Reviwer :Dr. Kaan Gökçe

Name of the Study: Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial

Published Congress:ESC 2023

Link: https://www.ahajournals.org/https://doi.org/10.1016/j.ahj.2023.01.018

Background:

Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. Atrial fibrillation (AF) in relation to surgery remains a clinical challenge. Major noncardiac thoracic surgery is associated with postoperative complications and mortality. However, the prevalence and impact of perioperative AF in this setting is not well examined.

Objective:

The purpose of this study tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery.

Methods:

The ‘Colchicine for the Prevention of Perioperative Atrial Fibrillation’ (COP-AF) trial is an international, double-blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia.

Patients undergoing noncardiac thoracic surgery were randomized to receive colchicine 0.5 mg twice daily (n = 1,608) or matching placebo (n = 1,601). Study drug was first administered within 4 hours preoperatively for a total duration of 10 days. Daily cardiac troponin was collected on postoperative days 1 to 3. Rhythm monitoring was conducted per site routine, but daily ECG on postoperative days 1 to 3 were encouraged.

Inclusion criteria: age ≥55 years, major noncardiac thoracic surgery (excluding lung transplantation) with general anesthesia, anticipated need for at least overnight hospital admissions.

Exclusion criteria: previously diagnosed AF, class I or III antiarrhythmic drug use, unable to take oral medication for >24 hours postoperatively, allergy or contraindication to colchicine (e.g., estimated glomerular filtration rate < 30 mL/min/1.73 m²), currently taking colchicine, severe hepatic dysfunction, aplastic anemia antiretroviral therapy for human immunodeficiency virus.

Results:

Coprimary outcomes for colchicine vs. placebo: clinically significant perioperative AF1: 6.4% vs. 7.5%, p = 0.22. MINS: 18.3% vs. 20.3%, p = 0.16 (Clinically significant AF: associated with angina, heart failure, or symptomatic hypotension or requiring rate or pharmacologic/electrical cardioversion).

Secondary outcomes for colchicine vs. placebo: composite of all-cause mortality, nonfatal MINS, and nonfatal stroke: 18.7% vs. 20.9%, p = 0.11. Myocardial infarction: 0.8% vs. 0.9%, p = 0.69. Hospital length of stay: 5.0 vs. 5.0 days, p = 0.48.

Safety outcomes for colchicine vs. placebo; composite of sepsis and infection: 6.4% vs. 5.2%, p = 0.14, noninfectious diarrhea; 8.3% vs. 2.4%, p < 0.0001.

Conclusion:

COP-AF Trial shows that colchicine does not significantly reduce perioperative AF or MINS in patients undergoing major non-cardiac thoracic surgery. However reducing the risk of perioperative AF and MINS is an unmet clinical need in patients who have major noncardiac thoracic surgery, and if causally related to these events such an intervention may also reduce mortality, stroke, and the duration of hospitalization. Colchicine is an inexpensive and effective anti-inflammatory agent that holds promise in reducing the incidence of these 2 perioperative complications. Post hoc analysis suggests that composite outcomes comprising AF and other adverse cardiovascular events may be fruitful avenues of future investigation into the potential cardioprotective effects of colchicine in noncardiac surgery.

Interpretations:

The COP-AF study did not observe a reduction in clinically significant perioperative AF or MINS with colchicine compared with placebo in patients undergoing major noncardiac thoracic surgery. Perioperative AF and MINS are more common in patients with elevated inflammatory biomarkers and have been associated with worse short- and long-term postoperative outcomes. This has generated continued interest in the potential cardioprotective effect of colchicine, which may be of some benefit. Though negative, COP-AF provides the first randomized, large-scale data examining the efficacy of colchicine in noncardiac surgery.

Given site variability in postoperative cardiac monitoring, with <50% of patients undergoing ECG on postoperative day 3, total AF events may have been undercounted. However, their silent nature suggests they would likely not have been clinically significant. Moreover, colchicine was associated with greater rates of study drug discontinuation primarily due to the frequency of noninfectious diarrhea.