A meta-analysis of 139 heart failure RCTs (292,027 patients, 28.1% women) tested whether pharmacological efficacy differs by sex. Across 78 trials reporting sex-stratified results the primary-endpoint effect was identical in women and men (delta ln[REM] 0.00; 95% CI −0.04 to 0.03), and meta-regression found no association between the proportion of women enrolled and treatment effect. Decades of female under-representation are therefore unlikely to have masked clinically meaningful sex differences — though better gender balance in HF trials remains ethically and socially essential.
A systematic search was conducted up to 21 March 2025, including randomized controlled trials (RCTs) (≥100 patients) evaluating pharmacological HF treatments vs. placebo or usual care, with clinical events as the primary outcome. Sex differences in the primary outcome were assessed using a random-effects meta-analysis of the reported relative effect measures (REM) and pooled estimates. For key clinical outcomes, meta-regression analyses were performed to examine the association between the proportion of women enrolled and sex differences in REMs, as well as the overall REMs without separating sex.
Of 5749 screened publications, 139 RCTs met inclusion criteria, with 292 027 patients (28.1% women). Based on 78 RCTs that reported sex-stratified treatment effects, pooled analysis showed no difference in treatment efficacy between women and men (delta ln[REM] 0.00; 95% confidence interval (CI) -0.04 to 0.03; P = .85; I2 = 4.1%). Meta-regression found no association between the proportion of women and sex differences in REM (78 RCTs, P = .25), overall efficacy (139 RCTs, P = .24), or other clinical outcomes.
These findings suggest that pharmacological efficacy in HF does not differ by sex and that historical female underrepresentation in trials is unlikely to have masked important sex differences. Nonetheless, improving sex balance in HF trials remains essential for societal and ethical reasons.
