Mavacamten improves functional status beyond peak O2 in patients with obstructive HCM
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Mavacamten improved a range of cardiopulmonary exercise testing parameters beyond peak oxygen uptake in patients with obstructive hypertrophic cardiomyopathy in the EXPLORER-HCM randomized trial, researchers reported.
A secondary analysis of the EXPLORER-HCM trial of mavacamten (Camzyos, Bristol Myers Squibb) — a first-in-class cardiac myosin inhibitor — compared with placebo for the treatment of obstructive hypertrophic cardiomyopathy (HCM) was published in JAMA Cardiology.
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The EXPLORER-HCM trial
EXPLORER-HCM was a randomized, double-blind, placebo-controlled trial that enrolled 251 patients with HCM and left ventricular outflow tract gradient of 50 mm Hg or greater and NYHA class II to III symptoms (mean age, 58 years; 59% men). The primary endpoint was a 1.5 mL/kg per minute or greater increase in peak oxygen uptake (VO2) and at least one NYHA class reduction, or a 3 mL/kg per minute or greater peak VO2 increase without worsening of NYHA class.
As Healio previously reported, in the main results of EXPLORER-HCM, mavacamten improved symptoms, quality of life and functional status compared with placebo in patients with symptomatic obstructive HCM.
In April 2022, the FDA approved mavacamten for the treatment of symptomatic, obstructive HCM, making it the first cardiac myosin inhibitor permitted for use in the U.S.
Secondary analysis of EXPLORER-HCM
For the present analysis of EXPLORER-HCM, Matthew T. Wheeler, MD, PhD, assistant professor of medicine (cardiovascular medicine) at Stanford University School of Medicine, and colleagues evaluated the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30 of mavacamten or placebo.
Parameters of interest included carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio, peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents, peak exercise time, partial pressure of end-tidal CO2 and VO2/workload slope.
Among participants assigned to mavacamten, the researchers observed significant improvements compared with placebo in the following cardiopulmonary exercise testing parameters:
- peak VE/VCO2 ratio (least squares [LS] mean difference, –2.2; 95% CI, –3.05 to –1.26; P < .001);
- peak metabolic equivalents (LS mean difference, 0.4; 95% CI, 0.17-0.6; P < .001);
- peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61; P = .001);
- peak partial pressure of end-tidal CO2 (LS mean difference, 2 mm Hg; 95% CI, 1.12-2.79; P < .001); and
- peak exercise time (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02).
Researchers also observed improvement in nonpeak-exercise cardiopulmonary exercise testing parameters in the mavacamten arm, such as VE/VCO2 slope (LS mean difference, –2.6; 95% CI, –3.58 to –1.52; P < .001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.9; P < .001), compared with placebo.
“A number of clinically meaningful cardiopulmonary exercising testing parameters consistently improved with mavacamten, and these benefits correlated with improvement in a biomarker of cardiac wall stress,” the researchers wrote. “Nevertheless, it seems that symptomatic improvement indicated by the change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score is more striking than that seen with cardiopulmonary exercising testing, suggesting that the pathophysiology of symptoms is not wholly captured by this testing. Thus, the benefits of mavacamten seem to extend beyond improvement in cardiopulmonary exercising testing parameters and fully understanding this represents an unmet need, and may help unravel further the pathophysiology of this complex disease.”
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