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Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial

Nature Medicine volume 27, pages 1477–1482 (2021)Cite this article

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Abstract

In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial (NCT02932566), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, −1.21%; 95% confidence interval, −2.12 to −0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials.

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Fig. 1: Screening, randomization and follow-up.
Fig. 2: Myocardial ECV.

Data availability

De-identified participant data will be made available on reasonable request one year after the date of publication, with no end date to availability, and may be used for any purpose. Requests should be directed to the corresponding author. Requestors will be required to sign a data access agreement. The study protocol is provided with the manuscript.

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Acknowledgements

We thank the members of the Trial Steering Committee, A.L. Clark (Chair), R. Gardner, C. Graham and N. Hartshorne-Evans, and members of the Independent Data and Safety Monitoring Committee, R. Emsley, S. Garg and M. Mamas. This study was funded by the United Kingdom National Institute for Health Research (grant no. CS-2015-15-003, C.A.M.). The funder of the study had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, the preparation, review or approval of the manuscript, and the decision to submit the manuscript for publication. Manchester University NHS Foundation Trust acted as the study sponsor, and participated in the design, conduct and management of the study. The sponsor conducted a factual accuracy check of this manuscript, but had no role in the collection, analysis or interpretation of the data, the preparation of the manuscript or the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    Gavin A. Lewis, Josephine H. Naish, Fozia Zahir Ahmed & Christopher A. Miller

  2. Manchester University NHS Foundation Trust, Manchester, UK

    Gavin A. Lewis, Beatriz Duran Jimenez, Simon G. Williams, Colin Cunnington, Fozia Zahir Ahmed & Christopher A. Miller

  3. Department of Health Data Science, University of Liverpool, a Member of Liverpool Health Partners, Liverpool, UK

    Susanna Dodd & Paula R. Williamson

  4. Liverpool Clinical Trials Centre, University of Liverpool, Institute of Child Health, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

    Dannii Clayton, Emma Bedson & Helen Eccleson

  5. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Erik B. Schelbert

  6. UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA, USA

    Erik B. Schelbert

  7. Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Erik B. Schelbert

  8. Salford Royal NHS Foundation Trust, Salford, UK

    Anne Cooper

  9. Stockport NHS Foundation Trust, Stepping Hill Hospital, Stockport, UK

    Rajavarma Viswesvaraiah

  10. East Cheshire NHS Trust, Macclesfield, UK

    Stuart Russell

  11. King’s College Hospital, London, UK

    Theresa McDonagh

  12. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    Christopher A. Miller

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Contributions

G.A.L. and C.A.M. had full access to all the data and take responsibility for the integrity of the data and accuracy of data analysis. Study concept and design was provided by G.A.L., S.D., E.B., E.B.S., J.H.N., B.D.J., S.G.W., C.C., F.Z.A., A.C., R.V., S.R., T.M., P.R.W. and C.A.M. Acquisition, analysis or interpretation of data was carried out by all authors. Drafting of the manuscript was performed by G.A.L. and C.A.M. All authors critically revised the manuscript for important intellectual content. Statistical analysis was carried out by S.D. and D.C. Funding was obtained by C.A.M. Administrative, technical or material support was provided by H.E., J.H.N. and B.D.J. The study was supervised by E.B., P.R.W. and C.A.M.

Corresponding author

Correspondence to Christopher A. Miller.

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Competing interests

C.A.M. has previously received research support for other research from Guerbet, has served on an advisory board for Novartis and serves has an advisor for HAYA Therapeutics. None of these relationships are relevant to the content of this paper. The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Roche Products Limited and Roche Diagnostics International Limited had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, the preparation or approval of the manuscript, and the decision to submit the manuscript for publication. Roche Products Limited and Roche Diagnostics International Limited conducted a factual accuracy check of this manuscript, but any decisions to incorporate comments were made solely at the discretion of the authors.

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Peer review information Nature Medicine thanks John Cleland, Kevin Anstrom, Rudolf de Boer 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.

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Lewis, G.A., Dodd, S., Clayton, D. et al. Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial. Nat Med 27, 1477–1482 (2021). https://doi.org/10.1038/s41591-021-01452-0

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