麻豆传媒

WASHINGTON – Treatment with investigational mavacamten allowed patients with advanced obstructive hypertrophic cardiomyopathy (oHCM) to avoid septal reduction therapies (SRT), a researcher reported.

In the VALOR-HCM study among 56 patients with documented oHCM who received add-on mavacamten to maximally-tolerated medical therapy, 17.9% met the composite endpoint (decision to move to SRT by week 16 or 2011 American College of Cardiology/American Heart Association guideline eligible at week 16) versus 76.8% who received placebo and maximally-tolerated medical therapy, reported Milind Y. Desai, MD, MBA, of the Cleveland Clinic.

The treatment difference was 58.93% (P<0.0001), he said in a presentation at the American College of Cardiology (ACC) meeting.

"Mavacamten, a targeted inhibitor of cardiac myosin, decreases the number of myosin-actin cross-bridges and reduces excessive contractility characteristic of HCM," the authors stated. In addition, in oHCM, the agent improves left ventricular outflow tract (LVOT), they said. In November 2021, the of mavacamten for the treatment of symptomatic oHCM to April 28, 2022.

"VALOR-HCM builds upon findings of the phase III, and shows mavacamten to be an effective potential treatment option for those with severe, symptomatic oHCM who meet guideline criteria for SRT," Desai said. "The data presented today [at ACC] are clinically meaningful and have demonstrated the potential to impact parameters leading to SRT eligibility."

Mortality rates with SRT (surgical septal myectomy or alcohol ablation) can be <1% in the hands of doctors at centers of excellence, Desai told 麻豆传媒, but overall statistics suggest a general mortality rate in the 5%-6% range. "In some cases where there is less experience in the surgical treatment, the mortality can be as high as 16%," he noted.

Joseph Cleveland Jr., MD, of the University of Colorado Anschutz Medical Campus in Aurora, told 麻豆传媒 that "Septal reduction surgery is a big deal. It requires patients be out on a heart-lung machine while cuts are made in muscles that are blocking heart valves."

He also noted that "unfortunately, I have inherited [SRT] patients from less experienced surgeons," who have either cut out too little muscle, which requires a second operation, or have cut out too much muscle, leading to much more intensive corrective surgery.

The placebo-controlled VALOR-HCM trial enrolled patients (age about 60; about half women; 85% white in both study arms) with documented oHCM, with a septal wall thickness ≥15 mm or ≥13 mm with a family history of HCM. Other enrollment criteria were:

• Severe symptoms (NYHA functional class III/IV or class II with exertional syncope or near syncope) despite maximally-tolerated therapy
• Dynamic LVOT gradient at rest or with provocation (Valsalva maneuver or exercise) of 50 mmHg
• Documented LV ejection fraction (LVEF) 60%
• Referral within past 12 months for SRT
• Actively considering scheduling SRT

The authors reported that nearly half of the patients were on beta blocker monotherapy, >92% were NYHA class ≥III, and that "Patients could elect to proceed to SRT at any time following randomization." For the 20% of patients taking disopyramide, the trial results offer "First evidence of concomitant use with disopyramide," Desai and colleagues pointed out.

They reported the following among patients who underwent SRT or remained guideline eligible for SRT, and among patients who improved by none, ≥1, or ≥2 NYHA class:

• Mavacamten: 18% guideline eligible vs 82% guideline ineligible; none 36%, ≥1 63%, ≥2 27%
• Placebo: 77% vs 23%; 77%, 21%, 2%, respectively

Desai reported that patients treated with mavacamten achieved a 10-point improvement over baseline versus a 3-point decline in placebo patients (P<0.001) in the Kansas City Cardiomyopathy Questionnaire.

As for adverse events (AEs) in the safety population (n=56 mavacamten; n=55 placebo), the authors reported:

• Nonsustained ventricular tachycardia: 0% on mavacamten vs 9.1% on placebo
• Nausea: 7.1% vs 1.8%
• Rash: 7.1% vs 0%

But no patients experienced serious AEs of congestive heart failure, syncope, or sudden cardiac death, and there were no permanent treatment discontinuations due to LVEF ≤30%.

Study limitations included the fact that the primary endpoint was driven by a reduction in guideline eligibility for SRT; the short duration of randomization; and uncertainty as to whether "myosin inhibition can allow patients to avoid SRT during long-term administration," the authors said. Also, long-term safety remains unknown, and the trial population was predominately white, and were treated at high-volume HCM centers with established SRT programs.

Cleveland, who was not involved in the trial, said that if mavacamten is FDA approved, and if a patient is recommended for SRT, he would ask if the patient had tried add-on mavacamten before moving on to invasive therapy.

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