Aernoud Fiolet

186 Chapter 7 DISCUSSION Thismeta-analysis includes five trials and endpoints in 11 816 randomized patients andshows consistent cardiovascularbenefitsof colchicine inawide rangeof patients with coronary disease. The most notable observations include the following: first, we found that colchicine, as compared with no colchicine or placebo, reduced the risk of the composite of myocardial infarction, stroke, or cardiovascular death by 25% with a low between-trial heterogeneity. With the addition of coronary revascularization to the composite endpoint, similar treatment benefits were observed. In addition, we observed significant reductions separately in the risks of myocardial infarction (22%), any stroke (46%), and coronary revascularization (23%). Second, we found no differences in all-cause death, with a lower incidence of cardiovascular death counterbalanced by a higher incidence of non-cardiovascular death. Third, risk for infectious or gastro-intestinal adverse events and cancer were similar between colchicine and no colchicine or placebo groups. Our results accord with the clinical benefit of targeted anti-inflammatory therapy in atherosclerosis which was found in the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS). 26 The anti-inflammatory mechanisms of action of colchicine are not yet fully elucidated. Multiple pathways are suggested, involving inhibition of microtubule formation, inhibition of leucocyte adhesion, and modulation of the nucleotide-binding oligomerization domain leucine- rich repeat-containing receptor family pyrin domain-containing 3 (NLRP3) inflammasome with reduced expression of interleukin-1 β , interleukin-6, and other pro-inflammatory cytokines. 11,12,27 The benefits of colchicine observed in these analyses were achieved against a background of standard secondary preventive therapies and are consistent with the concept of a residual inflammatory risk in patients with atherosclerosis. 28 The observed risk reduction matched that of other secondary preventive strategies in chronic coronary disease such as lipid-lowering or anti-thrombotic therapy. 29,30 The effects appeared to be consistent in both acute coronary syndrome and chronic coronary disease, and in women and men. Meta-analyses of current available data provide strong evidence for the efficacy of low-dose colchicine on composite cardiovascular endpoints and individual components. However, evaluation of safety of colchicine is currently limited to adverse events with high incidence rates such as hospitalizations for infection. None of the trials reported on infections that did not lead to hospitalization.