Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial

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

Abstract

Background: The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis.

Methods: The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy.

Discussion: PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566).

Clinical trial registration: clinicaltrials.gov (NCT02932566) https://ichgcp.net/clinical-trials-registry/NCT02932566.

Keywords: Fibrosis; Heart failure; Magnetic resonance imaging (MRI).

Conflict of interest statement

This study was supported with provision of pirfenidone by Roche Products Limited. Roche Products Ltd. was not involved in the preparation, drafting, or editing of this manuscript. Roche Products Ltd. has conducted a factual accuracy check on the final article, but any decisions to incorporate comments were made solely at the discretion of the authors.

Figures

Fig. 1
Fig. 1
HFpEF pathophysiological mechanism being targets, mechanism of action of pirfenidone and study schematic. Asterisk indicates MMPs, TIMPs, interleukins, renin-angiotensin-aldosterone system

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