Heart Failure Prevention: Evidence Generation, Trial Design, and Regulatory Pathways (JACC April 2026-2)-Article: Heart Failure Prevention: Evidence Generation, Trial Design, and Regulatory Pathways

Article: Heart Failure Prevention: Evidence Generation, Trial Design, and Regulatory Pathways

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This JACC state-of-the-art review argues that heart failure (HF) prevention is now a major public health priority. HF affects millions globally, has a lifetime risk of about 1 in 4, and is increasingly driven by obesity, hypertension, diabetes, chronic kidney disease, and cardio-kidney-metabolic (CKM) disease rather than only by atherosclerotic disease. Despite improved treatment once HF develops, outcomes remain poor and costs are rising sharply.<br /><br />The review emphasizes that HF prevention lags behind atherosclerotic cardiovascular disease prevention because no therapy is yet approved specifically for primary HF prevention, and existing trials usually focus on composite cardiovascular outcomes rather than HF alone. A major problem is how HF is defined in trials and practice: most studies capture only hospitalizations, even though many new HF diagnoses occur in outpatient settings. The authors argue that relying on hospitalization alone underestimates true HF burden and may miss clinically important prevention benefits.<br /><br />They summarize validated HF risk prediction tools and show how risk can be refined using biomarkers such as NT-proBNP, troponin, and albuminuria, plus imaging and even AI-based methods. They also review landmark trials showing that blood pressure lowering, SGLT2 inhibitors, finerenone, GLP-1 receptor agonists, and some post–myocardial infarction therapies can reduce HF events, though usually as secondary outcomes.<br /><br />Several ongoing trials are highlighted, including studies of SGLT2 inhibitors, mineralocorticoid pathway drugs, GLP-1–based therapies, and prevention strategies in diabetes, obesity, CKD, post-MI, and cardio-oncology populations. The authors recommend future trials use higher-risk cohorts, broader HF endpoints that include outpatient diagnoses, better adjudication methods, and more precise regulatory pathways.<br /><br />Overall, the review calls for a fundamental shift: HF prevention should move beyond ASCVD-only thinking toward risk-based, biomarker-guided, and CKM-informed strategies.

Keywords

heart failure prevention

public health priority

cardio-kidney-metabolic disease

risk prediction tools

NT-proBNP

SGLT2 inhibitors

finerenone

GLP-1 receptor agonists

outpatient heart failure diagnosis

biomarker-guided prevention