Myeloperoxidase inhibition with mitiperstat in heart failure with preserved or mildly reduced ejection fraction: a randomized phase 2b trial
In brief
Mitiperstat fails to improve symptoms or walking distance in 711 heart failure patients
In this 48-week trial of 711 people with heart failure and ejection fraction above 40%, mitiperstat did not improve symptom scores or six-minute walking distance at 16 weeks compared with placebo, and secondary measures also showed no benefit. Side effects were similar overall, though rash was more common with the drug; whether another approach to targeting this pathway could help remains unknown.
- Journal
- Nature medicine (Q1)
- Published
- 9 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Lars H Lund, Carolyn S P Lam, Patricia Ely Pizzato, Erik Michaëlsson, Andrea Mattsson, Hans Ericsson, et al.
- PMID
- 42717033
- DOI
- 10.1038/s41591-026-04615-z
Why clinicians should know about it
- Picked for Cardiology and Cardiovascular Medicine (top studies of the week, 11 October 2026): Phase 2b RCT of MPO inhibitor in HFpEF
- Picked for Pediatric Surgery (top studies of the week, 13 September 2026): Ranked by evidence level and journal quartile
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 .
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.