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Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial

Abstract

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.

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Fig. 1
Fig. 2: Forest plots of pre-specified subgroups and secondary outcomes.
Fig. 3: Longitudinal changes in key components of the primary composite outcome.

Data availability

The final study protocol and statistical analysis plan are provided as Supplementary Note. The corresponding author will consider requests for collaborative study and analysis of de-identified individual participant data to further understanding of the trial results or genetic cardiomyopathies. Interested researchers should submit proposals and analytic plans to the corresponding author, and approval will be granted by consensus of the executive committee. A data use agreement will be issued and will be compliant with relevant patient confidentiality and privacy regulations.

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Acknowledgements

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.

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Contributions

C.Y.H. was the principal investigator. E.J.O. performed statistical analyses. E.B., C.Y.H., C.A.M., J.J.V.M., E.J.O. and S.D.S. were on the executive committee, which designed and oversaw the conduct of the trial and data analysis. Other authors were site investigators and core laboratory directors. The first draft of the manuscript was prepared by C.Y.H., who had unrestricted access to the data. Drafts were reviewed and edited by all authors. All authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Corresponding author

Correspondence to Carolyn Y. Ho.

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The authors declare no competing interests.

Additional information

Peer review information Nature Medicine thanks John Atherton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Longitudinal changes in blood pressure.

Measures at baseline, Year 1, and Year 2 (end of study) for systolic (a) and diastolic (b) blood pressure are shown for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue). Values are presented as mean and standard deviation.

Extended Data Fig. 2 Longitudinal changes in serum creatinine and potassium levels.

Mean values and standard deviation are shown for serum creatinine (a) and potassium (b) levels for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue).

Supplementary information

Supplementary Information

Supplementary Tables 1–10, Statistical Analysis Plan and Trial Protocol

Reporting Summary

Supplementary Data 1

Trial protocol and statistical analysis plan

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Ho, C.Y., Day, S.M., Axelsson, A. et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial. Nat Med 27, 1818–1824 (2021). https://doi.org/10.1038/s41591-021-01505-4

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