Impact of Female Underrepresentation in Trials Investigating Long-Term Pharmacologic Therapy after Acute Coronary Syndrome A Meta-analysis and Meta-regression

Abstract Background Female underrepresentation in clinical trials of acute coronary syndromes (ACS) may hinder the assessment of sex-based differences in the outcomes of long-term pharmacological therapy. The presence of these differences and their potential association with female representation in clinical trials remain unclear. Methods A systematic search of Embase, Medline Ovid, and Cochrane Central was conducted through July 1, 2025, in accordance with the reporting standards of the PRISMA guidelines. Eligible randomized controlled trials (RCTs) compared long-term pharmacological therapy for ACS with placebo or standard care, included ≥1-year follow-up, and reported a clinical event as the primary outcome. Sex differences in treatment effects were analysed using a random-effects meta-analysis, while meta-regression was used to assess the association between the proportion of females in each trial and these differences. The main outcome was the sex difference in the relative effect measure (REM; mostly a hazard ratio) for the primary efficacy endpoint. Results Among 102 RCTs, female representation ranged from 10% to 52%. Forty-eight trials provided sex-stratified data. Pooled analysis showed no evidence of sex-related differences in efficacy: the mean difference in the log of the REM of males minus females was 0.00 (95% confidence interval, –0.05 to 0.05; P = 0.98; heterogeneity I² = 0%). Meta-regression indicated no relationship between female trial participation and sex-specific treatment effects. Conclusions In RCTs of long-term pharmacological therapy after ACS, treatment efficacy was comparable between sexes, irrespective of sex distribution. These findings support current guidelines recommending equivalent long-term pharmacological strategies for secondary prevention in both sexes.