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Myeloperoxidase Inhibition With Mitiperstat in Heart Failure With Preserved and Mildly Reduced Ejection Fraction - ENDEAVOR
Contribution To Literature:
The ENDEAVOR trial showed that in patients with HFpEF or HFmrEF, the myeloperoxidase inhibitor mitiperstat did not improve symptoms or 6-minute walk distance.
Description:
The goal of the trial was to evaluate the effect of mitiperstat, a selective myeloperoxidase inhibitor, on symptom burden in patients with heart failure with preserved or moderately reduced ejection fraction (HFpEF or HFmrEF, respectively).
Study Design
- International
- Randomized
- Double-blind
- Seamless phase 2b/3 design
Patients with symptomatic HFpEF or HFmrEF were randomized in 1:1:1 fashion to mitiperstat 2.5 mg (n = 235), 5 mg (n = 240), or placebo (n = 236).
- Total number of enrollees: 711
- Duration of follow-up: 48 weeks
- Mean patient age: 72 years
- Percentage female: 45%
Inclusion criteria:
- Age 40-85 years
- New York Heart Association (NYHA) functional class II-IV
- Left ventricular ejection fraction (LVEF) >40%
- 6-minute walk distance (6MWD) 30-400 m
- Kansas City Cardiomyopathy Questionnaire Total Summary Score (KCCQ-TSS) ≤90
- ≥1 of: left atrial enlargement, LV hypertrophy, average E/e’ ≥13, noninvasive estimated pulmonary artery systolic pressure >35 mm Hg, invasive pulmonary capillary wedge pressure >15 mm Hg at rest or >25 mm Hg with exercise
Exclusion criteria:
- Estimated glomerular filtration rate <30 mL/min/1.73 m2
- Decompensated HF or N-terminal pro-B-type natriuretic peptide >5000 pg/mL
- Major cardiac event or intervention ≤12 weeks prior
- Prior LVEF ≤40% at any time
Other salient features/characteristics:
- Mean body mass index: 30.5 kg/m2
- NYHA functional class III-IV: 24%
- LVEF ≥50%: 63%
- Mineralocorticoid receptor antagonist use: 42%
- Sodium-glucose cotransporter 2 inhibitor (SGLT2i) use: 21%
Principal Findings:
Co-primary outcome 1, change in KCCQ-TSS at 16 weeks, for mitiperstat vs. placebo, was: treatment difference -1.4 (95% confidence interval [CI] -3.9 to 1.2), p = 0.29.
Co-primary outcome 2, change in 6MWD at 16 weeks, for mitiperstat vs. placebo, was: treatment difference +3.8 m (95% CI -3.1 to 10.8), p = 0.28.
Secondary outcomes for mitiperstat vs. placebo at 16 weeks:
- Major adverse cardiovascular events (MACE), a composite of HF hospitalization or urgent visit, myocardial infarction, and CV and all-cause death: 7.4% vs. 10.2%, HR 0.71 (95% CI 0.42-1.19), p = 0.20
- HF hospitalization: 5.1% vs. 8.1%, HR 0.64 (95% CI 0.35-1.16), p = 0.14
Interpretation:
Myeloperoxidase, which is found in granulocytes as well as the vascular interstitium, has gained interest as a therapeutic target due to its potential roles in myocardial fibrosis and microvascular dysfunction. Preclinical models of mitiperstat have suggested a cardioprotective effect in myocardial infarction and effectively reduced plasma myeloperoxidase levels in the phase 2 SATELLITE study. However, no treatment effect was observed with respect to HF symptom burden or 6MWD in this cohort of HFpEF and HFmrEF patients. Numerically fewer MACE and HF hospitalizations were observed, but the significance of these exploratory findings after a relatively short treatment duration is uncertain. Moreover, SGLT2i use was low despite the efficacy of these agents as well as finerenone, as was recently described in the FINEARTS-HF trial, in patients with LVEF ≥40%. Incorporating a background of optimal medical therapy for HFpEF and HFmrEF would be essential for potential future studies to best understand mitiperstat’s clinical efficacy.
References:
Presented by Dr. Sanjiv J. Shah at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2024.
Clinical Topics: Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: AHA24, AHA Annual Scientific Sessions, Heart Failure, Peroxidase
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