AMSTERDAM — Anti-inflammatory colchicine (Lodoco) given perioperatively around major non-cardiac thoracic surgery did not cut atrial fibrillation (Afib) or myocardial injury complications, the COP-AF trial showed, although with some positive post hoc endpoints.
Clinically important Afib occurred in 6.4% of colchicine-treated patients and 7.5% of placebo recipients (HR 0.85, 95% CI 0.65-1.10, P=0.22), David Conen, MD, of the Population Health Research Institute in Hamilton, Ontario, reported here at the European Society of Cardiology (ESC) meeting and in The Lancet.
Colchicine likewise reduced the co-primary endpoint of myocardial injury after non-cardiac surgery (MINS) by a small degree without reaching statistical significance (18.3% vs 20.3%, HR 0.89, 95% CI 0.76-1.05, P=0.16).
However, colchicine did reduce the two endpoints when combined in a post hoc analysis (22.4% vs 25.9%, HR 0.84, 95% CI 0.73-0.97) and in a similarly post hoc composite outcome of vascular death, non-fatal MINS, non-fatal stroke, or clinically important perioperative Afib (22.6% vs 26.4%, HR 0.83, 95% CI 0.72-0.96).
“We believe that we found an encouraging and consistent trend of fewer cardiovascular events with colchicine that requires further research,” Conen said at an ESC press conference, adding that “there are no other treatments available that are safe and effective in this area, so I think that’s why this is a very important area.”
“The event rate in our trial was lower than anticipated, and we might have missed a small to moderate but clinically important effect of colchicine,” his group wrote.
As a relatively inexpensive and available drug with a fairly good safety profile, colchicine is attractive, acknowledged Ed Fry, MD, of Ascension Indiana St. Vincent Heart Center in Indianapolis, and immediate past president of the American College of Cardiology.
“If I had a patient with coronary disease and they have a thorascopic procedure, I might be more likely to put them on colchicine as part of their add-on-medical therapy, provided that I thought colchicine was a good idea for the management of their coronary disease — but that’s going to be a select group of people,” Fry told MedPage Today.
The potential benefit was consistent with previous studies in patients with coronary artery disease, the researchers noted, pointing to the similar nonsignificant reduction in clinically important perioperative Afib with colchicine in the secondary prevention LoDoCo2 and COLCOT trials (HR 0.84, 95% CI 0.66-1.07; and HR 0.93, 95% CI 0.59-1.46, respectively).
Those trials were positive for their primary endpoints, leading to an indication in secondary prevention for colchicine, which had previously been approved for treating gout.
For perioperative Afib prevention, randomized trials have been more positive for colchicine in cardiac surgery, with an eight-trial meta-analysis showing a relative 30% reduction in risk.
It’s possible that Afib in the cardiac surgery setting is more strongly driven by inflammation or that “publication bias could have been present in the cardiac surgery trials given the small size of the included trials,” Conen’s group noted. “[T]he overlap in the CIs for the treatment effects across the cardiac surgery meta-analysis and COP-AF results suggests that colchicine might have a similar moderate effect size in reducing the risk of clinically important atrial fibrillation in both settings.”
However, press conference moderator Martin Halle, MD, of the Technical University of Munich in Germany, was less generous: “Inflammation and stress during surgery does induce atrial fibrillation, but the anti-inflammatory drug colchicine is not the right one at this point in time.”
COP-AF included 3,209 patients ages 55 and older (mean age 68, 51.6% of whom were male) undergoing major non-cardiac thoracic surgery at 45 centers across 11 countries from Feb. 14, 2018, through June 27, 2023. They were randomly assigned in a double-blind fashion to a 10-day course of oral colchicine 0.5 mg twice daily or matching placebo, started within 4 hours before surgery.
For the main safety outcomes, colchicine significantly increased noninfectious diarrhea (8.3% vs 2.4%, HR 3.64, 95% CI 2.54–5.22), albeit mostly benign, and showed a nonsignificant trend for higher risk of the composite of sepsis or infection as well (6.4% vs 5.2%, HR 1.24, 95% CI 0.93-1.66).
Colchicine had no effect on time to chest tube removal or length of stay, although in the pilot trial there had been a reduction in total amount of fluid drained, suggesting less pleural inflammation. “The lack of effect on time to chest tube removal probably reflects the fact that other mechanisms are more important drivers of this outcome after thoracic surgery (eg, air leaks),” Conen’s group wrote.
Subgroup analysis showed a significant interaction with minimally invasive surgery, with “significant reduction in perioperative atrial fibrillation events with colchicine in patients undergoing thoracoscopic surgery, but an increased risk of atrial fibrillation in patients undergoing open surgery,” which ran counter to expectations.
“Taking away the mechanical complications of manipulation may have unmasked the anti-inflammatory benefit of colchicine in these patients,” Conen noted, although acknowledging this was only a hypothesis-generating finding.
ESC session study discussant Jean-Claude Tardif, MD, of the Montreal Heart Institute, noted that less than 20% of patients underwent open surgery, “so that population of patients was 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%.”
He cautioned that the study was underpowered for the primary endpoints and criticized the combination of endpoints in the post hoc analyses “given the different pathophysiology and clinical consequences of both outcomes.”
Limitations of the trial noted by Fry included the lack of continuous arrhythmic monitoring, which might have missed some cases, and lack of data on right- versus left-sided procedures.
Disclosures
The study was funded by grants from the Canadian Institutes of Health Research (CIHR), the Accelerating Clinical Trials Consortium, the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, the Population Health Research Institute, Hamilton Health Sciences, the Division of Cardiology at McMaster University, the Hanela Foundation, and the Hong Kong Special Administrative Region’s General Research Fund.
Conen disclosed financial relationships with the CIHR, Servier, Roche Diagnostics, and Trimedx.
Fry had no relevant disclosures.
Tardif disclosed relationships with AstraZeneca, Boehringer-Ingelheim, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Merck, Novartis, HLS Pharmaceuticals, Pendopharm, and Pfizer.
Primary Source
The Lancet
Source Reference: Conen D, et al “Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial” Lancet 2023; DOI: 10.1016/ S0140-6736(23)01689-6.
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