Globalization of heart failure clinical trials: a systematic review of 305 trials conducted over 16 years

Novel therapies for heart failure (HF) are increasingly being tested in larger, global populations.1 This trend, in large part, may be driven by logistics of global trial conduct and the ability to more expediently enrol patients from certain geographic regions.2 Consequently, these trial-level patterns may decrease relative participation from countries where patient enrolment is more difficult or expensive. Given key differences in patientlevel factors (e.g. race, diet, co-morbidities, socio-economic factors) and health care practices (e.g. baseline use of standard medical and device therapies) across geographic regions, there is potential that study results may not be generalizable to areas of the world under-represented in the trial.3 Moreover, increased regional heterogeneity may encumber site oversight and quality control, impacting the ability of the trial to include appropriately selected patients and demonstrate treatment benefit or harm, as exemplified in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial experience.4 To date, there has been limited quantitative appraisal of these aggregate triallevel patterns in geographic representation. Given the potential implications on future HF trial planning, we conducted a comprehensive systematic review of global region of enrolment in all HF trials published over the last 16 years in any peer-reviewed medical journal. We identified phase II–IV HF clinical trials with a sample size >100 (since smaller studies are by design single centre and unlikely to