Efficacy of Ranolazine in Patients With Symptomatic Hypertrophic Cardiomyopathy: The RESTYLE-HCM Randomized, Double-Blind, Placebo-Controlled Study

Background The late sodium current inhibitor ranolazinereverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazineon functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. Methods and Results In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine1000 mg bid (n=40) for 5 months. The primary end point was change in peak VO 2 compared with baseline using cardiopulmonary exercise test. Echocardiographic lateral and septal E/E′ ratio, prohormone brain natriuretic peptidelevels, 24-hour Holter arrhythmic profile, and quality of life were assessed. Ranolazinewas safe and well tolerated. Overall, there was no significant difference in VO 2 peak change at 5 months in the ranolazineversus placebo group (delta 0.15±3.96 versus −0.02±4.25 mL/kg per minute; P =0.832). Ranolazinetreatment was associated with a reduction in 24-hour burden of premature ventricular complexes compared with placebo (>50% reduction versus baseline in 61% versus 31%, respectively; P =0.042). However, changes in prohormone brain natriuretic peptidelevels did not differ in the ranolazinecompared with the placebo group (geometric mean median [interquartile range], −3 pg/mL [−107, 142 pg/mL] versus 78 pg/mL [−71, 242 pg/mL]; P =0.251). Furthermore, E/E′ ratioand quality of life scores showed no significant difference. Conclusions In patients with nonobstructive HCM, ranolazineshowed no overall effect on exercise performance, plasma prohormone brain natriuretic peptidelevels, diastolic function, or quality of life. The drug showed an excellent safety profile and was associated with reduced premature ventricular complex burden. Late sodium current inhibition does not seem to improve functional capacity in HCM. Clinical Trial Registration: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004507-20