Effect of Famotidine on Outcomes in Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Abstract

Background: Adaptation 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 question: Do H₂-receptor antagonists improve outcomes in patients with PAH?

Study design and methods: We conducted a 24-week, single-center, 1:1 randomized, double-masked, placebo-controlled trial of the H₂-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in 6-minute walk distance (6MWD) at 24 weeks. Secondary end points included B-type natriuretic peptide levels, New York Heart Association functional class, right ventricular parameters measured from echocardiography, health-related quality of life, and escalation in PAH-focused care.

Results: From May 2019 through July 2023, 80 participants were randomized with 79 receiving study drug. No significant difference in the primary outcome of 6MWD at 24 weeks was found, with an increase of 4.7 m seen in the placebo arm vs a decrease of 17.0 m in the famotidine arm (P = .24). Also no differences were found in secondary end points at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct were good overall. Participants with methamphetamine-associated PAH were similar in all aspects to the study participants more broadly.

Interpretation: The 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 findings of the Repurposing a Histamine Antagonist to Benefit Patients With Pulmonary Hypertension (REHAB-PH) trial argue against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies.

Clinical trial registry: ClinicalTrials.gov; No.: NCT03554291; URL: www.

Clinicaltrials: gov.

Keywords: cor pulmonale; heart failure; histaminic signaling; methamphetamine; pulmonary hypertension; right ventricular adaptation.

Graphical abstract

Figure 1

Consolidated Standards of Reporting Trials diagram.

Figure 2

A-D, Graphs showing the change in the primary and secondary outcomes (± SE) after 24 weeks of famotidine or placebo including change in 6MWD (A), BNP (B), emPHasis-10 patient-reported outcomes (C), and RV basal diameter (D). BNP = B-type natriuretic peptide; RV = right ventricular; 6MWD = 6-minute walk distance.