Low-dose colchicine: a new tool in the treatment of chronic coronary disease? Comment on the low-dose colchicine (LoDoCo)2 trial

Results of the LoDoCo2 trial have been presented at the ESC Congress 2020 and simultaneously published in the New England Journal of Medicine (https://doi.org/10.1056/NEJMoa2021372). Key points • LoDoCo2 is an investigator-initiated, double blind, placebo-controlled randomized trial evaluating whether low-dose colchicine prevents cardiovascular events in patients with chronic coronary disease. The trial randomized 5522 clinically stable patients who tolerated a colchicine dose of 0.5 mg daily during a 30-day, open-label, run-in phase. The majority were also treated with lipid-lowering and antiplatelet drugs. • During a median follow-up of 29 months, colchicine significantly reduced the primary endpoint, a composite of cardiovascular death, spontaneous (non-procedural) myocardial infarction, ischaemic stroke, or ischaemia-driven coronary revascularization, by 31% (2.5 events/100 person-year in the colchicine group vs. 3.6 events/100 person-year in the placebo group). The beneficial effect was apparent early and accrued over time. • Overall, colchicine appeared safe with no statistically significant differences in serious adverse events compared with placebo. However, non-cardiovascular deaths occurred more frequently among the colchicine-treated patients than among those who received placebo (53 vs. 35, respectively). The role of inflammation in coronary atherosclerosis and its complications is supported by several lines of evidence, including some recent trials of anti-inflammatory drug therapy (e.g. CANTOS and COLCOT). However, as with the role of platelets in both primary haemostasis and atherothrombosis, inflammation is both an important defence mechanism and contributor to the progression of several chronic diseases, raising the issue of long-term safety of anti-inflammatory therapy. Moreover, the limited information on the specific inflammatory pathways involved at different stages of atherosclerotic cardiovascular disease (ASCVD), and the lack of specific biomarkers to monitor these pathways, have hampered rational trial design in this area. Colchicine, an anti-inflammatory drug used for the short-term treatment of gout and pericarditis, works by inhibiting tubulin polymerization and microtubule formation, with dampening of the NLRP3 inflammasome pathway and neutrophil function. The LoDoCo2 trial’s positive outcome adds to the evidence that an intervention to mitigate inflammation can reduce the risk of cardiovascular events in ASCVD patients on top of lipid-lowering and antiplatelet therapy. The benefits of low-dose colchicine had been previously documented in the COLCOT trial involving patients with a myocardial infarction within 30 days (mean 13.5 days) before enrolment. In LoDoCo2, most patients had a history of acute coronary syndrome, and in two-thirds of the patients, the acute event had occurred more than 24 months before randomization. In both trials, over half of colchicine’s benefit was due to a reduction in ischaemia-driven coronary revascularization, with no effect on all-cause mortality. Although the observed difference in the incidence of non-cardiovascular death in LoDoCo2 was not significant, and could have been due to chance, the hazard ratio of 1.51 (95% confidence interval (CI) 0.99–2.31) is of potential concern. Are these findings ready to be transferred into clinical practice? We believe that the relatively short duration of both COLCOT and LoDoCo2 (23 and 29 months, respectively) is largely inadequate to assess the long-term safety of colchicine for secondary prevention of ASCVD. An individual patient data meta-analysis of all the randomized colchicine trials would be desirable to evaluate more reliably the effect size of this intervention, the key individual component(s) of the composite endpoint explaining its benefit, and to reassure about the existing concern on non-cardiovascular deaths. Conflict of interest: Prof. Liuzzo received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education University and Research. Prof. Patrono reports personal fees from Acticor Biotech, personal fees from Amgen, personal fees from Bayer, personal fees from GlaxoSmithKline, personal fees from Tremeau, personal fees from Zambon, grants from AIFA (Italian Drug Agency), grants from European Commission, other from Scientific Advisory Board of the International Aspirin Foundation, outside the submitted work.