Evidentiary Landscape of Heart Failure Therapies, Regulatory Decisions, and Translation Into Guidelines.

In the last decade, the U.S. Food and Drug Administration has approved 6 drugs to reduce morbidity or mortality and improve functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) and 3 drugs to reduce morbidity or mortality in patients with heart failure with preserved ejection fraction (HFpEF). Of the drugs approved for HFrEF, only 2 reduced mortality (sacubitril/valsartan in the PARADIGM-HF trial and dapagliflozin in the DAPA-HF trial). None of the drugs approved for HFpEF reduced mortality. Four trials, 1 with finerenone (FINEARTS-HF trial), 2 with semaglutide (STEP-HFpEF/DM trial), and 1 with tirzepatide (SUMMIT trial) met their primary endpoint in patients with HFpEF and are currently under review for approval. In contrast, before 2015, the U.S. Food and Drug Administration approved 11 drugs (captopril, enalapril, valsartan, candesartan, long-acting metoprolol succinate, bisoprolol, carvedilol, digoxin, isosorbide dinitrate-hydralazine, spironolactone, and epleronone) for patients with chronic stable HFrEF but none for HFpEF. All 11 drugs reduced mortality and morbidity except for digoxin, which only reduced hospitalization for heart failure. This state-of-the-art review examines the evidentiary support for regulatory actions and incorporation into guidelines of heart therapies approved since 2015.