Macitentan taken daily for 16 weeks was not superior to daily placebo in improving 6-minute walk distance (6MWD) for patients with Eisenmenger syndrome, according to a study published in Circulation. Novel elements to this study included enrolling patients with anatomically classified complex cardiac defects and patients with Down syndrome.
Researchers with the phase III, multicenter, randomized, double-blind, placebo-controlled, 16-week MAESTRO trial (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity, ClinicalTrials.gov identifier: NCT01743001) evaluated the safety and efficacy of endothelin receptor antagonist macitentan in participants ≥12 years with Eisenmenger syndrome.
Participants were randomized 1:1 into a once daily placebo group, or once daily macitentan group.
The primary study end point was week 16 change from baseline in 6MWD. Secondary end points included week 16 change from baseline in World Health Organization (WHO) functional class, and exploratory end points included end-of-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) and pulmonary vascular resistance index (PVRi) expressed as percentages of baseline. Safety of macitentan was also evaluated.
Of a total 226 participants from 71 centers in 26 countries, 114 were randomized into the macitentan group and 112 into the placebo group. A total of 20 participants had Down syndrome, 10 per treatment group. The number of participants who completed the full 16 weeks was 221 (macitentan n=111; placebo n=110). The majority of patients were in the WHO functional class II (59.7%), while 40.3% were WHO functional class III. What’s more, 24.3% of participants had complex cardiac defects.
Week 16 6MWD change from baseline in the macitentan group was 18.3±84.4 m compared with 19.7±53.0 m in the placebo group. The week 16 least-squares mean difference for change from baseline in macitentan vs placebo was -4.7 m (95% CI, -22.8 to 13.5; P =.612), and the proportion of participants with 6MWD improvement at week 16 (defined as change from baseline >0 m) was 72.8% in the macitentan group vs 65.2% in the placebo group.
In the macitentan group, 8.8% of participants experienced WHO functional class improvement compared with 14.3% of patients in the placebo group (odds ratio, 0.53; 95% CI, 0.23-1.24).
Levels of NT-proBNP decreased with macitentan compared with placebo (ratio of geometric means, 0.80; 95% CI, 0.68-0.94), and in a hemodynamic substudy of 39 patients, PVRi decreased with macitentan compared with placebo (ratio of geometric means, 0.87; 95% CI, 0.73-1.03).
The most common adverse events seen with macitentan compared with placebo were upper respiratory tract infection (9.6% vs 6.3%) and headache (11.4% vs 4.5%), and a hemoglobin decrease of ≥2 g/dL from baseline occurred in 36.0% vs 8.9% of participants. One macitentan patient died, and 5 patients (3 macitentan and 2 placebo) prematurely discontinued the study.
Study investigators conclude that the large placebo effect on exercise capacity in this study significantly contributed to macitentan’s failure to show superiority. They add that “gains in 6MWD may have resulted from familiarization with the 6MWT in a supervised clinical setting, or from adaptation to exercise and improved muscle strength.” This effect may have been amplified considering patients with Eisenmenger syndrome are usually restricted from exercising.
Multiple authors declare affiliations with the pharmaceutical industry. Please see original reference for a full list of authors’ disclosures.
Gatzoulis MA, Landzberg M, Beghetti M, et al. Evaluation of macitentan in patients with Eisenmenger syndrome. Circulation. 2019;139(1):51-63.