吡非尼酮治疗射血分数保留的心力衰竭的作用机制和 PIROUETTE 试验的设计。
Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial.
机构信息
Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK.
出版信息
Cardiovasc Drugs Ther. 2019 Aug;33(4):461-470. doi: 10.1007/s10557-019-06876-y.
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 phosphorus 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://clinicaltrials.gov/ct2/show/NCT02932566.
背景
PIROUETTE（PIRfenidOne 在有心力衰竭和保留左心室射血分数的患者中）试验旨在评估抗纤维化药物吡非尼酮在慢性心力衰竭和保留射血分数（HFpEF）以及心肌纤维化患者中的疗效和安全性。HFpEF 是一种与高发病率和死亡率相关的多种综合征。心肌纤维化是 HFpEF 的关键病理生理机制，心肌纤维化负担与不良结局密切相关且具有独立性。吡非尼酮是一种口服抗纤维化药物，无血液动力学作用，可在临床前模型中导致心肌纤维化消退。它已被证明在肺纤维化方面具有临床疗效。
方法
PIROUETTE 试验是一项随机、双盲、安慰剂对照的 II 期试验，评估 52 周吡非尼酮治疗慢性 HFpEF （心力衰竭症状和体征，左心室射血分数≥45%，升高的利钠肽[BNP≥100pg/ml 或 NT-proBNP≥300pg/ml；或 BNP≥300pg/ml 或 NT-proBNP≥900pg/ml，如果存在心房颤动]）和心肌纤维化（细胞外基质（ECM）体积≥27%，使用心血管磁共振测量）患者的疗效和安全性。主要观察指标是心肌 ECM 体积的变化。一项亚研究将使用磷磁共振波谱研究心肌纤维化与心肌能量之间的关系，以及吡非尼酮的影响。
讨论
PIROUETTE 将确定吡非尼酮是否优于安慰剂，与 HFpEF 和心肌纤维化患者的心肌纤维化消退和心肌能量改善相关（NCT02932566）。
临床试验注册
clinicaltrials.gov（NCT02932566）https://clinicaltrials.gov/ct2/show/NCT02932566。
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