medwireNews: Long-term treatment with mavacamten reduces the need for septal reduction therapy (SRT) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) but may be associated with a risk for left ventricular (LV) systolic dysfunction, VALOR-HCM study data show.
“This safety signal of potential left ventricular dysfunction highlights the need for conservative drug titration and continued, vigilant echocardiographic surveillance in patients treated with cardiac myosin inhibitors, as specified by the FDA Risk Evaluation and Mitigation Strategy program,” write Sharlene Day (University of Pennsylvania, Philadelphia, USA) and co-authors of an editorial that accompanies the study in JAMA Cardiology.
They add: “Maintaining a cautious approach will be important as the use of cardiac myosin inhibitors becomes more widespread beyond multidisciplinary HCM centers.”
The primary data from the VALOR-HCM trial showed that adding mavacamten to maximally tolerated medical therapy resulted in improvements that allowed patients with severely symptomatic obstructive HCM (New York Heart Association [NYHA] class III/IV) referred for SRT to avoid the procedure for up to 32 weeks.
For the current analysis, Milind Desai (Cleveland Clinic, Ohio, USA) and colleagues extended the observation period to 56 weeks for 56 patients who were randomly assigned to receive mavacamten 5 mg/day at baseline and 52 who were initially given placebo and then crossed over to mavacamten at week 16.
They report that, at week 56, 8.9% of patients in the initial mavacamten group met the criteria for treatment failure, which comprised a composite outcome of undergoing SRT (n=3), remaining guideline eligible for SRT (n=1), or having an unevaluable SRT status (n=1).
In addition, 19.2% of patients from the placebo crossover group met the treatment failure criteria, including three who underwent SRT, four who remained eligible, and three who were unevaluable at 56 weeks.
Overall, 89% of the 108 patients were still receiving mavacamten at week 56.
In terms of cardiac function parameters, 93% of patients in the original mavacamten group and 73% of those in the placebo crossover group demonstrated an NYHA improvement of at least one class, with 44% and 35%, respectively, improving by two classes or more by week 56.
Resting left ventricular outflow tract (LVOT) gradient fell by an average of 34.0 mmHg from a baseline of 46.6 mmHg in the mavacamten arm and by an average of 33.2 mmHg from 51.2 mmHg in the placebo-to-mavacamten arm.
The corresponding average reductions in Valsalva LVOT gradients were 45.6 mmHg and 54.6 mmHg from baseline levels of 79.3 mmHg and 75.3 mmHg.
Of note, “[t]he reduction in SRT eligibility, improvement in NYHA class, and LVOT gradients were similar in both sexes,” Desai et al remark.
With regards to long-term safety outcomes, the researchers found that, overall, 12 (11.1%) patients developed a left ventricular ejection fraction (LVEF) of less than 50%, including seven (12.5%) in the original mavacamten group and five (9.6%) in the placebo crossover group.
Nine of these 12 patients temporarily interrupted mavacamten treatment and resumed at a lower dose, with LVEF rebounding to above 50%. In the other three patients, mavacamten was permanently discontinued, with LVEF falling to 30% or lower in two patients, one of whom died shortly after discontinuation.
Desai et al conclude: “Although mavacamten must be used carefully, the ability to defer SRT in most patients for more than 1 year indicates a favorable balance of benefit to risk given the invasive nature of alternative treatments.”
However, they add that “understanding patient preferences regarding the choice of SRT vs mavacamten will be important, especially with more mainstream use of this drug after regulatory approval.”
The study was also presented at the ESC Congress 2023 in Amsterdam, the Netherlands,
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JAMA Cardiol 2023; doi:10.1001/jamacardio.2023.3342
JAMA Cardiol 2023; doi:10.1001/jamacardio.2023.3357
ESC Congress 2023; Amsterdam, the Netherlands: 25–28 August