Macitentan Associated With Right Ventricular Function, Structure Improvement in PAH

REPAIR study findings outline the benefits of macitentan for right ventricular functioning in pulmonary arterial hypertension.

Results of the REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study indicated that patients with pulmonary arterial hypertension (PAH) who received macitentan exhibited significant and clinically relevant improvements in right ventricular (RV) function and structure and cardiopulmonary hemodynamics. Findings were published in JACC: Cardiovascular Imaging and showed that RV improvements were sustained at 52 weeks.

RV failure accounts for most deaths among patients with PAH; a defining feature of the disease is “increased pulmonary vascular resistance (PVR), which results from obstructive remodeling of the pulmonary vasculature,” the authors explained. As a result, reversing maladaptive remodeling and maintaining RV function serve as key treatment goals in PAH, they added.

“Cardiac magnetic resonance (CMR) can provide detailed information relating to RV function and structure,” and “is regarded as the most accurate noninvasive method for assessing RV function and remodeling and provides complementary information to right heart catheterization (RHC),” the researchers wrote.

Macitentan is an oral dual endothelin receptor antagonist approved for long-term treatment of PAH, and in the current study, researchers aimed to evaluate its effect on RV and hemodynamic outcomes in patients via CMR and RHC.

The phase 4 open-label, single arm study enrolled 100 patients with symptomatic PAH, although “at interim analysis, baseline and week 26 images were assessed for the first 42 patients with available data.”

All participants received 10 mg of macitentan each day for a mean (SD) of 52 weeks (7 days). During the first 14 days of study drug treatment, physicians could initiate a phosphodiesterase type-5 inhibitor (PDE-5i), but initiation of rescue therapy before week 26 was only permitted in the event of disease progression.

All participants were between the ages 18 and 74 years and had PAH confirmed by RHC. In addition, “at screening, patients were required to be PAH treatment-naïve or receiving a stable background PDE-5i for at least 3 months, have a 6-minute walk distance [6MWD] of ≥150 m, and be in WHO Functional Class [FC] I-III.”

Participants underwent CMR at screening, week 26, and week 52, and all images were analyzed by a blinded assessor for the final analysis. Patients had a median age of 45 years at baseline and the majority (80.3%) were women; 59.2% had idiopathic PAH. “At a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive,” authors wrote.

Data revealed:

  • At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level [CL], 8.4-15.6 mL; P < .0001) and pulmonary vascular resistance decreased by 38% (99% CL, 31%-44%; P < .0001) at week 26.
  • Significant positive changes were observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional end points at week 26.
  • Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52.
  • Patients’ 6MWD (n = 71) significantly increased from baseline to week 26 by a mean of 35.6 m (95% CL, 19-52 m), and this change was maintained at week 52 (mean increase of 38.2 m [95% CL, 19-57 m]; n = 65).
  • Safety (n = 87) was consistent with previous clinical trials; the most frequent adverse events (≥20% of patients) were peripheral edema (n = 19, 21.8%) and headache (n = 18, 20.7%).
  • Macitentan was initiated as monotherapy in 23.9% of patients, on top of stable background PDE-5i therapy in 38% of patients, and simultaneously with a PDE-5i in 38% of patients.

In the current study, researchers showed “macitentan treatment, alone or in combination with a PDE-5i, led to statistically significant and clinically relevant improvements in right ventricular stroke volume (RVSV) and PVR at week 26, with improvements in RVSV maintained at week 52.”

Because changes were observed in RV structure and function, the authors hypothesized that macitentan results in beneficial remodeling of the right ventricle in this patient population. However, it is still unknown whether the treatment’s effects on hemodynamics and RV structure are mechanistically related.

The analysis also provided further confidence in CMR-assessed end points and their potential use in future trials, in addition to supporting the imaging modality “as a reliable noninvasive technique for monitoring disease status.”

An open-label design and limited population—precluding certain subgroup analyses— mark limitations to the study.


Noordegraaf AV, Channick R, Cottreel E, et al. The REPAIR study: effect of macitentan on the structure and function in pulmonary arterial hypertension. JACC Cardiovascular Imaging. Published online November 17, 2021. doi:10.1016/j.jcmg.2021.07.027