Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial
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Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years (NCT01912534). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Medicine |
| Vol/bind | 27 |
| Sider (fra-til) | 1818–1824 |
| ISSN | 1078-8956 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
We are indebted to the families and individuals who partnered with us in conducing this trial. This study was funded by the National Heart, Lung, and Blood Institute (P50HL112349 to C.Y.H.). The views expressed in this manuscript are those of the authors and do not reflect official positions of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Study medication (blinded valsartan and matching placebo) was provided by Novartis. Novartis was not involved in the design or conduct of the study; data collection, data management, data analysis or data interpretation; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.
Funding Information:
Study oversight. VANISH was funded by the National Institutes of Health/ National Heart, Lung, and Blood Institute and is registered at ClinicalTrials.gov (NCT01912534). An executive committee (E.B., C.Y.H., C.A.M., J.J.V.M., E.J.O. and S.D.S.) designed and oversaw the conduct of the trial and performed data analysis. Study medication was donated by Novartis, which played no role in the design, conduct or analysis of the trial. The trial was conducted and reported in accordance with the protocol and the statistical analysis plan, both of which are available in the Supplementary Note. The trial was approved by the ethics committee at each center, and all participants provided written informed consent and youth assent as appropriate. The safety of patients in the trial was overseen by an independent data and safety monitoring committee. An independent clinical events committee, unaware of treatment group assignments, adjudicated predefined clinical events.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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