Efficacy and safety of macitentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH): Results from the randomized controlled MERIT study

Medical treatment for patients with inoperable CTEPH is limited and controlled data on combination therapy are lacking. The randomised double-blind, placebo-controlled MERIT study (NCT02021292) evaluated the endothelin receptor agonist macitentan for the treatment of patients with inoperable CTEPH, including patients receiving pulmonary arterial hypertension (PAH) treatment at baseline (BL).

Patients with primary inoperable CTEPH in WHO functional class (FC) II-IV with a pulmonary vascular resistance (PVR) ≥400 dyn·s/cm⁵ and 6-minute walk distance (6MWD) ≥150 m and ≤450 m were enrolled. Inoperability/eligibility was assessed by an independent adjudication committee. Treatment with phosphodiesterase type-5 inhibitors (PDE-5i) or oral/inhaled prostanoids was allowed only for patients in WHO FC III-IV. Patients were randomised 1:1 to placebo (n = 40) or macitentan 10 mg once daily (n = 40) and treated for 24 weeks. The primary endpoint was PVR at Week 16, expressed as percent of BL. The main secondary endpoint was mean change from BL to Week 24 in 6MWD. Exploratory endpoints included mean change from BL to Week 16 in cardiac index (CI) and mean right atrial pressure (mRAP), and percent of BL N-terminal pro B-type natriuretic peptide (NT-proBNP) at Week 24. Evaluation of safety and tolerability was performed throughout.

At BL, 61% of patients were receiving treatment with a PAH therapy; of these, 96% were on PDE-5i and 24% were on oral/inhaled prostanoids. PVR and 6MWD significantly improved in the macitentan-treated group vs. placebo (Table). The treatment effect on PVR and 6MWD was similar in patients with and without PAH treatment at BL. Macitentan treatment also resulted in improvements in mean mRAP, CI and NT-proBNP compared with placebo (Table). The most common adverse events with macitentan vs. placebo were peripheral oedema (22.5% vs. 10.0%) and decreased haemoglobin/anaemia (17.5% vs. 2.5%). Haemotypsis was reported in one patient in each group; neither was a serious adverse event. Five patients prematurely discontinued treatment and2 patients died, all in the placebo group.

In conclusion, in the MERIT study in patients with inoperable CTEPH, macitentan led to significant improvements in cardiopulmonary haemodynamics and exercise capacity. Macitentan was well tolerated in this patient population.