Nat Med. 2026 Sep 9. doi: 10.1038/s41591-026-04615-z. Online ahead of print.
ABSTRACT
Myeloperoxidase (MPO)-derived oxidants reduce nitric oxide bioavailability and promote coronary microvascular dysfunction, cardiomyocyte stiffening and interstitial fibrosis-mechanisms implicated in the pathogenesis of heart failure with preserved and mildly reduced ejection fraction. Here, in a multicenter, randomized, double-blind, placebo-controlled, three-arm, parallel-group phase 2b trial of patients with heart failure and an ejection fraction of >40%, we evaluated whether treatment with the MPO inhibitor mitiperstat versus placebo for 48 weeks improved symptoms and exercise function at 16 weeks (the co-primary endpoints were the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and 6-minute walk distance (6MWD)). Secondary endpoints included changes in natriuretic peptides and inflammatory markers (up to 48 weeks) and echocardiographic parameters (up to 24 weeks). In total, 711 patients (45% women) were randomized 1:1:1 to mitiperstat 2.5 mg, mitiperstat 5 mg or placebo. Mitiperstat (pooled doses) did not improve KCCQ-TSS (placebo-corrected difference in mean change from baseline, -1.4 points (95% confidence interval (CI) -3.9, 1.2; P = 0.29), 6MWD (3.8 m (95% CI -3.1, 10.8)); P = 0.28) or any secondary endpoint. Adverse and serious adverse events, including infections, were similar among groups except for maculopapular rash (mitiperstat, 3.6%; placebo, 0.4%). These results indicate that mitiperstat was safe and well tolerated but did not improve symptoms or exercise function in chronic heart failure with preserved or mildly reduced ejection fraction. ClinicalTrials.gov registration: NCT04986202 .
PMID:42717033 | DOI:10.1038/s41591-026-04615-z