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Novel mavacamten had a big impact on quality of life in obstructive hypertrophic cardiomyopathy, according to a secondary analysis of the EXPLORER-HCM trial.

The cardiac myosin inhibitor improved Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score by 9.1 points more than that seen with placebo over 30 weeks (mean 14.9 vs 5.4 points, P<0.001 for difference). A 5-point change in score is considered clinically significant.

Similar advantages were seen across all KCCQ subscores, reported John Spertus, MD, MPH, of the University of Missouri-Kansas City and St. Luke's Mid America Heart Institute, at the virtual American College of Cardiology meeting and simultaneously in The Lancet.

A full 36% of patients gained 20 or more points on their KCCQ summary score, compared with 15% on placebo. The number needed to treat was just five for that large quality-of-life milestone.

"To me, the data from the KCCQ is much more impressive than the primary endpoint," Spertus told 名媛直播.

Main results from EXPLORER-HCM, reported last year at the European Society of Cardiology meeting, showed an increase in peak oxygen consumption and reduction in New York Heart Association class.

While that endpoint shows patients objectively were able to do more, KCCQ is a more direct measure of how patients feel, said Spertus, while acknowledging his bias as creator of the questionnaire. "The number-one treatment priority for patients with hypertrophic obstructive cardiomyopathy is to improve their symptoms, function, and quality of life," he noted.

"The other side of the coin is that 60% of patients had no large effect, so these would be patients who would continue to have symptoms," commented Mark Sherrid, MD, director of the hypertrophic cardiomyopathy program at NYU Langone Health in New York City.

There isn't much comparable data for other obstructive hypertrophic cardiomyopathy treatments, but the quality-of-life gains seen with mavacamten compare favorably with most treatments for heart failure, he added.

"We've primarily been using beta-blockers, disopyramide, verapamil -- things that weren't really necessarily designed for [obstructive hypertrophic cardiomyopathy] but that are negative inotropes that might decrease the force of contractility and decrease the dynamic outflow obstruction," said Spertus. "If it doesn't work, then we have to think about surgery or alcohol septal ablation. Those are very irreversible and major interventions that can be very effective but also have a lot of morbidity."

Such a stepped management strategy likely would work with mavacamten, Sherrid agreed, but more study is needed to determine how these agents stack up against each other. "There's a lot more to know about these drugs going forward and a lot of room for tailoring specific drugs to specific patients," he added.

For example, a patient with arrhythmia and obstructive HCM might do better with a drug with an antiarrythmic component, he noted.

The phase III trial included 251 patients with symptomatic obstructive hypertrophic cardiomyopathy and a left ventricular outflow tract gradient of at least 50 mm Hg at baseline. Among these patients randomized to mavacamten or placebo, 194 had KCCQ data for the analysis.

Other limitations included the relatively short follow-up and the severe spectrum of disease in the patients studied, so whether the drug would be as efficacious in less severely ill patients requires further study, Spertus said.

And it's not yet clear what is driving the symptomatic benefits -- diastolic function, changes in left ventricular outflow tract gradient, or some other pathway, he noted. While it wouldn't influence clinical decisions, it could be important for coming up with new therapeutics in obstructive hypertrophic cardiomyopathy, he suggested.

The FDA is reviewing the trial data for of mavacamten, with a decision expected by the end of January 2022.

If approved, "mavacamten will be another drug that we'll have to convince patients to continue taking even after benefit is seen initially... but maybe it'll be easier than statins since it seems to impact quality of life!," speculated session chair Geoffrey Barnes, MD, of the University of Michigan in Ann Arbor.

Seven patients in the mavacamten group had a reduction in ejection fraction to below 50% and had dose reduction that reversed it, but these patients had the same quality-of-life benefits as others in the treatment group. Overall, quality-of-life improvements faded with cessation of treatment.

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