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

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

doi:10.1007/s10557-019-06876-y

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

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

Division of Cardiovascular Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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 antifibrotic 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 ≥ 100pg/ml or NTproBNP ≥ 300pg/ml; or BNP ≥ 300pg/ml or NTproBNP ≥ 900pg/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).

Original language	English
Journal	Cardiovascular Drugs and Therapy
Early online date	8 May 2019
DOIs	https://doi.org/10.1007/s10557-019-06876-y
Publication status	Published - 2019

Keywords

Fibrosis
Heart failure
Magnetic resonance imaging (MRI)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lewis, G., Schelbert, E. B., Naish, J., Bedson, E., Dodd, S., Eccleson, H., Clayton, D., Duran-Jimenez, B., McDonagh, T., Williams, S. G., Cooper, A., Cunnington, C., Ahmed, F. Z., Viswesvaraiah, R., Russell, S., Neubauer, S., Williamson, P., & Miller, C. (2019). Pirfenidone in Heart Failure With Preserved Ejection Fraction - Rationale and Design of the PIROUETTE Trial. Cardiovascular Drugs and Therapy. https://doi.org/10.1007/s10557-019-06876-y

@article{fa66e626bff84452bd4163221a144c18,

title = "Pirfenidone in Heart Failure With Preserved Ejection Fraction - Rationale and Design of the PIROUETTE Trial",

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 antifibrotic 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 ≥ 100pg/ml or NTproBNP ≥ 300pg/ml; or BNP ≥ 300pg/ml or NTproBNP ≥ 900pg/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). ",

keywords = "Fibrosis, Heart failure, Magnetic resonance imaging (MRI)",

author = "Gavin Lewis and Schelbert, {Erik B} and Josephine Naish and Emma Bedson and Susanna Dodd and Helen Eccleson and Danni Clayton and Beatriz Duran-Jimenez and Theresa McDonagh and Williams, {Simon G.} and Anne Cooper and Colin Cunnington and Ahmed, {Fozia Zahir} and Rajavarma Viswesvaraiah and Stuart Russell and Stefan Neubauer and Paula Williamson and Christopher Miller",

year = "2019",

doi = "10.1007/s10557-019-06876-y",

language = "English",

journal = "Cardiovascular Drugs and Therapy",

issn = "0920-3206",

publisher = "Springer Nature",

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Lewis, G, Schelbert, EB, Naish, J, Bedson, E, Dodd, S, Eccleson, H, Clayton, D, Duran-Jimenez, B, McDonagh, T, Williams, SG, Cooper, A, Cunnington, C, Ahmed, FZ, Viswesvaraiah, R, Russell, S, Neubauer, S, Williamson, P & Miller, C 2019, 'Pirfenidone in Heart Failure With Preserved Ejection Fraction - Rationale and Design of the PIROUETTE Trial', Cardiovascular Drugs and Therapy. https://doi.org/10.1007/s10557-019-06876-y

TY - JOUR

T1 - Pirfenidone in Heart Failure With Preserved Ejection Fraction - Rationale and Design of the PIROUETTE Trial

AU - Lewis, Gavin

AU - Schelbert, Erik B

AU - Naish, Josephine

AU - Bedson, Emma

AU - Dodd, Susanna

AU - Eccleson, Helen

AU - Clayton, Danni

AU - Duran-Jimenez, Beatriz

AU - McDonagh, Theresa

AU - Williams, Simon G.

AU - Cooper, Anne

AU - Cunnington, Colin

AU - Ahmed, Fozia Zahir

AU - Viswesvaraiah, Rajavarma

AU - Russell, Stuart

AU - Neubauer, Stefan

AU - Williamson, Paula

AU - Miller, Christopher

PY - 2019

Y1 - 2019

N2 - 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 antifibrotic 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 ≥ 100pg/ml or NTproBNP ≥ 300pg/ml; or BNP ≥ 300pg/ml or NTproBNP ≥ 900pg/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).

AB - 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 antifibrotic 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 ≥ 100pg/ml or NTproBNP ≥ 300pg/ml; or BNP ≥ 300pg/ml or NTproBNP ≥ 900pg/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).

KW - Fibrosis

KW - Heart failure

KW - Magnetic resonance imaging (MRI)

UR - http://www.scopus.com/inward/record.url?scp=85065656242&partnerID=8YFLogxK

U2 - 10.1007/s10557-019-06876-y

DO - 10.1007/s10557-019-06876-y

M3 - Article

SN - 0920-3206

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

ER -

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

Abstract

Keywords

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