Background: Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) lacks approved therapies. The ODYSSEY-HCM trial (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy; NCT05582395), the largest to date in HCM patients, evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status). Objectives: This exploratory analysis of the phase 3, randomized, placebo-controlled trial evaluated echocardiographic changes in nHCM patients from baseline to week 48. Methods: Symptomatic nHCM patients were randomized to placebo or mavacamten (5 mg/d, titrated between 1 and 15 mg based on left ventricular ejection fraction [LVEF]). Echocardiographic assessments of LV systolic/diastolic function and left atrial (LA) function were performed at baseline and week 48. Results: Among 580 randomized patients (mean age 56 ± 15 years, 45.9% women), baseline measures included LVEF (65.8 ± 4%), maximal LV wall thickness (20.8 ± 4 mm), LV mass index (122.3 ± 31 g/m2), average E/e′ (13.3 ± 6), and LV-global longitudinal strain (−13.2 ± 4%). LA parameters included volume index (43.5 ± 16 mL/m2), reservoir strain (19.1 ± 9%), and conduit strain (−11.6 ± 6%). At week 48, there was significant placebo-corrected treatment difference with patients on mavacamten demonstrating significant reduction in maximal LV wall thickness (−2.1 mm [95% CI: −2.5 to −1.7 mm]), LV mass index (−3.8 g/m2 [95% CI: −7.1 to −0.5 g/m2]), and E/e′ (−1.3 [95% CI: −2.0 to −0.7]), with a −5.3% [95% CI: −5.9% to −4.1%]; P < 0.01) reduction in LVEF. A reduction in LVEF <50% occurred in 62 patients (21.5%) in the mavacamten arm vs 5 (1.7%) in the placebo arm and recovered following drug interruption. Patients in the mavacamten group maintaining LVEF ≥50% throughout the study (n = 212) demonstrated an improvement in LV-global longitudinal strain at week 48 (−0.4% [95% CI: −0.8% to −0.05%]; P < 0.05). LA functional parameters including contractile (−1.1% [95% CI: −1.8% to −0.4%]) and conduit (−1.4% [95% CI: −0.6% to −2.3%]) strain also improved significantly at week 48 (P < 0.05), whereas LA volume was significantly reduced in patients without atrial fibrillation (−2.6 mL/m2 [95% CI: −4.7 to −1.11 mL/m2]; P = 0.009). Conclusions: Symptomatic nHCM patients treated with mavacamten demonstrated directional improvements in markers of LV diastolic and LA function, modest regression in LV hypertrophy–related parameters, but 1 in 5 demonstrated an LVEF <50%, which reversed following therapy interruption.
Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial / Desai, Milind Y; Okushi, Yuichiro; Jadam, Shada; Olivotto, Iacopo; Owens, Anjali; Nissen, Steven E; Popovic, Zoran B; Garcia-Pavia, Pablo; Lopes, Renato D; Elliott, Perry M; Fernandes, Fabio; Geske, Jeffrey B; Maier, Lars; Wolski, Kathy; Wang, Qiuqing; Jaber, Wael; Gong, Zhiqun; Florea, Victoria; Fronheiser, Matthew; Leva, Arlene; Aronson, Ron; Abraham, Theodore. - In: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. - ISSN 1558-3597. - STAMPA. - 86:(2025), pp. 2434-2449. [10.1016/j.jacc.2025.08.019]
Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial
Olivotto, Iacopo;
2025
Abstract
Background: Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) lacks approved therapies. The ODYSSEY-HCM trial (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy; NCT05582395), the largest to date in HCM patients, evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status). Objectives: This exploratory analysis of the phase 3, randomized, placebo-controlled trial evaluated echocardiographic changes in nHCM patients from baseline to week 48. Methods: Symptomatic nHCM patients were randomized to placebo or mavacamten (5 mg/d, titrated between 1 and 15 mg based on left ventricular ejection fraction [LVEF]). Echocardiographic assessments of LV systolic/diastolic function and left atrial (LA) function were performed at baseline and week 48. Results: Among 580 randomized patients (mean age 56 ± 15 years, 45.9% women), baseline measures included LVEF (65.8 ± 4%), maximal LV wall thickness (20.8 ± 4 mm), LV mass index (122.3 ± 31 g/m2), average E/e′ (13.3 ± 6), and LV-global longitudinal strain (−13.2 ± 4%). LA parameters included volume index (43.5 ± 16 mL/m2), reservoir strain (19.1 ± 9%), and conduit strain (−11.6 ± 6%). At week 48, there was significant placebo-corrected treatment difference with patients on mavacamten demonstrating significant reduction in maximal LV wall thickness (−2.1 mm [95% CI: −2.5 to −1.7 mm]), LV mass index (−3.8 g/m2 [95% CI: −7.1 to −0.5 g/m2]), and E/e′ (−1.3 [95% CI: −2.0 to −0.7]), with a −5.3% [95% CI: −5.9% to −4.1%]; P < 0.01) reduction in LVEF. A reduction in LVEF <50% occurred in 62 patients (21.5%) in the mavacamten arm vs 5 (1.7%) in the placebo arm and recovered following drug interruption. Patients in the mavacamten group maintaining LVEF ≥50% throughout the study (n = 212) demonstrated an improvement in LV-global longitudinal strain at week 48 (−0.4% [95% CI: −0.8% to −0.05%]; P < 0.05). LA functional parameters including contractile (−1.1% [95% CI: −1.8% to −0.4%]) and conduit (−1.4% [95% CI: −0.6% to −2.3%]) strain also improved significantly at week 48 (P < 0.05), whereas LA volume was significantly reduced in patients without atrial fibrillation (−2.6 mL/m2 [95% CI: −4.7 to −1.11 mL/m2]; P = 0.009). Conclusions: Symptomatic nHCM patients treated with mavacamten demonstrated directional improvements in markers of LV diastolic and LA function, modest regression in LV hypertrophy–related parameters, but 1 in 5 demonstrated an LVEF <50%, which reversed following therapy interruption.
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