Mavacamten significantly reduced the number of obstructive hypertrophic cardiomyopathy (oHCM) patients meeting guideline criteria for septal reduction therapy (SRT) after 16 weeks, new trial data reveal. The study, published online Monday and in the July 12 issue of the Journal of the American College of Cardiology, noted that SRT, surgical myectomy, or alcohol ablation is recommended for oHCM patients with intractable symptoms despite maximal medical therapy, but is associated with increased morbidity and mortality risk. “Currently, SRT is recommended for oHCM patients with intractable symptoms despite maximal medical therapy,” said the authors, led by Milind Y. Desai, MD, MBA, at the Cleveland Clinic, noting that the procedures are invasive and that in order to achieve optimal results (defined as a postoperative mortality rate <1%), specialized care available only at a few experienced centers is required. “Accordingly, there is an unmet medical need for better non-invasive alternatives to SRT for highly symptomatic oHCM patients who respond sub-optimally to conventional medical therapy,” they said. “The current trial was a Phase 3, double-blind, placebo-controlled, multi-center randomized trial testing whether addition of mavacamten to maximally tolerated medical therapy could allow deferral of SRT in severely symptom.” Study setup The trial enrolled patients treated with maximally tolerated medical therapy who were referred for consideration of SRT (either surgical myectomy or alcohol septal ablation) within 12 months of the screening visit. Desai noted that patients were enrolled only if they met 2011 American College of Cardiology/American Heart Association guideline criteria for SRT and were willing to undergo the procedure. The trial enrolled 112 highly symptomatic oHCM patients (mean age 60 years, 51% men, 93% ≥ New York Heart Association [NYHA] functional class III) between July 2020 and October 2021 at 19 sites across the United States. Patients were randomized 1:1 to mavacamten 5 mg/day or matching placebo taken once daily by mouth. The primary endpoint was the composite of eligibility for SRT according to the 2011 guidelines or a patient decision to proceed with SRT after 16 weeks of treatment. Key findings The research team reported that compared with placebo, patients randomized to mavacamten were significantly less likely to proceed with SRT or meet guideline eligibility criteria for SRT after 16 weeks of treatment. After 16 weeks, 43 of 56 placebo patients (76.8%) and 10 of 56 mavacamten patients (17.9%) met guideline criteria or underwent SRT (difference: 58.9%; 95% confidence interval [CI]: 44.0%-73.9%; P < 0.001). This difference was driven entirely by guideline eligibility for SRT rather than patient decision to undergo the procedure, the team noted. Furthermore, hierarchical testing of secondary efficacy endpoints showed significant improvement (P < 0.001) in patients randomized to mavacamten including a 39 mm Hg greater reduction in postexercise LVOT gradient, a larger (41%) proportion of patients with ≥1 class improvement in NYHA functional classification (95% CI: 24.5% to 57.7%), a 9.4-point higher Kansas City Cardiomyopathy Questionnaire Clinical Score Summary (95% CI: 4.9-14.0 points), and geometric mean ratios for change in N-terminal pro–B-type natriuretic peptide 0.33 (95% CI: 0.26-0.42), and cardiac troponin I 0.53 (95% CI: 0.41-0.70). A benefit for HCM practice Writing in an accompanying editorial, Steve R. Ommen, MD, from the Mayo Clinic, Rochester, Minnesota, noted that the management of symptomatic obstructive hypertrophic cardiomyopathy (HCM) “has fascinated, frustrated, and fueled cardiologists for 6 decades.” “From the HCM provider community perspective, having another tool should be of benefit; however, the magnitude will only be realized once patients and providers outside of the trial environment start using it in clinical practice,” he noted, adding that mavacamten will be of benefit to HCM practice, specifically for patients who fail the first-line therapies such as beta-blockers and/or L-type calcium-channel blockers. “These patients should then be presented with a comprehensive discussion, including risks, benefits, and logistics of all advanced therapeutic options (eg, mavacamten, disopyramide, septal ablation, septal myectomy),” said the editorialist, noting that while some patients will use mavacamten as a destination therapy, “some may decide that they want definitive anatomic relief via septal reduction therapy (with the potential to obviate the need for lifelong medication), and some may use mavacamten as a bridge to septal reduction when other health or life considerations necessitate a delay in proceeding directly to the procedure.” “Yes, mavacamten will have an important role for patients with HCM, yet there is also no doubt that many patients will continue to benefit from old school first-line drugs, and that many will also need and want anatomic, rather than functional, relief of their symptomatic obstructive HCM,” he said. Sources: Desai MY, Owens A, Geske JB, et al. Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. J Am Coll Cardiol 2022;80:95-108. Ommen SR. Cardiac Myosin Inhibitors for Obstructive Hypertrophic Cardiomyopathy: Where Are We on the Hype Cycle? J Am Coll Cardiol 2022;80:109-110. Image Credit: molekuul.be – stock.adobe.com