Maron, Martin SMasri, AhmadChoudhury, LubnaOlivotto, IacopoSaberi, SaraWang, AndrewGarcia-Pavia, PabloLakdawala, Neal KNagueh, Sherif FRader, FlorianTower-Rader, AlbreeTurer, Aslan TCoats, CarolineFifer, Michael AOwens, AnjaliSolomon, Scott DWatkins, HughBarriales-Villa, RobertoKramer, Christopher MWong, Timothy CPaige, Sharon LHeitner, Stephen BKupfer, StuartMalik, Fady IMeng, LisaWohltman, AmyAbraham, Theodore2023-10-162023-10-162023-01-03J Am Coll Cardiol. 2023 Jan 3;81(1):34-45.http://hdl.handle.net/20.500.12105/16554BACKGROUND Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Cardiomyopathy, HypertrophicHeart FailureVentricular Outflow ObstructionHumansAttribution-NonCommercial-NoDerivatives 4.0 Internacional365996088113410.1016/j.jacc.2022.10.0201558-3597Journal of the American College of Cardiologyopen access