Generalizability of HFrEF trials 27 Netherlands and Sweden. Also, data in the registries were from more recent years than the trials, thus reflecting more contemporary prescribing practices. Accordingly, we would expect background therapies in newer HF trials to be at a higher rate than the ones described here. Therefore, our findings, along with other recent studies in acute HF suggest that the gap in HF guideline-adherent treatment between trial and real-world patients is narrowing.6,30 The differences observed between trial participants and trial-eligible registry patients highlight other factors besides eligibility criteria that influence patient selection in RCTs. Physicians intuitively recruit patients who are deemed less likely to drop out to ensure low attrition rates which retain high internal validity.31–33 Older patients and those with comorbidities are not always physically or mentally able to comply and finish the treatment protocol due to frailty, low mobility and increased risk for adverse events.7,34 Women with HF tend to be older and are less likely to participate due to perceived harm from clinical studies, transportation difficulties, or constraints from a caregiving role.33,35,36 Consequently, the additional criteria introduced by investigators alongside the eligibility criteria consistently cause underrepresentation of older patients, those with comorbidities and women in CV trials..37 However, expanding the study population to include these groups would increase the cost of already expensive HF trials, and other solutions to improve generalizability that have been proposed include individual participant data metaanalysis, proper reporting of subgroup analysis, registry-based trials or comparative effectiveness studies.38–40 The growing trend to conduct RCTs as site-less or directto-patient studies may reduce this bias in the future. We have shown, by direct comparisons between study groups that the risk of mortality and HF hospitalization was lowest in the trial population. However, after accounting for known prognostic factors for survival in HF, differences in survival between trial and registry patients disappeared. In fact, age and sex combined explained the largest variation in standardised mortality ratios between trials and registries. This observation is evident for both all-cause and cardiovascular mortality and highlights their important contribution on the generalizability of HF trials. Taken together, it seems that differences in overall survival between HF trials and registries behave predictably and could be addressed by clinical variables which are readily available in daily clinical practice. Although well-accepted, we have demonstrated for the first time that there are increased cardiovascular mortality rates 2.1
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