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Cardiac Myosin Inhibition in Heart Failure With Normal and Supranormal Ejection Fraction: Primary Results of the
Sanjiv J Shah1, Marzia Rigolli2, Atefeh Javidialsaadi2
1Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Insights
Mavacamten showed promise in treating heart failure with preserved ejection fraction (HFpEF) by reducing cardiac biomarkers and improving symptoms. No sustained decrease in left ventricular ejection fraction (LVEF) was observed, indicating a favorable safety profile.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Heart failure with preserved ejection fraction (HFpEF) and left ventricular ejection fraction (LVEF) ≥60% presents limited therapeutic options.
- Cardiac myosin inhibition is an emerging strategy for HFpEF treatment.
Purpose of the Study:
- To evaluate the efficacy and safety of mavacamten in patients with HFpEF and LVEF ≥60%.
Main Methods:
- EMBARK-HFpEF trial: a 26-week, open-label, single-arm, multicenter study.
- 30 patients with symptomatic HFpEF (NYHA class II-III), LVEF ≥60%, elevated NTproBNP, and LVH were enrolled.
- Mavacamten was administered, with dosage adjustments based on LVEF and NTproBNP levels.
Main Results:
- Mavacamten significantly reduced NTproBNP, hsTnT, and hsTnI levels.
- Improvements in NYHA functional class and echocardiographic measures of diastolic function were observed.
- Mean LVEF decreased slightly but without sustained reductions below 30%; transient LVEF reductions required dose interruption in 10% of patients, with recovery upon discontinuation.
Conclusions:
- Mavacamten demonstrated potential benefits in HFpEF patients with LVEF ≥60%, evidenced by biomarker improvements and functional class changes.
- The drug was generally well-tolerated, with no sustained detrimental effects on LVEF, suggesting a manageable safety profile.
Importance:
Patients with heart failure with preserved ejection fraction (HFpEF) who have left ventricular ejection fraction (LVEF) of 60% or greater have limited treatment options.
Objective:
To examine the effects of cardiac myosin inhibition with mavacamten in patients with HFpEF with LVEF of 60% or greater.
Design, Setting, And Participants:
The EMBARK-HFpEF trial was a phase 2a, open-label, single-arm, multicenter trial conducted from November 6, 2020, to February 26, 2024, at 20 sites in the US and Canada. Patients with symptomatic HFpEF (defined as a New York Heart Association [NYHA] functional class II or III), LVEF of 60% or greater, elevated N-terminal pro-B-type natriuretic peptide (NTproBNP), and left ventricular hypertrophy were eligible for inclusion.
Intervention:
Mavacamten treatment for 26 weeks, starting at 2.5 mg and potentially titrated up to 5 mg at week 14 based on prespecified LVEF and NTproBNP criteria.
Main Outcomes And Measures:
Primary efficacy end points (measured as the change from baseline to week 26) included NTproBNP and high-sensitivity troponin T (hsTnT); additional efficacy end points included changes in high-sensitivity troponin I (hsTnI), NYHA functional class, and echocardiographic parameters (resting and peak exercise). Safety end points included treatment-emergent adverse events and reductions in LVEF to less than 30%.
Results:
A total of 30 patients were enrolled and treated with mavacamten. Median (IQR) patient age was 76 (70-80) years, and 16 patients (53.3%) were female. From baseline to week 26, mavacamten was associated with reductions in NTproBNP (mean reduction, -26%; 95% CI, -44% to -4%; P = .04), hsTnT (mean reduction, -13%; 95% CI, -23% to -3%; P = .02), and hsTnI (mean reduction, -20%; 95% CI, -32% to -6%; P = .01). Cardiac biomarker values returned toward baseline levels 8 weeks after drug discontinuation. NYHA class improved in 10 of 24 patients (41.7%) who had evaluable NYHA class data at the end of treatment, and improvements in echocardiographic markers of LV diastolic function were observed. Mean LVEF decreased by 3.2 absolute percentage points (95% CI, 1.1-5.4; P = .005) during treatment. Mavacamten was interrupted in 3 patients (10% of the study population; 95% CI, 2.1%-26.5%) due to protocol prespecified criteria of LVEF less than 50% (n = 2) or a more than 20% relative decrease from baseline (n = 1; nadir LVEF, 58%), with LVEF recovery observed in all 3 patients. There were no deaths or instances of LVEF less than 30%; 1 patient had worsening heart failure deemed unrelated to the study drug.
Conclusions And Relevance:
In an open-label trial in patients with HFpEF with LVEF of 60% or greater, mavacamten was associated with improvements in biomarkers of cardiac wall stress and injury, with no sustained reductions in LVEF observed.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04766892.
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