Will myeloperoxidase inhibition benefit patients with heart failure?

Although mitiperstat did not improve symptoms or exercise function among patients with heart failure with preserved ejection fraction or mildly reduced ejection fraction (HFpEF; HFmrEF), an exploratory analysis revealed that it may impact hospitalisation rates for HF. Further trials are needed to confirm this finding.

The phase 2b ENDEAVOR trial (NCT04986202) randomised 709 patients with HFpEF or HFmrEF 1:1:1 to the myeloperoxidase inhibitor mitiperstat, 2.5 mg or 5.0 mg, or a placebo. Prof. Sanjiv Shah (Northwestern Feinberg School of Medicine, IL, USA) and colleagues looked at safety and the co-primary endpoints of Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and 6-minute walk distance after 48 weeks of treatment [1].

The authors did not see an effect of mitiperstat on KCCQ-TSS as compared with placebo after 48 weeks (LS mean difference -1.4; 95% CI -3.9 to 1.2; P=0.29). Similarly, mitiperstat and placebo produced comparable outcomes in 6-minute walk distance at week 48 (LS mean difference +3.8 metres; 95% CI -3.1 to 10.8; P=0.28). “We did see that hospitalisation rate for HF may be somewhat reduced in patients on mitiperstat,” said Prof. Shah (HR 0.64; 95% CI 0.35–1.16; P=0.14). “However, these outcomes were exploratory and not statistically significant.” The only difference between placebo and mitiperstat regarding adverse events was the increased occurrence of maculopapular rash in the active arms (4.0% vs 0.4%).

“Our proteomics analysis displayed that mitiperstat may influence clinical events through the mechanism of reducing mitochondrial oxidative stress and a subsequent decreased monocyte activation,” Prof. Shah mentioned at the end of his talk. “We need more research to investigate the potential of this agent.”

1. 
   
   1. Shah SJ, et al. Myeloperoxidase inhibition with mitiperstat in HFpEF and HFmrEF: primary results of the ENDEAVOR randomised clinical trial. LBS.06, AHA Scientific Sessions 2024, 16–18 November, Chicago, USA.

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Posted on 3 February 2025