significance. However, benefit was seen in a post-hoc analysis looking at a composite of both of those endpoints, the researchers note, as well as a composite of vascular death, nonfatal MINS, nonfatal stroke, and clinically important perioperative AFib, the researchers report.
“We interpret that as there is a trend that is promising, a trend that needs to be further explored,” lead author David Conen, MD, Population Health Research Institute, Hamilton, Ont., said in an interview. “We think that further studies are needed to tease out which patients can benefit from colchicine and in what setting it can be used.”
Treatment was safe, with no effect on the risk for sepsis or infection, but it did cause an increase in noninfectious diarrhea. “These events were mostly benign and did not increase length of stay, and only one patient was readmitted because of diarrhea,” Dr. Conen noted.
Results of the COP-AF trial were presented at the annual congress of the European Society of Cardiology, Amsterdam, and published online in The Lancet .
Inflammation and perioperative AFib
AFib and MINS are common complications in patients undergoing major thoracic surgery, Dr. Conen explained. The literature suggests AFib occurs in about 10% and MINS in about 20% of these patients, “and patients with these complications have a much higher risk of additional complications, such as stroke or MI [myocardial infarction],” Dr. Conen said.
Both disorders are associated with high levels of inflammatory biomarkers, so they set out to test colchicine, a well-known anti-inflammatory drug used in higher doses to treat common clinical disorders, such as gout and pericarditis. Small, randomized trials had shown it reduced the incidence of perioperative AFib after cardiac surgery, he noted.
Low-dose colchicine (LoDoCo, Agepha Pharma) was recently approved by the U.S. Food and Drug Administration to reduce the risk for MI, stroke, coronary revascularization, or death in patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. It was approved on the basis of the LoDoCo 2 trial in patients with stable coronary artery disease and the COLCOT trial in patients with recent MI.
COP-AF was a randomized trial, conducted at 45 sites in 11 countries, and enrolled 3,209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AFib, had any contraindications to colchicine, or required colchicine on a clinical basis.
Patients were randomly assigned 1:1 to receive oral colchicine at a dose of 0.5 mg twice daily (1,608 patients) or placebo (1,601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Health care providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.
The co-primary outcomes were clinically important perioperative AFib or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AFib, Dr. Conen noted, but after the publication of LoDoCo 2 and COLCOT, “MINS was added as an independent co-primary outcome,” requiring more patients to achieve adequate power.
The main safety outcomes were a composite of sepsis or infection, along with noninfectious diarrhea.
Clinically important AFib was defined as AFib that results in angina, heart failure, or symptomatic hypotension or required treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion. “This definition was chosen because of its prognostic relevance, and to avoid adding short, asymptomatic AFib episodes of uncertain clinical relevance to the primary outcome,” Dr. Conen said during his presentation.
MINS was defined as an MI or any postoperative troponin elevation that was judged by an adjudication panel to be of ischemic origin.
At 14 days, there was no significant difference between groups on either of the co-primary end points.
No significant differences but positive trends were similarly seen in secondary outcomes of a composite of all-cause death, nonfatal MINS, and nonfatal stroke; the composite of all-cause death, nonfatal MI, and nonfatal stroke; MINS not fulfilling the fourth universal definition of MI; or MI.
There were no differences in time to chest tube removal, days in hospital, nights in the step-down unit, or nights in the intensive care unit.
In terms of safety, there was no difference between groups on sepsis or infection, which occurred in 6.4% of patients in the colchicine group and 5.2% of those in the placebo group (hazard ratio, 1.24; 95% confidence interval, 0.93-1.66).
Noninfectious diarrhea was more common with colchicine, with 134 events (8.3%) versus 38 with placebo (2.4%), for an HR of 3.64 (95% CI, 2.54-5.22).
“In two post hoc analyses, colchicine significantly reduced the composite of the two co-primary outcomes,” Dr. Conen noted in his presentation. Clinically important perioperative AFib or MINS occurred in 22.4% in the colchicine group and 25.9% in the placebo group (HR, 0.84; 95% CI, 0.73-0.97; P = .02).
“Colchicine also significantly reduced the composite of vascular mortality, nonfatal MINS, nonfatal stroke, and clinically important AFib,” he said; 22.6% of patients in the colchicine group had one of these events versus 26.4% of those in the placebo group (HR, 0.83; 95% CI, 0.72-0.96; P = .01).
The researchers also reported significant interactions on both co-primary outcomes for the type of incision, “suggesting that stronger and statistically significant effects among patients undergoing thoracoscopic surgery as opposed to nonthoracoscopic surgery,” Dr. Conen said.
Patients undergoing thoracoscopic surgery treated with colchicine had a reduced risk for clinically important AFib (n = 2,397; HR, 0.53; 95% CI, 0.36-0.77), but colchicine treatment increased the risk in patients having open surgery (n = 784; HR, 1.59; 95% CI, 1.07-2.35; P for interaction < .0001).
There was a beneficial effect on MINS with colchicine among patients undergoing thoracoscopic surgery (HR, 0.80; 95% CI, 0.66-0.98), but no effect was seen among those having open surgery (HR, 1.15; 95% CI, 0.87-1.53; P for interaction = .041).