Exploring New and Old Therapies for Obstructive Hypertrophic Cardiomyopathy
Authors: Martin S. Maron, Steve R. Ommen
Journal: Circulation (2021)

The application of contemporary treatment strategies to hypertrophic cardiomyopathy (HCM) has transformed this common genetic heart disease from one of grim progression to one now compatible with normal longevity and excellent quality of life.Mavacamten, a myosin inhibitor, represents the first pharmacological strategy advanced for HCM in nearly 35 years, culminating recently with publication of a phase 3 randomized clinical trial (EXPLORER-HCM [Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy]). 1 Given the enthusiasm surrounding this novel drug, even before Food and Drug Administration approval, it is timely to provide perspective on the potential role for mavacamten, particularly compared with the current established therapies for patients with obstructive HCM.Left ventricular (LV) outflow tract obstruction results when the hypertrophied ventricular septum alters blood flow and creates abnormal hemodynamic forces that push the often-elongated mitral valve forward toward the septum, impeding flow and producing high LV systolic pressures.The severity of outflow obstruction is also highly dependent on preload, afterload, and contractility.By decreasing the number of available actin-myosin cross-bridges, mavacamten reduces myocardial contractility and can decrease mitral valve-septal contact and outflow tract gradients.Mavacamten did indeed demonstrate this capability by lowering gradients in many patients in EXPLORER-HCM. 1 The potential clinical benefit attributed to this hemodynamic effect was assessed by a combined primary end point of subjective symptomatic improvement (New York Heart Association class) and functional capacity (peak oxygen consumption). 1Over 30 weeks, 37% of the patients on mavacamten achieved the primary end point (compared with 17% on placebo), with 27% of patients demonstrating both relief of symptoms and gradient (to <30 mm Hg). 1 To fully comprehend the potential role of mavacamten, there are several important aspects of the EXPLORER-HCM study worth noting.First, the study cohort comprised predominantly New York Heart Association class II patients (72%) and a minority of class III patients, similar to previous drug studies in HCM.In contrast, studies of invasive septal reduction therapy (SRT) with myectomy and alternatively alcohol septal ablation comprised patients in whom >90% were severely limited (in class III/IV). 2,3Second, two-thirds of mavacamten-treated patients did not achieve the study end point, and 50% of patients were still limited by class II/III symptoms. 1Likewise, improvements in functional capacity were modest, with a similar increase in peak oxygen consumption to that achieved with only a structured exercise program (RESET-HCM study [Randomized Exploratory Study of Exercise Training in Hypertrophic Cardiomyopathy]).In this regard, it is important to note that EXPLORER-HCM did not directly compare mavacamten with time-honored therapies in HCM known to lower gradient and improve symptoms.Historical data show that myectomy and alcohol septal ablation provide more complete reduction in outflow tract gradients and symptoms Exploring New and Old Therapies for Obstructive Hypertrophic CardiomyopathyMavacamten in Perspective