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 enrolled patients, there were significant improvements with mavacamten versus placebo in cardiopulmonary exercise testing (CPET) parameters, including peak VE/VCO2 ratio, peak metabolic equivalents (METs), peak circulatory power , and peak end-tidal partial pressure of carbon dioxide (PETCO2).

2. Mavacamten improved maximal exercise time compared to placebo by a mean difference of 0.7 minutes.

Level of evidence rating:1 (excellent)

Study overview: 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 affect quality of life. Mavacamten is a cardiac myosin inhibitor that was found to improve oxygen uptake in patients with symptomatic HCM in the EXPLORER-HCM trial. The aim of this study was to investigate the effect of mavacamtene 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). Main results included carbon dioxide output (VCO₂), minute ventilation (V_E), top (V_E/VCO₂) ratio, ventilation efficiency (V_E/VCO₂ slope), PETCO₂VO₂/workload slope and various peak CPET outcomes including respiratory exchange ratio (RER), circulatory power, ventilatory force and threshold, METs and exercise time. Compared with placebo, mavacamten showed significant improvements in the following peak exercise CPET parameters: peak V_E/VCO₂ ratio, peak METs, peak circulatory power and peak PETCO₂. Mavacamten improved maximal exercise time by 0.7 minutes compared with placebo. The use of a single point at which CPET was measured is a limitation of this study, due to the variable nature of HCM symptom status. The main strength of this study was the wide range of CPET parameters included, which represent reproducible clinical surrogates of functional capacity.

Click to read the study in JAMA Cardiology

Relevant reading: Mavacamten for the 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 age SD, 58.5 (11.9), 59% male) were randomized to receive either mavacamten (n = 123) or placebo (n = 128). At baseline, the majority of patients (183 of 251) presented with NIHA class II symptoms. In both intervention groups, 45% of patients performed CPET using an exercise bike and 55% using a treadmill. Analysis of peak exercise CPET parameters revealed that, compared with placebo, mavacamten improved peak V_E/VCO₂ ratio (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 power circulation (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 = 0.02), and PETCO₂ (LS mean difference, 2.0 mm Hg; 95% CI, 1.12 – 2.79 mm Hg; P < 0.001). No significant difference was found between mavacamten versus placebo in peak RER (LS mean difference, 0.02; 95% CI, -0.003 to 0.040; P = .09). Regarding non-peak 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). In addition, significant increases in ventilatory capacity (LS mean difference, 0.6 mm Hg; 95% CI, 0.29 – 0.90 mm Hg; P < 0.001) and VO₂/load slope (LS mean difference, 0.04; 95% CI, 0.002 to 0.09; P = .04) were observed with mavacamten versus 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 = 0.03).

Picture: PD

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