Combination therapy with macitentan and phosphodiesterase type-5 inhibitor (PDE5i) in pulmonary arterial hypertension (PAH): real-world data from OPUS and OrPHeUS
Authors: McLaughlin V , Channick R , Kim N.H , Flynn M , Leroy S , Wetherill G , Chin K 
Published: November 2020

Abstract

Introduction
Guidelines for the management of PAH recommend combination therapy for most patients, yet real-world data on treatment patterns in PAH are limited.

Purpose
To describe the characteristics, safety and clinical outcomes of PAH patients newly treated with double combination therapy with macitentan and PDE5i in the OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers cohort study (OrPHeUS) combined dataset.

Methods
OPUS is a prospective, US, multicentre, observational drug registry (NCT02126943) ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review (NCT03197688); Oct 2013–Mar 2017. This cohort included patients initiating combination therapy with macitentan and a PDE5i (in any order) ≤60 days apart. Baseline was defined as the start date of the second therapy (i.e., start of combination therapy). Patient characteristics at baseline, changes in 6-minute walk distance (6MWD) and WHO functional class (FC) from baseline to follow-up, safety and outcomes are described.

Results
Of the 4428 OPUS/OrPHeUS PAH patients initiating macitentan, 2490 received this in combination with a PDE5i; of these patients, 740 (29.7%) initiated macitentan and a PDE5i concurrently (≤60 days apart). Data on disease duration was recorded in 729 patients at baseline; of these, 588 (80.7%) patients were incident (≤6 months since diagnosis) and 141 (19.3%) were prevalent (&gt;6 months since diagnosis); median time from diagnosis to start of combination therapy of was 1.4 (Q1=0.6, Q3=3.6) months. At baseline, median age was 60 (Q1=49, Q3=70) years and 73.6% of patients were female. Mean baseline 6MWD was 264.5 (SD=119.8) m, recorded in 240 (32.4%) patients. WHO FC was recorded at baseline for 347 (46.9%) patients; 263 (75.8%) were in FC III/IV. Median combination therapy exposure was 10.2 (Q1=3.4, Q3=21.8) months, with 58.8% of patients ongoing at data cut. Changes from baseline to follow up in FC and 6MWD are shown in the figure. There was ≥1 adverse event (AE) reported in 455 (61.5%) patients and ≥1 hepatic AE (HAE) in 76 (10.3%) patients. In total, 232 (31.4%) patients discontinued macitentan; 122 (16.5%) due to AEs, 4 (0.5%) due to HAEs, 98 (13.2%) not due to an AE/HAE, and 8 (1.1%) for unknown reasons. Of the 305 patients who discontinued combination therapy, 137 (18.5%) discontinued macitentan only, 73 (9.9%) discontinued PDE5i only, and 95 (12.8%) discontinued both drugs at the same time. Kaplan-Meier estimates (95% CI) showed that 60.7% (56.4, 64.8) of patients were free from hospitalisation and 88.7% (85.7, 91.1) were alive at 12 months.

Conclusions
In this real-world setting, less than one third of patients treated with macitentan received initial oral combination therapy, despite current expert consensus favouring such therapeutic approaches. Patients initiating macitentan+PDE5i ≤60 days apart had improved 6MWD and WHO FC from baseline to follow-up.

Funding Acknowledgement
Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd