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

Gavin Lewis, Susanna Dodd, Dannii Clayton, Emma Bedson, Helen Eccleson, Erik B. Schelbert, Josephine H. Naish, Beatriz Duran-Jimenez, Simon G. Williams, Colin Cunnington, Fozia Zahir Ahmed, Anne Cooper, Rajavarma Viswesvaraiah, Stuart Russell, Theresa McDonagh, Paula R. Williamson, Christopher Miller

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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 haemodynamic 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. 47 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 favourable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials.
Original languageEnglish
Pages (from-to)1477–1482
JournalNature Medicine
Publication statusPublished - 12 Aug 2021


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