Generalizability of HFrEF trials 15 INTRODUCTION Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of investigational therapies due to their robust methodology conducted within a strict regulatory framework.1 A well-conducted RCT has high internal validity, which ensures that the observed treatment effect is directly the result of the therapy tested.1–4 However, high internal validity can come at the expense of external validity, defined as the degree to which the treatment effect found in the study can be generalized and replicated outside the RCT.1 If the RCT results found in the study population are not generalizable to the target population, it is unclear which patients in routine care can receive a treatment safely and effectively.1–5 Physicians’ uncertainty and criticism of RCTs’ generalizability has been suggested as one reason for the underuse of evidence-based treatments, specifically in the field of heart failure (HF).2,6 There is currently no consensus on how to assess generalizability, but a logical and important first step is to assess if an RCT study population is representative of the projected target population.2–4,7 Studies comparing summary data on baseline characteristics between RCTs and observational data have already been conducted, specifically for heart failure with reduced ejection fraction (HFrEF).5,8–10 Although these studies have shown differences in crude outcomes between trial and real-world patients, it is not known how differences in patient characteristics drive the observed differences in prognosis. In addition, some of these comparisons have been limited by the small sample sizes from single trials. Here, we compared individual patient data of five HFrEF randomized clinical trials and two HF registries by direct data access and collaboration between academic researchers and pharmaceutical industry partners. We first determined their differences in patient characteristics, treatment, and clinical outcomes. Then, we identified the proportion of registry patients who were eligible for inclusion in the trials and compared their outcomes with trial participants while adjusting for known prognostic factors of HF at the individual patient level. 2.1
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