Cardiac Myosin Inhibitor Aficamten Beats Beta-Blocker Metoprolol in Head-to-Head Phase 3 Trial
As first-line treatment for obstructive hypertrophic cardiomyopathy, aficamten alone improved exercise capacity and symptoms more than metoprolol alone.
Obstructive hypertrophic cardiomyopathy (obstructive HCM) is a disease in which the heart muscle thickens and narrows the outflow tract of the left ventricle, causing shortness of breath and reduced exercise capacity. Beta-blockers have long been used as first-line treatment, but the evidence for them is limited. Professor Pablo Garcia-Pavia of Hospital Universitario Puerta de Hierro Majadahonda in Spain and colleagues published in NEJM the results of MAPLE-HCM, a phase 3 trial that directly compared the cardiac myosin inhibitor aficamten with metoprolol.
Double-blind, double-dummy phase 3 trial of 175 patients
Adult patients with symptoms were randomly assigned 1:1 to receive either aficamten alone (5 to 20 mg per day) or metoprolol alone (50 to 200 mg per day). Each drug was paired with a matching placebo so that no one knew which drug a patient was taking. The primary endpoint was the change in peak oxygen uptake (peak VO2) at week 24. Peak VO2 rose by 1.1 mL/kg/min in the aficamten group (88 patients) and fell by 1.2 in the metoprolol group (87 patients), a difference of 2.3 mL/kg/min.
New York Heart Association (NYHA) functional class, the patient-reported symptom score (KCCQ-CSS), left ventricular outflow tract pressure gradient, NT-proBNP and left atrial volume also improved more in the aficamten group. Left ventricular mass did not differ, and the frequency of adverse events was similar in the two groups.
Implications and limitations
The result could support using a drug that targets the disease mechanism as first-line treatment. However, the results cover only 24 weeks, the sample was small, and outcomes such as death and hospitalisation were not assessed. Because the drug works by suppressing heart muscle contraction, long-term monitoring for a decline in cardiac pumping function is needed. The trial was funded by the developer, Cytokinetics.
- Difference in the primary endpoint (peak oxygen uptake at week 24) was 2.3 mL/kg/min, favouring aficamten
- Double-blind, double-dummy phase 3 trial of 175 patients with symptomatic obstructive HCM, with metoprolol as the comparator
- Symptoms, pressure gradient and NT-proBNP improved; adverse events were similar in the two groups
Limitations These are short-term results from 24 weeks and 175 patients. Long-term outcomes such as death and hospitalisation, and the safety of reduced contractile function, need further confirmation.
Original research
- Garcia-Pavia P, et al. · Hospital Universitario Puerta de Hierro Majadahonda. Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2504654
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