• Peter J Leary, Samuel G Rayner, Kelley R H Branch, Laurie Hogl, Nancy M Liston, Lia M Barros, Jessi Prout, Stephanie Nolley, Jonathan Buber, David D Ralph, and Jeffrey L Probstfield.
• Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington; Department of Epidemiology, University of Washington.
• Chest. 2025 Jan 4.

BackgroundAdaptation of the right ventricle is a key determinant of outcomes in pulmonary arterial hypertension (PAH). Despite a compelling rationale to develop targeted therapies for the right ventricle in PAH, no such treatments exist. H2-receptor antagonism is a potential myocardial-focused paradigm in heart failure.Research QuestionDo H2-receptor antagonists improve outcomes in participants with PAH?Study Design And MethodsWe conducted a 24-week, single-center, 1:1 randomized, double-blind, placebo-controlled trial of the H2-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in six-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included B-type natriuretic peptide levels, NYHA functional class, right ventricular parameters, health-related quality of life, and escalation in PAH-focused care.ResultsFrom May 2019 to July 2023, 80 participants were randomized with 79 receiving study drug. There was no significant difference in the primary outcome of 6MWD at 24 weeks, with an increase of 4.7 meters seen in the placebo arm versus a decrease of 17.0 meters in the famotidine arm (p = 0.24). There were also no differences in secondary endpoints at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct was good overall. Participants with methamphetamine-associated PAH were similar in all aspects to the study participants more broadly.InterpretationThe results of this trial do not support the routine use of famotidine 20 mg daily as an adjunct therapy for the treatment of PAH. The REHAB-PH trial argues against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies.Clinical Trials RegistrationThe trial was registered at clinicaltrials.gov (NCT03554291).Copyright © 2025. Published by Elsevier Inc.

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