Sex differences in efficacy of pharmacological therapies in heart failure with reduced ejection fraction: a meta-analysis

Abstract

Aims: Recent studies have suggested potential sex differences in treatment response to pharmacological therapies in heart failure (HF). We performed a systematic review and meta-analysis of studies comparing treatment effects between men and women with HF and reduced ejection fraction (HFrEF) using established guideline-directed medical therapy and other emerging pharmacological treatments.

Methods and results: Systematic search was performed on PubMed, Embase, and Cochrane Library for randomized controlled trials published in 1990-2021. Outcomes were all-cause mortality and combined outcome of all-cause mortality and/or hospitalization for HF. Of 618 articles identified, 25 articles and 100 213 patients (mean age 62 ± 1.7 years, women 23.1%, mean left ventricular ejection fraction 26.6 ± 1.3%) were included in the systematic review and meta-analysis. For the outcome of all-cause mortality, there was no evidence of treatment heterogeneity by sex for renin-angiotensin system inhibitors (RASi) [hazard ratio (HR) 0.86 (95% confidence interval 0.75-0.99) in men; HR 0.97 (0.77-1.23) in women; P_interaction = 0.288], or for beta-blockers (BB) [HR 0.71 (0.59-0.86) in men; HR 0.87 (0.73-1.03) in women; P_interaction = 0.345]. Similarly, for the composite outcome of death or HF hospitalization, there was no evidence of treatment heterogeneity by sex for RASi [HR 0.84 (0.77-0.93) in men; HR 0.94 (0.81-1.08) in women; P_interaction = 0.210] or BB [HR 0.76 (0.64-0.90) in men; HR 0.72 (0.60-0.86) in women; P_interaction = 0.650]. Results for mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) from previously published meta-analyses were included in the review. For the combined outcome of cardiovascular death or HF hospitalization, no significant interaction for sex was observed for MRA (P_interaction = 0.78) or SGLT2i (P_interaction = 0.37). Results for emerging pharmacological treatments, such as soluble guanylate cyclase stimulators and cardiac myosin activators, were included in the review and showed consistent treatment effects between men and women.

Conclusions: Our meta-analysis showed no differences between sex in treatment effect for BB and RASi. Review on previously published trials for MRA, SGLT2i, and emerging therapies presented consistent treatment effects between men and women.

Keywords: Guideline-directed medical therapy; Heart failure with reduced ejection fraction; Pharmacology; Sex differences.

Figure 1

Meta‐analysis of renin‐angiotensin system inhibitors (RASi) and beta‐blockers (BB) effects in heart failure with reduced ejection fraction treatment in men vs. women presented as hazard ratios with 95% confidence intervals. RASi effect was evaluated for the outcome of all‐cause mortality (A) and combined outcome of all‐cause mortality and HF hospitalization (B) in men and women. BB effect was respectively evaluated for all‐cause mortality (C) and combined outcome of all‐cause mortality and HF hospitalization (D). BB, beta‐blockers; CI, confidence interval; HR, hazard ratio; RASi, renin‐angiotensin system inhibitors; RE, random effects.