Colchicine for Secondary Prevention in Coronary Disease

S. Mark Nidorf; Jan H Cornel; Aernoud T.L. Fiolet

Disclosures

Eur Heart J. 2021;42(11):1060-1061. 

Patients with coronary disease have a life-long risk of cardiovascular death, myocardial infarction, ischaemic stroke, and the need for coronary intervention despite the use of lipid-lowering and anti-thrombotic therapy. This residual risk relates to on-going low-grade inflammation within the arterial wall that drives the atherosclerotic process and predisposes to acute plaque rupture and atherothrombosis.[1]

The self-assembly of free cholesterol into its crystalline form is suggested as one of the components that drives the inflammatory cascade within the atherosclerotic plaque. This implies that agents that reduce the availability of free cholesterol in the vascular wall or inhibit aspects of cholesterol crystal-induced inflammation could alter the atherosclerotic process.[2,3]

The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) confirmed that modulating the inflammatory response by selective cytokine inhibition can translate to clinical benefit. Implementing anti-inflammatory treatment as secondary prevention in regular clinical care requires a widely available drug with a favourable safety profile. Recent clinical data provide evidence for the broad acting anti-inflammatory drug colchicine to have such potential.[4,5]

Colchicine is an ancient drug with broad anti-inflammatory effects. It is avidly taken up by leucocytes, affects tubulin binding, inhibits the interleukin-6 expression and alters crystal-induced inflammasome activity.[6,7] Long-term use of the drug is used for gout prophylaxis, in pericarditis, and Familial Mediterranean Fever. Chronic exposure in these patients appears to be safe.[8]

The evidence supporting the cardiovascular benefits of colchicine 0.5 mg once daily in coronary disease now includes two randomized placebo-controlled multi-centre trials [the Colchicine Cardiovascular Outcomes Trial (COLCOT) and Low-Dose Colchicine trial (LoDoCo2)] that collectively included over 10 000 participants.[4,5] These trials investigated colchicine 0.5 mg after recent myocardial infarction and in patients with chronic coronary disease. Patients were treated according to guidelines, with the majority of patients receiving lipid-lowering therapy and anti-thrombotic therapy. Colchicine was associated with a relative risk reduction for cardiovascular death, myocardial infarction, stroke, and coronary revascularization of 23–31% as compared to placebo.

In both trials, the benefits of colchicine appeared soon after initiation and continued to accrue over time and were seen in addition to other established secondary prevention therapies including high dose statins. Notably, both trials recruited patients in a pragmatic manner without selecting for inflammatory phenotype. Both trials excluded patients with manifest heart failure and severe renal failure. Pre-specified analyses showed the efficacy of treatment to be consistent among relevant clinical subgroups.

These trials were not primarily designed to assess the long-term safety of colchicine. Median follow-up was 23–29 months, with a maximum of 5 years. Nevertheless, both trials did report safety parameters of special interest. Up to 9.4% of patients experienced initial transient side effects in LoDoCo2, a proportion similar to statin intolerance.[9] Long-term compliance with the drug was high, with equal rates of study drug discontinuation between treatment groups. An increased incidence of hospitalization for pneumonia seen in COLCOT was not confirmed in LoDoCo2. Incidence of new cancers did not differ between treatment groups in both trials. In addition, relating to concern based on anecdotal evidence, the risk for myotoxicity or neutropenia was low and without evident relation to colchicine. An increased incidence in non-cardiovascular deaths in LoDoCo2 was noted as a potential concern. This finding was not explained by an increase in the incidence of death from cancer or infection and the low absolute mortality rates limit interpretation. How this observation relates to the net clinical benefit and whether it represents a true signal, however, requires future pharmacovigilance studies with extended follow-up.

When interpreting these findings in the context of introducing the drug as an adjuvant in secondary prevention for coronary disease, one should also bear in mind that the mean age of patients varied from 60 to 65 years and none of the patients had an advanced cardio-renal failure. In addition, although the drug is not associated with risks for bleeding, haemodynamic disturbances, or pro-arrhythmogenic effects, it does interact with strong CYP3A4 substrates. It should not be used concomitant with clarithromycin, anti-fungal, or immunosuppressive therapy.

The residual risk for cardiovascular events justifies intensification of a secondary prevention in patients with coronary disease. The apparent efficacy of colchicine demonstrated so far add to the relevance of addressing the inflammatory driver in this regard. The effect estimates that were observed in acute and chronic coronary disease represent a clinically meaningful treatment benefit. Hence, the introduction of the drug as secondary preventive strategy in patients without extensive cardiovascular comorbidity could be considered. Evidence from long-term use in coronary disease will provide additional insight in the magnitude of relevant but yet undetermined safety signals.

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