Macitentan improves pulmonary vascular resistance and 6-minute walk distance in CTEPH patients

Liz Meszaros, MDLinx | June 15, 2017

In patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), treatment with macitentan may bring about significant improvements in both cardiopulmonary hemodynamics and exercise capacity, according to results from the MERIT study, presented in Washington, DC, in late May at the American Thoracic Society 2017 International Conference.

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Inoperable CTEPH

“Currently, we only have one medical therapy available, and there is an unmet medical need for combination therapies or complementary therapies for what is the current gold standard.

“In this disease, there are multiple treatment options which do not apply to all patients. Primary therapy is surgery for those patients who have rather proximal occlusions of their pulmonary vessels. For all the other patients who are not amenable to surgery, medical therapy is required,” explained lead author HA Ghofrani, MD, pulmonologist and intensivist, University Hospital, Geissen, Germany.

“Currently, we only have one medical therapy available, and there is an unmet medical need for combination therapies or complementary therapies for what is the current gold standard,” he added.

Dr. Ghofrani and colleagues conducted the MERIT study, a randomized, double-blind, placebo-controlled trial in which they assessed macitentan—a dual endothelin receptor antagonist—for the treatment of patients with inoperable CTEPH, including those receiving pulmonary arterial hypertension (PAH) treatment at baseline.

They included patients with primary inoperable CTEPH in WHO functional class (FC) II-IV, with a pulmonary vascular resistance (PVR) ≥ 400 dyn*sec/cm5, and 6-minute walk distance (6MWD) ≥ 150 m and ≤ 450 m.

For patients in WHO FC III-IV, treatment with phosphodiesterase type-5 inhibitors (PDE-5i) or oral/inhaled prostanoids was permitted, but not for those in WHO FC II.

Researchers randomized 80 patients 1:1 to placebo (n=40) or macitentan (10 mg once daily; n=40) for 24 weeks. The primary endpoint of the study was PVR at week 16, and the main secondary endpoint was mean change from baseline to week 24 in 6MWD. In addition, they included exploratory endpoints, which were comprised of mean change from baseline to week 16 in cardiac index (CI) and mean right atrial pressure (mRAP), and percent of baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) at week 24.

A full 61% of patients were being treated with a PAH therapy at baseline, of whom 96% were on PDE-5i, and 24% on oral/inhaled prostanoids.

Dr. Ghofrani and fellow researchers found significant improvement in the macitentan group compared with placebo in PVR (929 vs 723 m*sec/cm5 and 984 vs 899 m*sec/cm5, respectively) and 6MWD (353 vs 388 m and 351 vs 352 m, respectively). These effects were similar in patients both with and without PAH treatment at baseline. Patients treated with macitentan also demonstrated improvements in mean mRAP, CI, and NT-proBNP compared with placebo (see table).

The most common adverse events included peripheral edema (22.5% with macitentan versus 10.0%) with placebo; and decreased hemoglobin/anemia (17.5% vs 2.5%, respectively). Hemoptysis occurred in one patient in each group, and neither constituted a serious adverse event. Five patients in the placebo group discontinued treatment, and two patients in this group died.

“Besides improving the primary endpoint of the study, there were numerous other endpoints, including secondary and exploratory endpoints, which actually moved in the right direction. So despite the study being of small size, and being a phase II study, the results already were very encouraging,” said Dr. Ghofrani.

“It was also encouraging because for the first time, patients who not only were treatment-naïve with regards to PH-specific therapies, and also [those] on background therapy were investigated and showed beneficial effects with macitentan. So for the first time, there is an indication of efficacy for a combination therapy in this indication,” he concluded.

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