2023-08-26 15:52:19
Auteur :
Corentin Bourg
Member of the College of Cardiologists in Training,
Rennes
Proofreader:
Guillaume Bonnet
Member of the College of Cardiologists in Training,
Pessac
Live from the ESC Congress 2023
D’après la présentation de David Conen (Hamilton, Canada) : “COP-AF – Colchicine for the prevention of perioperative atrial fibrillation following major thoracic surgery”
Atrial fibrillation (AF) and myocardial injury following non-cardiac surgery (“myocardial injury following non-cardiac surgery” = MINS) are factors affecting the prognosis of patients undergoing major non-cardiological thoracic surgery1,2. This is an important issue, since in the perioperative period, the prevalence of atrial fibrillation is high (up to 10%) and that of MINS is estimated at 20%.
Anti-inflammatory treatments are renowned for their ability to reduce the occurrence of these complications.
Furthermore, the anti-inflammatory effect of colchicine is well known and has demonstrated benefit in reducing the risk of AF following cardiac surgery in small clinical trials3. Colchicine has also shown benefits in reducing cardiovascular events in patients with coronary artery disease (LoDoCo2 and COLCOT trial)4,5.
The objective of the COP-AF study is to study the effect of colchicine (oral) on the occurrence of “clinically significant perioperative AF” atrial fibrillation and myocardial damage following non-cardiac surgery (MINS). This in a population of patients undergoing major non-cardiac thoracic surgery.
Principle of the study, methodology and results
Figure 1: Central illustration summarizing the main methodological elements and main results of COP-AF
Source : ESC
Methodology
The study included patients over the age of 55 undergoing elective non-cardiac surgery under general anesthesia and requiring at least one night of postoperative hospitalization.
The main judgment criteria evaluated following 14 days of follow-up are:
“Clinically significant AF”: AF associated with angina symptoms or causing a picture of heart failure or symptomatic arterial hypotension requiring the implementation of specific treatment (bradycardiac, antiarrhythmic, electrical cardioversion) Myocardial lesions following surgery non-cardiac (MINS): myocardial infarction or elevated postoperative troponin levels, considered to be due to significant myocardial ischemia
Participants were randomized in a 1:1 ratio to receive either oral colchicine 0.5 mg twice daily or a matching placebo, beginning on the day of surgery, and for a total duration of 10 days.
NB: the protocol was modified during the study. Indeed, this was only to assess the prevalence of AF, but the myocardial ischemia endpoint (MINS) was added following the publication of the LoDoCo2 and COLCOT studies. Thus, the recruitment objective went from 2,800 to 3,200 patients.
The study included 3,209 patients from 45 sites in 11 countries. The average age was 68 years and 48.4% of the patients included were women.
The results show no statistically significant difference between the groups for the primary endpoints (Figure 2):
Clinically significant atrial fibrillation (AF) developed in 103 of 1608 patients (6.4%) assigned to colchicine, and in 120 of 1601 patients (7.5%) assigned to placebo, with a “hazard ratio” (HR) of 0.85 (95% CI 0.65 to 1.10) and an absolute risk reduction (ARR) of 1.1% (95% CI -0.7 to 2.8, p = 0.22). MINS occurred in 295 patients (18.3%) assigned to colchicine, and 325 patients (20.3%) assigned to placebo, HR 0.89 (95% CI 0.76 to 1.05) and RAR at 2.0% (95% CI -0.8 to 4.7, p=0.16).
Figure 2: Kaplan-Meier curve of the main endpoints between the group treated with colchicine and the placebo group (left: on atrial fibrillation; left: on MINS)
Source: slideshow by Pr Conen during the Hotline-1 session of the ESC 2023
No significant differences were observed between treatment groups for secondary outcomes including composite of all-cause mortality, non-fatal MINS, and non-fatal stroke, HR 0.88 (95% CI 0.75 to 1.03); the composite of all-cause mortality, nonfatal myocardial infarction (MI) and nonfatal stroke, HR 0.67 (95% CI 0.39 to 1.17); MINS not fulfilling the fourth universal definition of MI, HR 0.90 (95% CI 0.76 to 1.06); and MI, HR 0.86 (95% CI 0.41 to 1.81).
In post hoc analyses, the composite endpoint of clinically significant perioperative AF or MINS occurred in 360 patients (22.4%) in the colchicine group and in 415 patients (25.9%) in the placebo (HR 0.84; 95% CI 0.73 to 0.97).
Six patients had a stroke, 1 (0.1%) in the colchicine group and 5 (0.3%) in the placebo group (p = 0.12).
From a safety perspective, the composite endpoint of sepsis or infection occurred in 103 (6.4%) patients in the colchicine group, and 83 (5.2%) patients in the placebo group (HR 1.24; 95% CI 0.93 to 1.66).
Colchicine increased the incidence of noninfectious diarrhea, with 134 (8.3%) patients versus 38 (2.4%) patients, HR 3.64 (95% CI 2.54 to 5.22). No treatment was needed in 66 (38.4%) cases of diarrhea, 15 (8.7%) patients required intravenous hydration, 2 (1.2%) received antibiotics and 1 (0 .7%) patient required readmission for diarrhea. In the colchicine group, the median length of hospitalization was comparable between the two groups (5 days).
In conclusion, the administration of colchicine in patients undergoing major non-cardiological thoracic surgery does not significantly reduce the incidence of atrial fibrillation or myocardial ischemia.
Several elements that might explain the neutral results of this study:
The power of the study is not quite sufficient in view of the predicted incidences versus those actually observed (lower) for the 2 main endpoints. The authors used a composite of FA and MINS in a post-hoc analysis which came out positive, but the clinical relevance is unclear. Indeed, their physiopathologies and their clinical consequences are different. We have no feedback on the proportion of postoperative pericarditis; moreover, we have no information on the presence of valvulopathies
Of note, patients (n=1219) who had thoracoscopy appeared to have a significant benefit from colchicine. This type of surgical approach might be subject to further studies in the future.
The results show positive signals regarding the safety of colchicine use. This leaves the door open to other studies with greater power. These results might make it possible to judge the efficacy of colchicine in reducing the risk of AF, in particular following cardiac surgery or percutaneous ablation procedure.
Conen D, Alonso-Coello P, Douketis J, et al. Risk of stroke and other adverse outcomes in patients with perioperative atrial fibrillation 1 year following non-cardiac surgery. Eur Heart J. 2020;41:645-651.
Devereaux PJ, Biccard BM, Sigamani A, et al. Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017;317:1642-1651.
Agarwal S, Beard CW, Khosla J, et al. Safety and efficacy of colchicine for the prevention of post- operative atrial fibrillation in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. Europace. 2023;25:euad169.
Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383:1838-1847.
Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine following myocardial infarction. N Engl J Med. 2019;381:2497-2505.
To learn more, check out the full LBS, LBT and hotlines, in English, presented at ESC 2023:
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