No Reduction in AF After Noncardiac Surgery With Colchicine: COP-AF

A new trial testing perioperative treatment with colchicine has shown no significant benefit on the co-primary outcomes of clinically important atrial fibrillation (AF) or myocardial injury after noncardiac surgery (MINS) in patients undergoing thoracic surgery.

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 AF, 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, Ontario, Canada, told theheart.org | Medscape Cardiology. “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,” Conen noted.

Results of the COP-AF trial were presented at the European Society of Cardiology (ESC) Congress 2023 in Amsterdam, the Netherlands, and published online August 25 in The Lancet.

Inflammation and Perioperative AF

AF and MINS are common complications in patients undergoing major thoracic surgery, Conen explained. The literature suggests AF 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],” 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 AF 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 3209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AF, 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 (1608 patients) or placebo (1601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Healthcare providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.

The co-primary outcomes were clinically important perioperative AF or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AF, 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 AF was defined as AF 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 AF episodes of uncertain clinical relevance to the primary outcome,” 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.

Table: COP-AF: Co-Primary Endpoints

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 [HR], 1.24; 95% CI, 0.93 – 1.66).

Noninfectious diarrhea was more common with colchicine, with 134 events (8.3%) vs 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,” Conen noted in his presentation. Clinically important perioperative AF 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 AF,” he said; 22.6% of patients in the colchicine group had one of these events vs 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,” Conen said.

Patients undergoing thoracoscopic surgery treated with colchicine had a reduced risk for clinically important AF (n = 2397; 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).

Low-Risk Patients

Jean-Claude Tardif, MD, Montreal Heart Institute and Université de Montréal, Canada, was the invited discussant for the COP-AF presentation and congratulated the researchers on “a job well done.”

He made the point that the risk for perioperative AF has decreased substantially with the greater use of thoracoscopic rather than open surgical approaches. The population of this trial was relatively young, with an average age of 68 years; the presence of concomitant CVD was low, at about 9%; by design, patients with previous AF were excluded; and only about 20% of patients had surgery with an open approach.

“So that population of patients were probably at relatively low risk of atrial fibrillation, and sure enough, the incidence of perioperative AFib in that population at 7.5% was lower than the assumed rate in the statistical powering of the study at 9%,” Tardif noted.

The post hoc analyses showed a “nominally significant effect on the composite of MINS and AFib; however, that combination is fairly difficult to justify given the different pathophysiology and clinical consequences of both outcomes,” he pointed out.

The incidence of postoperative MI as a secondary outcome was low, less than 1%, as was the incidence of postoperative stroke in that study, Tardif added. “Given the link between presence of blood in the pericardium as a trigger for AFib, it would be interesting to know the incidence of perioperative pericarditis in COP-AF.”

In conclusion, he said, “when trying to put these results into the bigger picture of colchicine in cardiovascular disease, I believe we need large, well-powered clinical trials to determine the value of colchicine to reduce the risk of AFib after cardiac surgery and after catheter ablation,” Tardif said.

“We all know that colchicine represents the first line of therapy for the treatment of acute and recurrent pericarditis, and finally, low-dose colchicine, at a lower dose than was used in COP-AF, 0.5 mg once daily, is the first anti-inflammatory agent approved by both U.S. FDA and Health Canada to reduce the risk of atherothombotic events in patients with ASCVD [atherosclerotic cardiovascular disease], I believe offering a new pillar of treatment for the prevention of ischemic events in such patients.”

Session co-moderator Franz Weidinger, MD, Landstrasse Clinic, Vienna, Austria, called the COP-AF results “very important” but also noted that they show “the challenge of doing well-powered randomized trials these days when we have patients so well treated for a wide array of cardiovascular disease.”

The study was supported by the Canadian Institutes of Health Research (CIHR); Accelerating Clinical Trials Consortium; Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; Population Health Research Institute; Hamilton Health Sciences; Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong. Conen reports receiving research grants from CIHR, speaker fees from Servier outside the current study, and advisory board fees from Roche Diagnostics and Trimedics outside the current study.

Lancet. Published online August 25, 2023. Abstract

European Society of Cardiology (ESC) Congress 2023. Presented August 25, 2023.

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