Purpose of review <p>To synthesize geographic variation in heart failure (HF) trials across baseline characteristics, treatment effects, and safety over the whole spectrum of ejection fraction, and to identify methodological and implementation factors that influence external validity and equity.</p> Recent findings <p>Historical and contemporary HF trials reveal marked regional heterogeneity in enrollment, age, comorbidities, biomarkers, background guideline-directed medical therapy, and device use. Despite this, relative efficacy is generally consistent across regions, while absolute risk reduction, safety signals, and discontinuation rates may vary with baseline risk, care delivery, and trial conduct.</p> Summary <p>Geographic differences in HF trials largely reflect health-system and methodological factors rather than biology alone, challenging generalizability. Future research should ensure balanced enrollment, prespecified region-by-treatment analyses, and pragmatic designs. Integrating implementation science will improve the widespread use of effective therapies and lead to more globally applicable evidence.</p>