3.42 General discussion 193 of HFrEF trial generalizability and the future path toward generalizable clinical evidence. Quantitative representation by key demographic groups The most pressing concern in HFrEF efficacy trial generalizability lies in persistent under-enrolment of females, which stands between 21% and 27%, 15–18 though females make up to 41% and 47% of hospitalized and ambulatory HFrEF patient cohorts.19,20 In light of clear epidemiological differences between sexes, from predisposing factors to pathophysiology, diagnostic features, treatment practices, pharmaco-kinetics and -dynamics and clinical outcomes13,21–25, the assumption that male-driven efficacy results can be safely extrapolated to female HF patients no longer holds. In fact, a recent meta-analysis on sex-stratified efficacy of HFrEF trials found neutral pooled effects in females for renin-angiotensin system (RAS) antagonists and beta-blockers, indicating that overall positive treatment effects reflect results seen only in male participants.26 In a post-hoc comparison between HFrEF trials and registry, we demonstrated that men in the trials have a-third higher residual cardiovascular risk than trial women. Furthermore, standard target doses in guidelines for HFrEF are being called into question as females from Asian and European cohorts were found to reach maximal treatment benefits for ACE-inhibitors / ARBs and beta-blockers with just half the recommended doses.27 Thus, existing practices of reporting subgroup analyses by sex or post-hoc meta-analyses are no longer sufficient in mitigating generalizability concerns if females continue to make up only a quarter of participants. Closing of gaps in evidence among females requires proactive modernization of HF clinical trials, considering alternatives including stratified purposive sampling28 and built-in mechanisms to increase enrolment of females. The next important subgroup to represent in efficacy trials is older patients. In HFrEF trials, mean participant age continue to remain at 65 years, 15,16 10 years younger than the general HFrEF population in Western Europe and Northern America (72-74 years).29–31 It is necessary to note that the gap in trial representativeness depends on the reference population in question. Comparatively, the average age in the trials is similar when compared to HFrEF patients from Asia, where onset of HF is earlier.13,32 While age is an important prognostic indicator, underrepresentation of older patients is tied to under-representation based on other characteristics, for
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