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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.

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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.

References

  1. Redfield, M. M. Heart failure with preserved ejection fraction. N. Engl. J. Med. 375, 1868–1877 (2016).

    Article  PubMed  Google Scholar 

  2. Lewis, G. A. et al. Biological phenotypes of heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 70, 2186–2200 (2017).

    Article  PubMed  Google Scholar 

  3. Maurer, M. S. et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N. Engl. J. Med. 379, 1007–1016 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Branch, K. R. et al. Rivaroxaban with or without aspirin in patients with heart failure and chronic coronary or peripheral artery disease. Circulation 140, 529–537 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shah, S. J. Innovative clinical trial designs for precision medicine in heart failure with preserved ejection fraction. J. Cardiovasc. Transl. Res. 10, 322–336 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Antman, E. M. & Loscalzo, J. Precision medicine in cardiology. Nat. Rev. Cardiol. 13, 591–602 (2016).

    Article  PubMed  Google Scholar 

  7. Weber, K. T. Cardiac interstitium in health and disease: the fibrillar collagen network. J. Am. Coll. Cardiol. 13, 1637–1652 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Zile, M. R. et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131, 1247–1259 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schelbert, E. B. et al. Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: association with baseline disease severity and subsequent outcome. JAMA Cardiol. 2, 995–1006 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. King, T. E. Jr et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2083–2092 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Miric, G. et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br. J. Pharmacol. 133, 687–694 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mirkovic, S. et al. Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats. Br. J. Pharmacol. 135, 961–968 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Giri, S. N. et al. Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone in rats. Cancer Chemother. Pharmacol. 53, 141–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Van Erp, C., Irwin, N. G. & Hoey, A. J. Long-term administration of pirfenidone improves cardiac function in mdx mice. Muscle Nerve 34, 327–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, K. W. et al. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation 114, 1703–1712 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nguyen, D. T., Ding, C., Wilson, E., Marcus, G. M. & Olgin, J. E. Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm 7, 1438–1445 (2010).

    Article  PubMed  Google Scholar 

  18. Yamazaki, T. et al. The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice. Hypertension Res. 35, 34–40 (2012).

    Article  CAS  Google Scholar 

  19. Wang, Y., Wu, Y., Chen, J., Zhao, S. & Li, H. Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC-induced left ventricular remodeling by suppressing NLRP3 inflammasome formation. Cardiology 126, 1–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Li, C. et al. Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis. Sci. Rep. 7, 40523 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Spertus, J. et al. Monitoring clinical changes in patients with heart failure: a comparison of methods. Am. Heart J. 150, 707–715 (2005).

    Article  PubMed  Google Scholar 

  22. Vaduganathan, M., Greene, S. J., Ambrosy, A. P., Gheorghiade, M. & Butler, J. The disconnect between phase II and phase III trials of drugs for heart failure. Nat. Rev. Cardiol. 10, 85–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Butler, J. et al. Reassessing phase II heart failure clinical trials: consensus recommendations. Circ. Heart Fail 10, e003800 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Brilla, C. G., Funck, R. C. & Rupp, H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 102, 1388–1393 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Diez, J. et al. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105, 2512–2517 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Izawa, H. et al. Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 112, 2940–2945 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Treibel, T. A. et al. Reverse myocardial remodeling following valve replacement in patients with aortic stenosis. J. Am. Coll. Cardiol. 71, 860–871 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Roy, C. et al. Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction. J. Cardiovasc. Magn. Reson. 20, 55 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rommel, K.-P. et al. Extracellular volume fraction for characterization of patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 67, 1815–1825 (2016).

    Article  PubMed  Google Scholar 

  30. Lopez, B., Querejeta, R., Gonzalez, A., Larman, M. & Diez, J. Coll′agen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase. Hypertension 60, 677–683 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Santos, M. et al. E/e′ ratio in patients with unexplained dyspnea: lack of accuracy in estimating left ventricular filling pressure. Circ. Heart Fail 8, 749–756 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sharifov, O. F., Schiros, C. G., Aban, I., Denney, T. S. & Gupta, H. Diagnostic accuracy of tissue doppler index E/e′ for evaluating left ventricular filling pressure and diastolic dysfunction/heart failure with preserved ejection fraction: a systematic review and meta-analysis. J. Am. Heart Assoc. 5, e002530 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Obokata, M. et al. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation 135, 825–838 (2017).

    Article  PubMed  Google Scholar 

  34. Macias-Barragan, J., Sandoval-Rodriguez, A., Navarro-Partida, J. & Armendariz-Borunda, J. The multifaceted role of pirfenidone and its novel targets. Fibrogenes Tissue Repair 3, 16 (2010).

    Article  CAS  Google Scholar 

  35. Lewis, G. A. et al. Pirfenidone in heart failure with preserved ejection fraction-rationale and design of the PIROUETTE trial. Cardiovasc. Drugs Ther. 33, 461–470 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Garg, R. et al. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes 64, 236–242 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Noble, P. W. et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377, 1760–1769 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Phan, T. T. et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J. Am. Coll. Cardiol. 54, 402–409 (2009).

    Article  PubMed  Google Scholar 

  39. Hudsmith, L. E. & Neubauer, S. Magnetic resonance spectroscopy in myocardial disease. JACC Cardiovasc. Imaging 2, 87–96 (2009).

    Article  PubMed  Google Scholar 

  40. Beadle, R. M. et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 3, 202–211 (2015).

    Article  PubMed  Google Scholar 

  41. Abozguia, K. et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 122, 1562–1569 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Beadle, R. M. et al. Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial. Trials 12, 140 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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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