# Macitentan and phosphodiesterase-5 inhibitor alone or in combination in newly diagnosed pulmonary arterial hypertension: a pooled analysis

## TL;DR

Combining macitentan and PDE5 inhibitors may improve survival in newly diagnosed pulmonary arterial hypertension compared to using either drug alone.

## Contribution

This study provides evidence that upfront combination therapy with macitentan and PDE5 inhibitors is associated with reduced mortality in PAH patients.

## Key findings

- Macitentan+PDE5i combination therapy was associated with a 39% lower risk of mortality compared to PDE5i alone.
- Combination therapy also showed a 32% lower mortality risk compared to macitentan monotherapy.
- Specific combinations like macitentan+tadalafil showed up to a 49% reduction in mortality compared to tadalafil alone.

## Abstract

Upfront combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5i) is guideline-recommended for low- or intermediate-risk pulmonary arterial hypertension (PAH). This study compared time to all-cause mortality for macitentan+PDE5i combination and each monotherapy.

Long-term patient-level data (planned follow-up ≥1 year) were pooled from four clinical trials and three observational registries. All-cause mortality data were available from adults with incident PAH initiated on macitentan 10 mg or PDE5i monotherapy, or macitentan+PDE5i. Propensity-score (PS) methods balanced key demographic and disease characteristics across cohorts. Hazard ratios (HRs) were computed from a Cox-regression model that included PS-calculated weights. Weighted Kaplan–Meier estimates with 95% confidence intervals (CI) were computed 6-monthly.

2201 patients were included: 754 received macitentan+PDE5i (421 tadalafil, 324 sildenafil, 9 other), 654 macitentan, and 793 PDE5i (301 tadalafil, 490 sildenafil, 2 other). After weighting, characteristics were similar across cohorts. Upfront macitentan+PDE5i was associated with a 39% risk reduction of all-cause mortality versus PDE5i (HR 0.61 [95% CI 0.46–0.82]) and 32% versus macitentan (HR 0.68 [95% CI 0.37–0.95]). Reduction in all-cause mortality was 49% for macitentan+tadalafil vs tadalafil (HR 0.51 [95% CI 0.30–0.85]), 43% for macitentan+tadalafil vs macitentan (HR 0.57 [95% CI 0.37–0.88]), 31% for macitentan+sildenafil vs sildenafil (HR 0.69 [95% CI 0.45–1.0]) and 26% for macitentan+sildenafil vs macitentan (HR 0.74 [95% CI 0.46–1.17]).

This large, pooled analysis suggests an observed statistical association indicating a potential survival benefit for early macitentan+PDE5i versus either monotherapy in newly diagnosed PAH.

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