Mavacamten associated with improvement in submaximal exertional tolerance: A secondary analysis of the EXPLORER-HCM randomized trial

1. In the EXPLORER-HCM trial, among 251 included patients, there were significant improvements with mavacamten vs placebo in cardiopulmonary exercise testing (CPET) parameters, including the peak VE/VCO2 ratio, peak metabolic equivalents (METs), peak circulator power, and peak partial pressure of end-tidal carbon dioxide (PETCO2).

2. Mavacamten improved peak exercise time compared to placebo with a mean difference of 0.7 minutes.

Evidence Rating Level:1 (Excellent)

Study Rundown: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, hypercontractility, and diastolic dysfunction. This complex disease can impair functional capacity, with symptoms such as dyspnea, fatigue, chest pain, and syncope, among others, all of which can impact quality of life. Mavacamten is a cardiac myosin inhibitor that was found to improve peak oxygen uptake in patients with symptomatic HCM in the EXPLORER-HCM trial. The objective of this study was to investigate the effect of mavacamten on CPET parameters. CPET is a useful clinical tool that can provide valuable insight into the functional capacity of individuals living with HCM. A total of 251 patients living with symptomatic obstructive HCM were randomly assigned to receive either mavacamten (n = 123) or placebo (n = 128). The main outcomes included carbon dioxide output (VCO₂), minute ventilation (V_E), peak (V_E/VCO₂) ratio, ventilatory efficiency (V_E/VCO₂ slope), PETCO₂, VO₂/workload slope, and various peak CPET outcomes including respiratory exchange ratio (RER), circulatory power, ventilatory power and threshold, METs, and exercise time. Compared with placebo, mavacamten demonstrated significant improvements in the following peak-exercise CPET parameters: peak V_E/VCO₂ ratio, peak METs, peak circulatory power, and peak PETCO₂. Mavacamten improved peak exercise time by 0.7 minutes when compared with placebo. The use of a single-time point at which CPET was measured is a limitation of this study, due to the variable nature of HCM symptom status. A major strength of this study was the wide scope of CPET parameters included, which represent reproducible clinical surrogates for functional capacity.

Click to read the study in JAMA Cardiology

Relevant Reading: Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomized double-blind, placebo-controlled, phase 3 trial

In-Depth [randomized controlled trial]: This study investigated the effect of mavacamten on exercise physiology using CPET. A total of 251 patients (mean SD age, 58.5 (11.9), 59% male) were randomized to receive either mavacamten (n = 123) or placebo (n = 128). At baseline, a majority of patients (183 of 251) exhibited NYHA class II symptoms. Among both intervention groups, 45% of patients performed CPET using an exercise bicycle and 55% using a treadmill. Analysis of peak-exercise CPET parameters revealed, compared with placebo, mavacamten improved peak V_E/VCO₂ ration (LS mean difference, -2.2; 95% CI, -3.05 to -1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17 – 0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min x mm Hg; 95% CI, 153.12 – 592.61 mL/kg/min x mm Hg; P = .001), peak exercise time (LS mean difference, 0.7 minutes; 95% CI, 0.13 – 1.24 minutes; P = .02), and PETCO₂ (LS mean difference, 2.0 mm Hg; 95% CI, 1.12 – 2.79 mm Hg; P < .001). No significant difference was found between mavacamten vs placebo in peak RER (LS mean difference, 0.02; 95% CI, -0.003 to 0.040; P = .09). In terms of nonpeak-exercise CPET parameters, compared with placebo, mavacamten was associated with a significant improvement in V_E/VCO₂ slope (LS mean difference, -2.6; 95% CI, -3.58 to -1.52; P < .001). Additionally, a significant increase in ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29 – 0.90 mm Hg; P < .001) and in VO₂/ workload slope (LS mean difference, 0.04; 95% CI, 0.002 to 0.09; P = .04) were observed in mavacamten over placebo. Compared with placebo, mavacamten also improved PETCO₂ at rest (LS mean difference: 0.8 mm Hg; 95% CI, 0.07 – 1.53 mm Hg; P = .03).

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