Sex Differences in the Generalizability of Randomized Clinical Trials in Heart Failure with Reduced Ejection Fraction.

Abstract

To understand how sex differences impact the generalizability of randomized controlled trials (RCTs) in patients with heart failure and reduced ejection fraction (HFrEF, we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. Data from 2 HF registries and 5 HFrEF RCTs were used to create three subpopulations: one RCT population (n=16,917; 21.7% females), registry patients eligible for RCT inclusion (n=26,104; 31.8% females), and registry patients ineligible for RCT inclusion (n=20,910; 30.2% females). Clinical endpoints included all-cause mortality, CV mortality, and first HF hospitalization at one-year. Males and females were equally eligible for trial enrollment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (Standardized mortality ratio (SMR) 0.72; 95% CI 0.62 - 0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95%CI 0.76-1.03 for females, SMR 1.43; 95%CI 1.33-1.53 for males). Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and females trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries. This article is protected by copyright. All rights reserved.