Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials
- 1Institute for Cardiomyopathies Heidelberg (ICH.), University Hospital Heidelberg, Heidelberg Faculty of Medicine, Heidelberg University
Abstract
BackgroundCardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic non-obstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM.
MethodsWe systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trials primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes.
ResultsThree RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQCSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001).
ConclusionsIn this meta-analysis of randomized trials in symptomatic nHCM, CMIs pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.
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BibTeX
@misc{koelemen2026cardiac,
title = {{Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials}},
author = {J. Koelemen and D. Koeckerling and S. Rosskopf and C. Reich and A. Amr and E. Kayvanpour and N. Frey and F. Sedaghat-Hamedani and B. Meder},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362195},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362195v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cardiac Myosin Inhibitors in Adults with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials
AU - J. Koelemen
AU - D. Koeckerling
AU - S. Rosskopf
AU - C. Reich
AU - A. Amr
AU - E. Kayvanpour
AU - N. Frey
AU - F. Sedaghat-Hamedani
AU - B. Meder
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362195
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362195v1
AB - BackgroundCardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic non-obstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM. MethodsWe systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trials primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes. ResultsThree RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQCSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001). ConclusionsIn this meta-analysis of randomized trials in symptomatic nHCM, CMIs pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.
ER -