Debating Oral Diuretic Intensification as an Endpoint in Heart Failure Trials

At the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025, hosts Muthiah Vaduganathan, MD, MPH, a cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, and Stephen Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, discussed the evolving role of oral diuretic intensification as a potential endpoint in heart failure clinical trials.



Historically, endpoints progressed from all-cause mortality to cardiovascular mortality, then to composites that included heart failure hospitalization and urgent outpatient visits. Recent trials have gone further, considering changes in oral loop diuretic therapy as signals of worsening disease.



The rationale for including oral diuretic intensification is its frequency, prognostic value, and potential to increase event capture in trials. Data from real-world cohorts and secondary analyses demonstrate that escalation of oral diuretics is associated with increased risks of hospitalization and death, suggesting it is not a benign event. Incorporating these events could enhance trial efficiency by substantially increasing the number of captured endpoints, allowing for smaller and shorter studies while maintaining clinical relevance.



However, challenges remain. Definitions vary across studies, raising questions about what constitutes a meaningful intensification—dose doubling, drug class switching, or short-term use of additional diuretics. Distinguishing heart failure–related changes from adjustments for comorbid conditions such as kidney disease or obesity further complicates endpoint validity. Concerns also exist that clinician-driven medication changes may introduce variability or bias unless standardized symptom-based criteria are applied.



Despite these complexities, retrospective analyses suggest consistent findings across different statistical approaches, reinforcing the prognostic importance of oral diuretic changes. Broader adoption would require consensus definitions, regulatory acceptance, and frameworks to account for overlapping events, such as escalation followed by IV diuretics or hospitalization. The speakers concluded that oral diuretic intensification represents an important step toward more inclusive and globally applicable trial endpoints that better capture the continuum of worsening heart failure.



Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others.



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