Sex-specific differences in the efficacy of heart failure therapies: a meta-analysis of 84,818 patients

Women have been historically underrepresented in clinical trials of heart failure (HF). We aimed to assess for sex differences in patient characteristics and the efficacy of guideline-directed medical therapy (GDMT) in HF. Systematic literature search for randomized controlled trials (RCTs) of GDMT reporting cardiovascular outcomes by sex in patients with HF. The primary outcome was the composite of cardiovascular death and hospitalization for HF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using inverse variance weighting and random effects meta-analysis. Twenty-six RCTs totaling 84,818 participants (27% women) were included. Women with HF were older, had higher New York Heart Association (NYHA) class, more hypertension and obesity, and higher mean left ventricular ejection fraction compared to men. There was evidence for most GDMT in reducing the primary outcome in women with HF with reduced ejection fraction (HFrEF) (angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker [RR 0.86, 95% CI 0.75-0.97], angiotensin-receptor blocker/neprilysin inhibitor (ARNI) [RR 0.77, 95% CI 0.62-0.94], beta-blocker [RR 0.67, 95% CI 0.51-0.89], ivabradine [RR 0.74, 95% CI 0.60-0.91], and sodium-glucose cotransporter-2 (SGLT2) inhibitors [RR 0.66, 95% CI 0.54-0.81]) and a non-significant trend for benefit with mineralocorticoid-receptor-antagonist (MRA) [RR 0.77, 95% CI 0.52-1.16]). Compared to men with HFrEF, GDMT reduced the primary outcome in women to a similar degree across all drug classes (ratio of RR 1.05, 95% CI 0.96-1.14). Despite differences in baseline characteristics and an underrepresentation of women in HF clinical trials, GDMT are as efficacious in women as compared to men in reducing cardiovascular events in HF.