OBJECTIVES

PAH is a rare and fatal disease associated with significant morbidity. In SERAPHIN (N=750) [1], the endothelin receptor antagonist (ERA) macitentan decreased the risk of a composite outcome endpoint by 45% vs placebo (hazard ratio, HR [97.5% confidence interval, CI] 0.547 [0.392, 0.762]). In COMPASS-2 (N=334) [2], bosentan (another ERA) did not significantly decrease the risk of a similar endpoint vs placebo (HR [97.3% CI] 0.831 [0.582, 1.187]). This analysis compares the long-term efficacy and safety of macitentan vs bosentan using SERAPHIN and COMPASS-2 data.

METHODS

An anchored indirect treatment comparison (ITC) intention-to-treat analysis was performed using the Bucher method [3]. The composite endpoints of morbidity/mortality in both trials were re-mapped to the endpoint defined by the Committee for Medicinal Products for Human Use [4] to maximize comparability. Comparisons used 95% CIs around the HR. Safety endpoints included liver function tests, hemoglobin decrease and occurrence of peripheral edema.

RESULTS

Analyses showed a statistically significant, clinically relevant risk reduction of 31% in the primary endpoint for macitentan vs bosentan (HR [95% CI] 0.694 [0.484, 0.996]). An advantage for macitentan vs bosentan in the point estimates was seen for other endpoints including PAH-related hospitalization and death. Safety comparisons highlighted decreased risks in pulmonary edema of 76% (0.235 [0.063, 0.880]) and alanine aminotransferase/aspartate aminotransferase elevation of 35% (0.648 [0.360, 1.167]) for macitentan vs bosentan. The risk of hemoglobin decrease below 10g/dL was higher in macitentan although not statistically significant (1.934 [0.643, 5.811]).

CONCLUSIONS

Acknowledging the limitations of the ITC method, this analysis suggests superiority of macitentan vs bosentan in PAH in both efficacy and safety.

1. Pulido et al. N Engl J Med 2013;369809-18.
2. McLaughlin et al. Eur Resp J 2015;46:405-413.
3. Bucher et al. Journal of Clinical Epidemiology 1997;6:683-691.
4. Guideline on the clinical investigations of medicinal products for the treatment of PAH, CHMP 2009.