The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension

Abstract

Objectives: The REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patients with pulmonary arterial hypertension (PAH), using cardiac magnetic resonance (CMR) and right heart catheterization (RHC).

Background: RV failure is the primary cause of death in PAH. CMR is regarded as the most accurate noninvasive method for assessing RV function and remodeling and CMR measures of RV function and structure are strongly prognostic for survival in patients with PAH. Despite this, CMR is not routinely used in PAH clinical trials.

Methods: REPAIR was a 52-week, open-label, single-arm, multicenter, phase 4 study evaluating the effect of macitentan 10 mg, with or without phosphodiesterase type-5 inhibition, on RV remodeling and function and cardiopulmonary hemodynamics. Primary endpoints were change from baseline to week 26 in RV stroke volume, determined by CMR; and pulmonary vascular resistance, determined by RHC. Efficacy measures were assessed for all patients with baseline and week 26 data for both primary endpoints.

Results: At a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive. At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level: 8.4-15.6 mL; P < 0.0001) and pulmonary vascular resistance decreased by 38% (99% confidence level: 31%-44%; P < 0.0001) at week 26. Significant positive changes were also observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional endpoints at week 26. Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52. Safety (n = 87) was consistent with previous clinical trials.

Conclusions: In the context of this study, macitentan treatment in patients with PAH resulted in significant and clinically-relevant improvements in RV function and structure and cardiopulmonary hemodynamics. At 52 weeks, improvements in RV function and structure were sustained. (REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension [REPAIR]; NCT02310672).

Keywords: cardiac magnetic resonance; hemodynamics; macitentan; pulmonary arterial hypertension; right ventricle.

Conflict of interest statement

Funding Support and Author Disclosures This study was funded by Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. All statistical analyses were performed by the sponsor, in accordance with the prespecified statistical analysis plan. Dr Vonk Noordegraaf has received ongoing grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, GlaxoSmithKline, and Merck Sharp & Dohme; and has received Speakers Bureau payments from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Channick has received consultancy fees from Arena Pharmaceuticals Ltd and Bayer; has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson and United Therapeutics; and is an advisory board member for Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer. Dr Cottreel is a former employee and patent holder with Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. Dr Kiely has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and GlaxoSmithKline; and has received other financial or material support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme. Dr Marcus has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Martin is an employee of Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson; and currently holds shares in Johnson & Johnson. Dr Moiseeva has received lecture fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and Pfizer. Dr Peacock has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and GlaxoSmithKline, in addition to other financial or material support from Arena Pharmaceuticals Ltd and Merck Sharp & Dohme. Dr Swift has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson and General Electric Ltd; and has received grant support from GlaxoSmithKline. Dr Tawakol has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson and Esperion; and has received grant/research support from Genentech. Dr Torbicki has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena Pharmaceuticals Ltd, Bayer, Merck Sharp & Dohme, Pfizer, and United Therapeutics; has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson; has received Speakers Bureau fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP, Bayer, Merck Sharp & Dohme, and Pfizer; and is an advisory board member for Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Rosenkranz has received consultancy and/or lecture fees from Abbott, Acceleron, Arena Pharmaceuticals Ltd, Bayer, Bristol-Myers Squibb, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and United Therapeutics; and has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, AstraZeneca, Bayer, and Novartis. Dr Galiè has received grant/research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Pfizer; and has received Speakers Bureau fees from Merck Sharp & Dohme.

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