Sex-Based Differences in Chronic Heart Failure: a Systematic Review and Meta-Analysis of Randomized Controlled Trials

BACKGROUND: Sex-based disparities in patient enrollment and treatment effects in heart failure (HF) randomized controlled trials (RCTs) have been reported. We aim to systematically analyze sex-based enrollment and treatment effect differences in HF RCTs over time. METHODS: RCTs enrolling patients with chronic HF were systematically searched on PubMed-MEDLINE. Eligible trials included pharmacological or device-based interventions with a hard primary endpoint (mortality and hospitalization) and reporting enrollment of women. Sex-specific treatment effects (HR or RR) were extracted. Meta-analyses were performed using random-effects models, and pre-specified subgroup analyses were performed. RESULTS: A total of 56 RCTs (39 drug, 17 device) were included. The pooled proportion of women enrollment was 27.0% (95%CI: 22.0% to 32.4%) in drug trials and 25.3% (95%CI: 21.0% to 29.9%) in device trials. Women were more underrepresented in HF with reduced ejection fraction (HFrEF) than in HF with preserved EF (HFpEF) trials (21.0% vs 49.6%, p < 0.001). Among drug trials reporting sex-specific effects, the pooled sex interaction for RCTs reporting HR was 0.94 (95%CI 0.89-1.01) and RR was 0.81 (95%CI 0.68-0.96), suggesting potentially greater benefit for women. No interaction was observed between HFrEF and HFpEF trials (HR: p = 0.44; RR: p = 0.95). The pooled interaction estimate on event counts was 0.90 (95%CI 0.84-0.96). For devices, the pooled sex interaction for RCTs reporting HR was 1.05 (95%CI 0.90-1.22) and RR was 0.68 (95%CI 0.50-0.93). CONCLUSION: Women remain underrepresented in HF RCTs. Sex-stratified analyses suggest a potentially greater relative benefit of drug intervention in women, which might inform future RCTs. Further studies are required to investigate the mechanisms of these differences.