Efficacy of new immunomodulatory drugs on major adverse cardiovascular events in patients with coronary heart disease: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Despite optimal standard therapy, residual inflammation continues to increase major adverse cardiovascular events (MACE) in patients with coronary heart disease (CHD). New immunomodulatory drugs targeting specific immune pathways have shown mixed efficacy across trials, warranting comprehensive evaluation of their role in secondary prevention. METHODS: We performed a systematic review and meta-analysis of 25 randomized controlled trials (RCTs) from January 1, 2014, to October 1, 2024, identified from eight databases: the cochrane library, (public medicine) pubmed, embase, web of science, china national knowledge infrastructure (CNKI), wanfang data knowledge service platform(WanFang), Weipu information database(VIP), and china biomedical literature database (SinoMed). Eligible studies assessed the efficacy of immunomodulatory agents, including colchicine, and canakinumab on MACE. Primary outcome was MACE incidence; secondary outcomes included, angina, and inflammatory biomarkers. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using fixed or random-effects models. Subgroup analyses were conducted by drug class, follow-up duration, and CHD subtype (acute vs. chronic coronary syndrome). Risk of bias was assessed via Cochrane RoB 1.0, and evidence certainty rated with GRADE. RESULTS: Overall, new immunomodulatory drugs did not significantly reduce MACE (RR = 0.92; 95% CI: [0.84,1.01]; P = 0.09; I²=60%). However, subgroup analyses revealed heterogeneous effects across drug classes. Significant reductions in MACE were observed with NLRP3 inflammasome inhibitors (RR = 0.75; 95% CI: 0.65,0.86; P < 0.0001) and interleukin-pathway inhibitors (RR = 0.86; 95% CI: 0.75,0.97; P = 0.02). In contrast, no significant reduction in MACE incidence was found in the broad-spectrum immunomodulator group, Lp-PLA2 inhibitor group, or p38 MAPK kinase inhibitor group (all P > 0.05). Besides, benefits were evident only in trials with follow-up exceeding 6 months (RR = 0.89; 95% CI: [0.82,0.98]. Secondary outcomes showed significant reductions in angina (RR = 0.72; 95%CI: [0.58,0.90], P = 0.004), revascularization (RR = 0.85; 95%CI: [0.73,0.98], P = 0.03), IL-6 (SMD = - 0.82;95༅CI: [-1.62,-0.03], P = 0.02), and neutrophil count, but no effect on (cardiac arrest)CA, all-cause mortality, incidence of gastrointestinal adverse effect and high-sensitivity c-reactive protein(hs-CRP). The quality of evidence for MACE was assessed as moderate. CONCLUSION: Targeted anti-inflammatory therapies, particularly colchicine and canakinumab, significantly reduce MACE in CHD patients when used for longer than six months. Efficacy varies by mechanism of action, supporting precision use of NLRP3 and IL-1β inhibitors. Future trials should been focus on biomarker-guided, long-term anti-inflammatory interventions in cardiovascular care. TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024597008PROSPERO : CRD42024597008.