Analysis: Macitentan May Reduce Morbidity, Mortality of Patients With PAH on Spironolactone

Research presented at CHEST 2021 showed that administration of Opsumit (macitentan) reduced the risk of a morbidity/mortality (M/M) event in patients with pulmonary arterial hypertension (PAH) taking spironolactone and among those not taking spironolactone, although the reduction seen in the treated group was more pronounced.

Diuretics such as spironolactone are frequently used as adjunctive therapy in patients with PAH, as the treatment may inhibit the renin-angiotensin-aldosterone system—which is thought to contribute to the pathophysiology of PAH—and provide cardioprotective effects, researchers wrote.

However, no established guidelines for diuretic use in PAH exist and data on its use with other PAH therapies are limited. Using data from SERAPHIN, a randomized, placebo-controlled phase 3 trial on the efficacy and safety of macitentan, investigators conducted a post hoc analysis to better understand the effect of macitentan 10 mg vs placebo in patients who were or were not taking the diuretic at baseline.

All trial participants were aged 12 or older, had PAH, and were randomized to receive placebo, macitentan 3 mg once daily, or macitentan 10 mg once daily, while only those who received placebo and 10-mg doses were included in the current analysis.

In addition to a primary end point of time to M/M, defined as composite of death or PAH-related complication, the researchers also assessed change in 6-minute walk distance (6MWD) “collected at screening or randomization, at months 3 and 6, and every 6 months thereafter, up to and including the end of treatment.”

At baseline, 82 of 242 of the patients receiving macitentan 10 mg were also receiving spironolactone compared with 77 of 250 individuals in the placebo group. Those taking the diuretic at baseline also had more severe PAH and a higher M/M event rate.

Analyses revealed:

• Patients who were taking spironolactone had a higher incidence of M/M events than those who were not taking spironolactone (53.5% vs 32.1%)
• Macitentan 10 mg reduced the risk of an M/M event in patient groups who were taking spironolactone and in those who were not taking spironolactone
• Compared with placebo, macitentan 10 mg was associated with a 61% reduction in the risk of an M/M event in patients taking spironolactone (HR, 0.39; 95% CI, 0.24-0.64; P = .0002)and a 54% reduction in those not taking spironolactone(HR, 0.46; 95% CI, 0.30-0.70; P = .0003)
• Patients taking spironolactone had a more marked improvement in 6MWD than those not taking spironolactone
• Types and rates of adverse events leading to treatment discontinuation were comparable across groups
• The most common M/M event in all groups was worsening of PAH

“While spironolactone did not seem to result in decreased risk of an M/M event, patients taking spironolactone had more severe disease at baseline, so it cannot be ruled out,” the researchers wrote.

The post hoc design and exploratory nature mark limitations to the analysis, and because patients were not stratified according to diuretic use, additional confounding factors may have contributed to outcomes observed.

Overall, “this post hoc analysis demonstrates that macitentan provides a robust treatment effect in patients with severe PAH who are taking spironolactone, and no new safety signals were discovered among patients taking macitentan and spironolactone,” the authors concluded.

Reference:

Safdar Z, Jansa P, Mehta S, et al. Macitentan treatment effect in patients with pulmonary arterial hypertention taking spironolactone: post hoc analysis of the phase 3 SERAPHIN trial. Presented at: CHEST Annual Meeting 2021; October 17-20, 2021; virtual. Abstract 37497.