Is there a role for colchicine in secondary prevention of coronary artery disease?

This editorial refers to ‘Efficacy and safety of colchicine for the prevention of major cardiovascular and cerebrovascular events in patients with coronary artery disease: a systematic review and meta-analysis on 12 869 patients’, by A. Andreis et al., pp. 1916–1925.

Among the non-communicable diseases, coronary artery disease (CAD) stands tall as the major contributor of mortality and morbidity on a global scale.¹ Statistics have shown that the burden of CAD is more in low- and middle-income countries.² CAD has a chronic nature with risk factors of the disease evolving from the early childhood onwards. CAD indefinitely needs effective preventive measures, treatment strategies, regular monitoring of compliance to treatment strategies, and rehabilitation programmes.² There is also the need for quantifying the cost-effectiveness of each measures taken.² Among the strategies mentioned, secondary prevention has a crucial role in mitigating CAD disease progression in documented CAD patients.

Inflammation has a lead role in the pathogenesis of CAD and the treatment for CAD should focus on alleviating the inflammatory processes.³ If not addressed properly, this inflammatory state may worsen the prognosis of the disease.³ The contemporary evidence regarding the medical management of CAD shows that a combination of drugs specifically prescribed to prevent the reoccurrence, increase the survival and to improve the quality of life is the standard of care globally.⁴ Several studies have indicated the benefits of anti-inflammatory drugs in the secondary prevention of CAD along with the standard of care drugs.^5–7

Among the anti-inflammatory drugs, colchicine deserves a special mention. Colchicine is a plant alkaloid and is widely studied for its ability in reducing the thrombin-mediated platelet aggregation and mean platelet volume as well as its role in stabilizing the vascular endothelium. These potential effects are significant in secondary prevention of CAD.^5,6 The use of colchicine in the secondary prevention of CAD is still met with confusing observations. The present study aimed to amalgamate the evidence related to the efficacy and safety of colchicine in preventing the adverse outcomes of CAD through a systematic review and meta-analysis.

Andreis et al.⁸ included 11 high quality randomized controlled trials (RCTs) as per the Cochrane quality assessment tool for the meta-analysis in which colchicine was used for secondary prevention in acute as well as chronic CAD. There were a total of 12 869 eligible patients in which 6501 patients were on colchicine and 6368 on placebo with a median follow-up period of 6 months (interquartile range, 1–16). Among the 11 RCTs selected, six tested acute coronary syndrome patients, three tested chronic syndrome patients, and two studies included both types of patients mentioned above. The primary endpoint taken was a composite of major adverse cardiovascular and cerebrovascular events (MACCE). MACCE consisted of cardiac death, myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for cardiovascular events. The secondary endpoints were all-cause death and drug adverse events (DAEs). The dosage of colchicine used was 0.5–1 mg daily. The RR for MACCE in the colchicine group was 0.67 [95% confidence interval (CI) 0.56–0.80]. The RRs for MI was 0.76 (95% CI 0.61–0.96) and that for coronary revascularization was 0.61 (95% CI 0.42–0.89). The RR reported for stroke was 0.48 (95% CI 0.30–0.77) and for hospitalization from cardiovascular cause was 0.32 (95% CI 0.12–0.87). All reported values suggest a significantly lower risk of individual MACCE events with colchicine use with the best reductions seen for stroke and hospitalization. On the contrary, the results reported were negative for cardiovascular death and all-cause mortality. The RR for the two were 0.73 (95% CI 0.45–1.21) and 1.01 (95% CI 0.71–1.43), respectively.

The safety side shows results that are concerning. Colchicine showed an increased risk for gastrointestinal events (RR = 1.67, 95% CI 1.20–2.34), myalgia (RR = 1.16, 95% CI 1.02–1.32), and DAEs-related discontinuation (RR = 1.54, 95% CI 1.02–2.32) prompting clinicians to be on the look-out for these side effects. The current study concluded that colchicine is effective in secondary prevention of CAD with an increased risk of DAEs that could be minimized with low-dose regimens.

The study results appear to contrast the findings of a recent meta-analysis in the same theme by Al-Abdouh et al. in 2020.⁶ This meta-analysis included six RCTs (median follow-up of 3.5 months) and reported non-significant results for MACE, MI, and stroke quite different from that of the current study. The risk reductions (RDs) for MACE (RD −0.032; 95% CI −0.083 to 0.018; P 0.15), MI (RD −0.011; 95% CI −0.030 to 0.007; P 0.16), and stroke (RD −0.001, 95% CI −0.005 to 0.004; P 0.69) suggests that there was no significant benefit from colchicine use for these three outcomes.⁶ The results reported for all-cause mortality (RD −0.001; 95% CI −0.009 to 0.006; P 0.65) and cardiovascular mortality (RD −0.003; 95% CI −0.010 to 0.004; P 0.34) were not significant and in similar lines to that reported by the current study. Smaller number of studies, smaller duration of follow-up and a different summary measure may be the probable reasons for the disparity in results.

Another recent meta-analysis by Ullah et al.⁷ in 2020 shows both similarities as well as differences with the current study. This meta-analysis included six RCTs with a median follow-up of 5.5 months had shown that the pooled RR of MACE (0.64, 95% CI 0.36–1.14, P 0.13), ACS (0.62, 95% CI 0.27–1.41, P 0.25), cardiac arrest (0.74, 95% CI 0.26–2.14, P 0.58), and stent restenosis (0.71, 95% CI 0.41–1.23, P 0.22) with colchicine was not significantly different from placebo or control groups contrasting the current study results. There were some similarities with the overall RR of revascularization (0.53, 95% CI 0.34–0.83, P 0.005) and that for stroke (0.26, 95% CI 0.11–0.62, P 0.002) showing beneficial effect for colchicine use similar to the current study. The RR for mortality (0.95, 95% CI 0.63–1.42, P 0.79) was non-significant similar to the current study. This meta-analysis too reported higher RR for GI adverse events (hazard ratio 2.66, 95% CI 1.21–5.87, P 0.02) in the colchicine group, a finding that aligns well with the current study in terms of safety profile of colchicine use for patients with CAD.

The message from two recent reviews presents a mixed bag for colchicine use in CAD patients.^9,10 The first comprehensive review by Amario et al.⁹ examines colchicine use in CAD and summarizes the advantages and disadvantages of the same. The advantages outlined were reduction of ischaemic events in acute and chronic coronary syndrome patients with a complimenting cost/benefit ratio. The disadvantages noted were narrow therapeutic index, long-term toxicity and significant drug to drug interactions. Another review by Casanova et al.¹⁰ concludes that colchicine is effective in the management of pericardial disease, atrial fibrillation, stable CAD and congestive heart failure.

The overall message from the existing evidence pool is yet not convincing to prescribe colchicine for regular use aimed at secondary prevention for CAD. There is a definite need for conducting large, multicentric, longer duration prospective studies related to this theme. Such studies may bring more clarity regarding the efficacy and safety of colchicine in secondary prevention of CAD. Use of candidate biomarkers or tools to predict the response to colchicine treatment should be explored by future studies. The documentation of cost-effectiveness of colchicine use in CAD setting may also contribute to the evidence base enabling better clinical decisions related to usage of this drug for secondary prevention of CAD.

Conflict of interest: none declared.

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