Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial

Literature - Wheeler MT, Olivotto I, Elliott PM, et al. - JAMA Cardiol. 2023 Jan 18;e225099 [Online ahead of print]. doi: 10.1001/jamacardio.2022.5099

Introduction and methods

Background

Previously, the EXPLORER-HCM study investigated the efficacy and safety of the cardiac myosin inhibitor mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). This RCT showed that treatment with mavacamten reduced symptoms and improved the peak oxygen uptake (pVO2) compared with placebo [1]. However, mavacamten’s effects on additional maximal and submaximal parameters of exercise performance in this population remain unclear.

Aim of the study

The study aim was to investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET) in patients with symptomatic obstructive HCM and thereby expand knowledge of this disease.

Methods

This was a prespecified exploratory analysis of the EXPLORER-HCM (Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy) trial. In this multinational, double-blind, placebo-controlled, phase 3 RCT, 251 patients with symptomatic obstructive HCM were randomized to mavacamten (starting dose of 5 mg) or matching placebo for 30 weeks. CPET was performed using a standardized treadmill or bicycle ergometer test protocol at baseline and week 30.

Outcomes

In addition to pVO2 (which was a component of the composite primary endpoint and a prespecified secondary efficacy endpoint), the following prespecified exploratory CV and performance parameters were assessed: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power (pVO2 × peak systolic blood pressure), ventilatory power (peak systolic blood pressure/VE/VCO2 slope), peak metabolic equivalents (METs), partial pressure of end-tidal CO2 (PETCO2), peak exercise time, ventilatory threshold, and VO2/workload slope.

Main results

• Mavacamten improved the following peak-exercise CPET parameters compared with placebo at week 30: peak VE/VCO2 ratio (least-squares (LS) mean difference: –2.2; 95%CI: –3.05 to –1.26; P<0.001), peak METs (LS mean difference: 0.4; 95%CI: 0.17–0.60; P<0.001), peak circulatory power (LS mean difference: 372.9 mL/kg/min × mmHg; 95%CI: 153.12–592.61; P=0.001), peak PETCO2 (LS mean difference: 2.0 mmHg; 95%CI: 1.12–2.79; P<0.001), and peak exercise time (LS mean difference: 0.7 min; 95%CI: 0.13–1.24; P=0.02).
• There was no significant difference in peak RER between the mavacamten and placebo groups.
• With regard to the nonpeak-exercise CPET parameters, treatment with mavacamten versus placebo resulted in improvements in VE/VCO2 slope (LS mean difference: –2.6; 95%CI: –3.58 to –1.52; P<0.001), ventilatory power (LS mean difference: 0.6 mmHg; 95%CI: 0.29–0.90; P<0.001), PETCO2 at rest (LS mean difference: 0.8 mmHg; 95%CI: 0.07–1.53; P=0.03), and VO2/workload slope (LS mean difference: 0.04; 95%CI: 0.002–0.086; P=0.04).
• A numerical, albeit nonsignificant, trend toward improvement favoring mavacamten over placebo was observed for ventilatory threshold (LS mean difference: 0.6 mL/kg/min; 95%CI: −0.03 to 1.17 mL/kg/min; P=0.06).
• In additional analyses, a negative correlation was observed between change in pVO2 and change in log2 NT-proBNP levels at week 30 in the mavacamten group (Pearson correlation coefficient: −0.30; P=0.002) but not the placebo group (Pearson correlation coefficient: 0.064; P=0.48).
• In the mavacamten group, there was also a positive correlation between improvement in VE/VCO2 slope and reduction in NT-proBNP levels (Pearson correlation coefficient: 0.27; P=0.003). However, there was no significant association between VE/VCO2 slope and patient-reported symptoms.

Conclusion

References

Find this article online at JAMA Cardiol.