Comparative efficacy of colchicine and intensive LDL-C lowering in patients with ASCVD receiving statins: a network meta-analysis of randomised controlled trials

Abstract Background Adding intensive low-density lipoprotein cholesterol (LDL-C) lowering treatments or colchicine to statins resulted in additional cardiovascular benefits. However, the relative efficacy and priority of these agents are unclear. Purpose We aimed to compare the effects of these supplementary agents on cardiovascular outcomes in patients with atherosclerotic cardiovascular diseases (ASCVD) receiving statins. Methods We performed a systematic review and frequentist network meta-analysis on randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death and all-cause mortality. The safety endpoints were treatment discontinuation and non-cardiovascular death. Colchicine was used as reference treatment. Random-effects model was used in case of high heterogeneity, the fixed-effects model was preferred otherwise. We ranked the comparative effects of all drugs with surface under the cumulative ranking (SUCRA) probabilities. Results 17 trials totaling 85823 participants treated with colchicine, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor and ATP citrate lyase (ACL) inhibitor were included. Compared with colchicine, NPC1L1 inhibitor was associated with increased risk of MACE (risk ratio [RR]: 1.39, 1.21-1.59), stroke (RR: 1.81, 1.09-3.00) and coronary revascularization (RR: 1.36, 1.11-1.68), and PCSK9 inhibitor was associated with increased risk of MACE (RR: 1.27, 1.10-1.46). However, NPC1L1 inhibitor (RR: 0.68, 0.48-0.96) and PCSK9 inhibitor (RR: 0.64, 0.44-0.93) were associated with reduced risk of non-cardiovascular death in comparison to colchicine. PCSK9 inhibitors had a lower risk of MACE (RR: 0.91, 95% CI: 0.85-0.98) and coronary revascularization (RR: 0.89, 95% CI: 0.81-0.97) compared with NPC1L1 inhibitor. Although no regimen prolonged survival, colchicine had the lowest rank at non-cardiovascular death and the worse performance on all-cause mortality. Conclusions In patients with ASCVD receiving statins, inflammation-inhibiting with colchicine seems to be superior to intensive LDL-C lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor in cardiovascular prevention. However, using colchicine as an alternative to intensive lipid-lowering therapy may need to be weighed against the greater cardiovascular benefits and the potential harms of higher non-cardiovascular death. Given the worse performance of colchicine on survival based on current evidence, colchicine may be more appropriate for patients who have been treated with intensive LDL-C-lowering agents but still have recurrent cardiovascular events.Forest plots of included agentsRadar plot of treatments based on SUCRA