Introduction: The Food and Drug Administration (FDA) provides guidance on the use of endpoints for drug approvals in heart failure (HF). Hypothesis: The aim of this study was to systematically review whether clinical studies in HF report the FDA recommendations for endpoints. Methods: All studies targeting HF available on the clinical trials platform from the National Library of Medicine were analyzed. The FDA recommends a decrease in mortality as the primary efficacy endpoint and an increase in survival as the safety endpoint. Others include single or composite scores of hospitalizations, biomarkers, or symptoms and/or physical function. Results: Trials (n=4,978) were narrowed down to 1,299 (26%) studies with an active, but not recruiting, enrolling by invitations, not yet recruiting, and recruiting statuses. Only 132 (3%) studies using intervention with drugs reported endpoints. Up to 7,200 participants were randomly (n=95, 72%) assigned to parallel designs (n=81, 61%) followed by single group (n=19, 14%) or crossover designs (n=18, 14%) with open label (n=48, 36%) or quadruple masking methods (n=29, 22%). Interventions tested sodium-glucose co-transporter 2 (n=21, 16%) and angiotensin receptor-neprilysin inhibitors (n=13, 10%). Dapagliflozin (n=8, 8%), Sacubitril and Valsartan (n=6, 6%) followed by Levosimendan, Metformin, or Warfarin (n=3, 3%) were compared to placebo (n=51, 53%). Equivalence trials (n=35, 27%) analyzed Sacubitril and Valsartan (n=5, 14%), Dapagliflozin, Beta-hydroxybutyrate Ester, or Sacubitril and Valsartan with Para-aminohippurate, Lohexol, and Aprepitant (n=2, 6%). Most studies (n=55, 42%) assessed endpoints related to symptoms and/or physical function. Other endpoints included cardiac function (n=24, 18%) and biomarkers (n=19, 14%) followed by mortality and survival (n=18, 14%) or hospitalization (n=5, 4%). Conclusions: Most studies assessed symptoms, physical function, cardiac function, or biomarkers for primary endpoints. They have included non-fatal endpoints such as patient-reported outcomes or objective indicators likely due to the increasing number of patients with worsening heart failure in outpatient settings.