Evaluation of Macitentan in Patients With Eisenmenger Syndrome

Abstract

Background: Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome.

Methods: Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline.

Results: Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group).

Conclusions: Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.

Keywords: Down syndrome; Eisenmenger syndrome; congenital heart disease; endothelin receptor antagonist; macitentan; pulmonary arterial hypertension.

Figure 1.

Patient disposition. Patients were considered to have completed the study if they completed the 30-day safety follow-up period and Week 16 assessments, regardless of premature study treatment discontinuation. *The 3 patients who discontinued macitentan treatment prior to week 16 did not complete the study. †The 2 patients who discontinued placebo treatment prior to week 16 did complete the study. ‡The patient did not fulfill the inclusion criteria.

Figure 2.

Primary end point of change from baseline to week 16 in 6-minute walk distance. 6MWD indicates 6-minute walk distance; and CL, confidence limit. Mean (plus 95% CL) change from baseline to week 16 in 6MWD is shown for macitentan and placebo in the intention-to-treat population with missing values imputed. The 6MWD increased from baseline by a mean of 18.3 m in the macitentan group and 19.7 m in the placebo group. The macitentan minus placebo least-squares mean difference (treatment effect) was -4.7 m (95% CL -22.8 to 13.5; P=0.612) calculated using an analysis of covariance model including the treatment group, Down syndrome (yes/no), WHO functional class at baseline (II versus III/IV), and baseline 6MWD as covariates. Missing values were imputed for 3 patients.

Figure 3.

Percent of baseline PVRi at Week 16 and change in 6MWD from baseline to week 16 in the hemodynamic substudy. 6MWD indicates 6-minute walk distance; PVRi, pulmonary vascular resistance index; and CL, confidence limit. A, Unadjusted geometric mean PVRi (95% CL) at week 16, expressed as a percentage of baseline, is shown for the macitentan and placebo groups in the intention-to-treat population with missing values imputed. The geometric mean PVRi decreased to 85.3% of the baseline value in the macitentan group and increased to 101.1% of the baseline value in the placebo group. The macitentan:placebo ratio of geometric means (treatment effect) was 0.87 (95% CL, 0.73–1.03) calculated using an analysis of covariance model on the log transformed ratio (week 16/baseline), including the treatment group, location of cardiac defect and PVRi at baseline as covariates. Missing values were imputed for 4 patients. B, Mean (plus 95% CL) change from baseline to week 16 in 6MWD in the hemodynamic study (posthoc analysis) is shown for the macitentan and placebo groups in the intention-to-treat population. There were no patients with missing data. The 6MWD increased from baseline by a mean of 34.1 m in the macitentan group and 3.5 m in the placebo group. The macitentan minus placebo least-squares mean difference (treatment effect) was 24.9 m (95% CL, -9.1 to 59.0) calculated using an analysis of covariance model, including treatment group and baseline 6MWD as covariates.