Abstract
BackgroundThe 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.MethodsThe 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.DiscussionPIROUETTE 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 Registrationclinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566
Highlights
As highlighted in recent commentaries, there is a disconnect between phase II and phase III drug trials in heart failure (HF); despite often promising phase II results, most phase III trials prove neutral or negative [1,2,3]
The reasons for this include a lack of understanding and identification of prognostically important pathophysiological mechanisms, failure of therapies to target these underlying mechanisms, non-specific phase II end points that are not reflective of disease pathway modulation and a one-size-fits-all approach that does not take account of pathophysiological heterogeneity
Up to one-half of HF patients have a preserved left ventricular (LV) ejection fraction (HFpEF), and the prevalence of heart failure and preserved ejection fraction (HFpEF) is rising as the population ages [6]
Summary
As highlighted in recent commentaries, there is a disconnect between phase II and phase III drug trials in heart failure (HF); despite often promising phase II results, most phase III trials prove neutral or negative [1,2,3]. There is a disconnect between phase II and phase III drug trials in heart failure (HF); despite often promising phase II results, most phase III trials prove neutral or negative [1,2,3] The reasons for this include a lack of understanding and identification of prognostically important pathophysiological mechanisms, failure of therapies to target these underlying mechanisms, non-specific phase II end points that are not reflective of disease pathway modulation and a one-size-fits-all approach that does not take account of pathophysiological heterogeneity. It is with these factors in mind that the PIROUETTE trial has been designed.
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