Upfront combination lipid-lowering therapy in acute coronary syndrome: a bayesian network meta-analysis of low-density lipoprotein cholesterol reduction and major adverse cardiovascular events

Introduction Acute coronary syndrome (ACS) is a leading cause of death worldwide. Guidelines recommend initiation of high-intensity statin therapy after ACS, followed by combination therapy in patients who are unable to achieve target low-density lipoprotein cholesterol (LDL-C) lowering. Upfront combination lipid-lowering therapy (LLT) has shown promise in reducing the time taken to achieve the target LDL-C level and improved efficacy in reducing recurrent events. Purpose This study aims to compare the efficacy of various upfront LLT combinations on LDL-C and the incidence of three-point major adverse cardiovascular events (MACE). Methods This study was conducted in accordance with the PRISMA guidelines. PubMed, MEDLINE, Embase, and Cochrane Library were searched for eligible studies published before 6 August 2025. Studies enrolling adult ACS patients with upfront (in-hospital or within 4 weeks of ACS) combination LLT (statin plus ezetimibe or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors or both (triple therapy)) were included. Three independent reviewers screened studies, extracted data, and the senior author resolved disagreements. Risk of bias was assessed using the Newcastle–Ottawa Scale and the RoB2 scale. Bayesian network meta-analysis was performed in R using a random-effects model with weakly informative priors. Results LDL-C The network had 39 studies. Combination strategies achieved significantly greater LDL-C reduction versus statin monotherapy (S) (Figure 1). Mean differences (95% Credible Interval) were 11.9 mg/dL (10.9–13.0) for ezetimibe + statin (E+S), 36.0 mg/dL (34.0–38.1) for PCSK9 inhibitor + statin (P+S), and 44.4 mg/dL (37.9–50.8) for triple therapy. Node-splitting confirmed consistency between direct and indirect evidence (p≥0.23). Between-study heterogeneity was substantial (τ=0.49 mg/dL; I²=91%). Triple therapy ranked first with near-certainty (SUCRA=1.00), followed by P+S (0.67), E+S (0.33), and S (0.00; Figure 2). Findings were robust to priors on sensitivity analysis. MACE The network had 16 studies. Combination strategies showed a trend toward fewer MACE events versus S: odds ratio (95% Credible Interval) 0.86 (0.50–1.31) for E+S, 0.70 (0.50–1.02) for P+S, and 0.42 (0.07–2.09) for triple therapy. Between-study heterogeneity was low (τ=0.21; I²=11%). Convergence was satisfactory (Gelman–Rubin≤1.02). Triple therapy ranked highest for MACE reduction (SUCRA=0.80), followed by P+S (0.67), E+S (0.42), and S (0.11), though non-deterministic. Sensitivity analyses confirmed directional consistency across priors. Conclusions Upfront combination LLT showed substantial LDL-C reduction, with triple therapy demonstrating the highest efficacy. While all combinations showed a trend towards fewer MACE events, none reached significance. The consistent ranking hierarchy across both the outcomes and the robustness of findings to priors supports the consideration of upfront combination LLT in ACS.