3.1 Sex differences in generalizability of HFrEF trials 85 INTRODUCTION There are sex and gender differences across multiple diseases and clinical syndromes. Some of the most profound differences can be seen in heart failure (HF).1,2 Females and males differ in HF etiology, age, risk factors, biomarkers, pathophysiology, comorbidities, and clinical presentation.2–7 There is increasing awareness on sex differences in HF, however there are still large gaps in knowledge of sex-specific mechanisms, optimal treatment, and prognosis of HF.2 One driving factor of the knowledge gap in sex differences is the widespread underrepresentation of females recruited to HF clinical trials. From observational HF registries, the percentage of females with HF and reduced ejection fraction (HFrEF) in the population is around 30-50%,8,9 whereas the percentage of enrolled females in HFrEF trials is on average 24%.10 As a consequence, contemporary treatment guidelines are predominantly based on male-derived data.10–13 Post-hoc analyses from trials and observational data currently suggest that females may need lower dosages.14,15 Currently, several uncertainties remain to be elucidated, for example i) differences in characteristics and background treatment are known to exist between trials and the broader population. Are these differences equal for males and females? ii) if differences in characteristics and treatment do vary by sex, to what extent are clinical outcomes influenced? Although there are now numerous calls to increase female representation in HF trials, especially from cardiology societies and regulators, little data is available to shed light on how under-enrollment of females in HFrEF trials affects generalizability to daily clinical practice.16,17 To address these uncertainties, in the present study, we sought to assess differences in clinical characteristics, medication dose and use, and explored unadjusted and case-mix adjusted mortality rates stratified for each of the sexes using individual patient data from 5 RCTs and 2 large HF registries.
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