This commentary refers to ‘Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT)’ by N. Bouabdallaoui et al., doi:10.1093/eurheartj/ehaa659 and the discussion piece ‘Colchicine administered early in acute MI: ready, set. . . go?’, by D. Vrachatis et al., doi:10.1093/eurheartj/ehab010; ‘Initiation of low-dose colchicine early after myocardial infarction’, by N. Bouabdallaoui and J-C Tardif, doi:10.1093/eurheartj/ehab038; and ‘Lessons from COLCOTand LoDoCo2: colchicine for secondary prevention in coronary artery disease’, by N. Bouabdallaoui et al., doi:10.1093/eurheartj/ehab020.

For decades, Cardiologists have been keen on adopting drugs originally developed for other indications. So was the case with the local anaesthetic lidocaine and several heart failure medications. Colchicine, an anti-inflammatory drug used to treat and prevent gouty attacks for centuries, was first adopted by Cardiologists to reduce the rate of recurrent pericarditis;1 more recently, however, the understanding of the pivotal role of inflammation in atherothrombosis drew Cardiologists’ attention to colchicine again. Activated macrophages and granulocytes infiltrating atherosclerotic sites produce a broad range of inflammatory molecules which can elicit local and systemic immune responses and induce plaque rupture, thrombosis, and ischaemia. Colchicine is an inexpensive, orally administered and potent anti-inflammatory agent mainly acting by tubulin disruption but also interfering with the activation of the inflammasome reducing the release of activated pro-inflammatory cytokines.

The use of anti-inflammatory therapy in coronary artery disease (CAD) was first appraised in 2013 by the LoDoCo trial, showing an association between low-dose colchicine (0.5 mg/day) and fewer cardiovascular events at 3-year follow-up in stable CAD patients.2 This encouraging result was recently confirmed by the LoDoCo2 trial on chronic CAD patients reporting a 31% lower relative risk of cardiovascular events in patients treated with colchicine compared to placebo.3 As for acute coronary syndromes, COLCOT demonstrated that colchicine initiated within 30 days after myocardial infarction (MI) yields a significantly lower risk of cardiovascular outcomes compared to placebo at 22.6 months follow-up [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61–0.96; P = 0.02], this result being mainly driven by a lower incidence of strokes and urgent hospitalizations for angina leading to coronary revascularization.4

The ‘virtuous adoption’ of colchicine offers the Cardiologists a new weapon against CAD. Nevertheless, several blind sides remain to be explored: what is the right timing to introduce colchicine treatment in CAD patients? Which patients better deserve it? For how long should they be treated? And how should they be monitored?

In this scenario, Bouabdallaoui et al.5 performed a COLCOT analysis defining three-time frames for time-to-treatment initiation (TTI), namely 0–3 days, 4–7 days, and 8–30 days following MI, in the attempt to evaluate the optimal timing for colchicine initiation after MI. This study provides precious evidence showing that an early initiation of low-dose colchicine within 3 days following MI was associated with a significant reduction of cardiovascular outcomes compared to placebo (HR 0.52, 95% CI 0.32–0.84; P = 0.007), driven by a lower incidence of MI, strokes, and urgent hospitalizations for angina leading to revascularization. Conversely, later colchicine initiation did not provide significant benefit on the primary study outcome. Despite these promising findings highlighting the positive effect of earlier initiation of colchicine after MI, it must be noted that baseline characteristics were significantly different among the TTI groups, as patients receiving colchicine earlier were younger, less likely had hypertension or diabetes, more frequently received statins and beta-blockers and presented a shorter time from the index MI to revascularization. Randomized data are needed to confirm these encouraging results and to further determine patients’ selection and monitoring criteria and optimal treatment duration.

Funding

the authors report no specific funding related to this article.

Conflict of interest: none declared.

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