CHAPTER 3.1 98 DISCUSSION Using individual patient data of over 62 000 patients from five HFrEF RCTs and two HF registries, we found several sex differences that impacted the efficacy of enrichment strategies in the clinical trials itself and influenced the generalizability of their results into daily clinical practice. 31% of patients in the registries were females, whereas 22% trial participants were females. Contrary to males, females in trials had a significantly better survival than expected from the registries, even after extensive adjustments for HF prognostic factors. HF hospitalizations were much more frequent in the observational registry compared to the trials, but here there was no relevant difference between the sexes. Taken together, these data show that although in- and exclusion criteria are similar, the populations of males and females enrolled in the RCTs show substantial differences in comparison with HF patients in the general population, and the magnitude and direction of these differences were unique to both sexes. We confirm that there are sex-related differences in clinical profile, comorbidities, medication use, and outcomes in HFrEF.2,36–38 Females in all 3 groups were older, less often smokers, had higher LVEF, less ischemic-related disease, more often diagnosed with hypertension, and had higher NYHA class III/IV proportions across all populations.2,4,5,38–40 Females typically have shorter HF duration due to later onset HFrEF which was only confirmed here in the RCT population, but not in the registry populations.8 Depression rates were more than doubled compared to males.41 These sex differences were consistent across the 3 groups, however the proportion differences between the sexes were much more striking in the registry populations. Females and males in the RCTs were more similar. Target dosing did not meaningfully differ between the sexes in any group, which emphasizes the impact of male-derived treatment guidelines and the need for this topic to be explored further. Data on prognostic differences between males and females with HFrEF are conflicting although females often seem to fare better than males.4,7,8,42–44 In the present study, females in both registry populations, i.e., RCT-eligible and -ineligible, experienced higher unadjusted mortality rates due to all causes and CV causes compared to males in the registries, whereas the mortality rates were roughly similar between males and females in the trials. However, after adjusting for known prognostic factors in HF, males in the RCTs had consistently higher mortality risk in
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