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

Nature Medicine volume 27, pages 1818–1824 (2021)Cite this article

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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.

Author information

Author notes

  1. Sharlene M. Day

    Present address: Division of Cardiovascular Medicine Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

  2. Jason R. Becker

    Present address: Division of Cardiology, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA

Authors and Affiliations

  1. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Carolyn Y. Ho, Christine E. Seidman, Neal K. Lakdawala, Allison L. Cirino, Akshay S. Desai, Calum A. MacRae, Scott D. Solomon, E. John Orav & Eugene Braunwald

  2. University of Michigan, Ann Arbor, MI, USA

    Sharlene M. Day & Mark W. Russell

  3. Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Anna Axelsson & Henning Bundgaard

  4. Cleveland Clinic Foundation, Cleveland, OH, USA

    Kenneth Zahka & Harry M. Lever

  5. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo Medical School, Sao Paulo, Brazil

    Alexandre C. Pereira

  6. Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA

    Steven D. Colan & Renee Margossian

  7. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anne M. Murphy

  8. Washington University School of Medicine, St. Louis, MO, USA

    Charles Canter & Richard G. Bach

  9. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Matthew T. Wheeler

  10. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Joseph W. Rossano & Kimberly Y. Lin

  11. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Henning Bundgaard

  12. Toronto Hospital for Sick Children, Toronto, ON, Canada

    Lee Benson

  13. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Luisa Mestroni & Matthew R. G. Taylor

  14. Departments of Medicine and Radiology, University of Chicago, Chicago, IL, USA

    Amit R. Patel

  15. Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Ivan Wilmot

  16. Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Philip Thrush & Elfriede Pahl

  17. MedStar Heart and Vascular Institute, Washington, USA

    Jose D. Vargas

  18. Vanderbilt University Medical Center, Nashville, TN, USA

    Jonathan H. Soslow & Jason R. Becker

  19. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Christine E. Seidman

  20. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Kristin M. Burns

  21. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    John J. V. McMurray

  22. Division of Cardiovascular Medicine Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Anjali T. Owens

  23. Heart Institute, University of Sao Paulo Medical School, Sao Paulo, Brazil

    Jose E. Krieger, Luciana Sacilotto, Edmundo Arteaga & Murilo O. Antunes

  24. Yale University School of Medicine, New Haven, CT, USA

    E. Kevin Hall

  25. Feinberg School of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, IL, USA

    Lubna Choudhury

  26. Cardiac Unit, Massachusetts General Hospital, Boston, MA, USA

    Gregory D. Lewis

Authors
  1. Carolyn Y. Ho
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  5. Kenneth Zahka
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  27. Neal K. Lakdawala
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  28. Allison L. Cirino
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  30. John J. V. McMurray
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  31. Calum A. MacRae
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  32. Scott D. Solomon
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  33. E. John Orav
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  34. Eugene Braunwald
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Consortia

VANISH Investigators

  • Jose E. Krieger
  • , Luciana Sacilotto
  • , Edmundo Arteaga
  • , Murilo O. Antunes
  • , E. Kevin Hall
  • , Lubna Choudhury
  • , Elfriede Pahl
  • , Kimberly Y. Lin
  • , Gregory D. Lewis
  •  & Akshay S. Desai

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.

Ethics declarations

Competing interests

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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