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; Pinteraction = 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 in men; HR 0.94 (0.81-1.08) in women; P interaction = 0.210] or BB 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.

Italian Association of Hospital Cardiologists Position Paper ‘Gender discrepancy: time to implement gender-based clinical management’

“…91–93 However, a recent meta-analysis of 5 RCTs concerning the role of beta-blockers in HF patients, showed no gender difference in treatment effect between males and females for the outcome of all-cause mortality and the composite of death or HF hospitalization. 85 The same results have also been shown in a European observational registry, wherein beta-blockers had a comparable effect in both sexes in reducing all causes of death and HF hospitalization. Importantly, similar to ACE-I, women needed lower doses of beta-blockers than males (50–60% of the target doses) to achieve the same reduction of the outcomes.…”

“… 84 These data have further been confirmed in a recent meta-analysis from 7 RCTs showing no difference in the ACE-I or ARB's treatment between sex in all-cause mortality and the combined outcome of mortality and HF hospitalization. 85 HF guidelines recommend up-titration of these drugs to the same target dose in both sexes. However, two post-doc analyses from the HEAAL 86 and ATLAS 87 studies have shown that a lower dosage in women was equally effective compared to higher dosages.…”

Sex and gender differences in myocarditis and dilated cardiomyopathy: An update

“…In the PARADIGM-HF trial, only 21.8% of patients enrolled were women. However, ARNI therapy was shown to reduce cardiovascular mortality and heart failure hospitalizations in both men and women (HR 0.80, 90.72-0.90; HR 0.77, 0.62-0.95, respectively; p = 0.63) (212). A previous prospective registry in 10 centers examined sex differences in efficacy, safety, and tolerability of sacubitril-valsartan and found no difference in discontinuation of ARNI therapy, no difference in received dose, and no difference in adverse events between women and men.…”

CWHHA ATLAS: EPIDEMIOLOGY, DIAGNOSIS AND MANAGEMENT OF CARDIOVASCULAR DISEASES IN WOMEN Chapter 9: Summary of Current Status, Challenges, Opportunities, and Recommendations

“… 13 , 14 , 15 , 16 , 17 Newly emerging therapies such as the soluble guanylate cyclase stimulators and cardiac myosin activators in the V er ic igua t Gl o bal Study in Subjects With Heart Failure With R educed Eject i on Fr a ction (VICTORIA)-HF and G lobal A pproach to L owering A dverse C ardiac Outcomes T hrough I mproving C ontractility in H eart F ailure (GALACTIC-HF) trials respectively, showed no sex-based differences in heart failure hospitalizations or CV death. 18 …”