Precision Anti-Inflammatory Therapy in Atherosclerosis: A Systematic Review and Meta-Analysis of Colchicine Timing and Clinical Outcomes in Patients with Atherosclerotic Cardiovascular Disease

Abstract Background Despite optimal lipid-lowering and antithrombotic therapy, substantial residual cardiovascular risk persists in established atherosclerotic cardiovascular disease (ASCVD), partly driven by chronic vascular inflammation through the NLRP3 inflammasome pathway. In an open-label pilot using colchicine 0.5 mg twice daily, hsCRP was reduced by approximately 60%. However, landmark trials report divergent results, most notably the null CLEAR SYNERGY trial (HR 0.99) versus the positive LoDoCo2 (HR 0.69) and COLCOT (HR 0.77), generating controversy about the role of timing and cumulative exposure. Methods Systematic review and meta-analysis of RCTs comparing colchicine to placebo or no treatment in adults with established ASCVD. Searches on March 21, 2026 (PubMed, Embase, CENTRAL, ClinicalTrials.gov , WHO ICTRP) identified 1,315 records; 5 trials (N=18,656) were included. Primary outcome: 4-point MACE. Random-effects pooling used DerSimonian-Laird (DL) estimation; Hartung-Knapp-Sidik-Jonkman (HKSJ)-adjusted analysis and a 95% prediction interval were computed as pre-specified methodological sensitivity analyses. Trial-level meta-regression tested time-to-initiation (TTI) and cumulative dose as exploratory moderators. PROSPERO CRD420261346516. Results DL pooled HR for 4-point MACE: 0.68 (95% CI 0.51–0.89; p=0.0060) . HKSJ-adjusted HR: 0.68 (95% CI 0.27–1.70; p=0.3018). Substantial heterogeneity (I 2 =81.4%; 95% prediction interval 0.29–1.57, crossing 1.0). Exploratory trial-level meta-regression identified TTI as a significant moderator (β=−0.00187/day; p=0.003) and cumulative dose as an independent moderator (β=−0.00163/mg-day; p=0.0003); these associations are hypothesis-generating given k=5 trials. Non-cardiovascular mortality was not significantly increased (HR 1.07; 0.76–1.50; p=0.6937). GI drug discontinuation was significantly higher with colchicine (RR 1.95; 1.09– 3.48; p=0.0236). Conclusions Low-dose colchicine is associated with reduced 4-point MACE in ASCVD (DL HR 0.68; HKSJ HR 0.68). The substantial heterogeneity and wide prediction interval indicate that effect size varies substantially across settings. Trial-level associations suggest benefit is more consistent with sub-acute or chronic initiation and sustained exposure, while hyper-acute post-PCI initiation does not show benefit. The non-CV mortality safety concern is not confirmed. These findings are exploratory given the small trial pool and should be interpreted with appropriate caution pending larger synthesis.