TY - JOUR
T1 - Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy
AU - Maron, Martin S.
AU - Masri, Ahmad
AU - Nassif, Michael E
AU - Barriales-Villa, Roberto
AU - Arad, Michael
AU - Cardim, Nuno
AU - Choudhury, Lubna
AU - Claggett, Brian
AU - Coats, Caroline J
AU - Düngen, Hans-Dirk
AU - Garcia-Pavia, Pablo
AU - Hagège, Albert A
AU - Januzzi, James L
AU - Lee, Matthew M.Y.
AU - Lewis, Gregory D
AU - Ma, Chang-Sheng
AU - Michels, Michelle
AU - Olivotto, Iacopo
AU - Oreziak, Artur
AU - Owens, Anjali T
AU - Spertus, John A
AU - Solomon, Scott D
AU - Tfelt-Hansen, Jacob
AU - van Sinttruije, Marion
AU - Veselka, Josef
AU - Watkins, Hugh
AU - Jacoby, Daniel L
AU - Heitner, Stephen B
AU - Kupfer, Stuart
AU - Malik, Fady I
AU - Meng, Lisa
AU - Wohltman, Amy
AU - Abraham, Theodore P
AU - SEQUOIA-HCM Investigators
N1 - Copyright © 2024 Massachusetts Medical Society.
PY - 2024
Y1 - 2024
N2 - BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).
AB - BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).
KW - Humans
KW - Double-Blind Method
KW - Male
KW - Middle Aged
KW - Female
KW - Cardiomyopathy, Hypertrophic/drug therapy
KW - Aged
KW - Exercise Test
KW - Oxygen Consumption/drug effects
KW - Ventricular Outflow Obstruction/drug therapy
KW - Adult
KW - Cardiac Myosins/antagonists & inhibitors
KW - Exercise Tolerance/drug effects
KW - Valsalva Maneuver
KW - Benzylamines
KW - Uracil/analogs & derivatives
U2 - 10.1056/NEJMoa2401424
DO - 10.1056/NEJMoa2401424
M3 - Journal article
C2 - 38739079
VL - 390
SP - 1849
EP - 1861
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 20
ER -