Macitentan Safety, Effectiveness in PAH Confirmed in New Analysis

Data from the OPsumit Users Registry (OPUS) and OPsumit Historical USers cohort (OrPHeUS) demonstrate the safety and effectiveness of macitentan (Opsumit) monotherapy among patients with severe pulmonary arterial hypertension (PAH) despite guidelines calling for combination therapy, even among patients with World Health Organizational functional class I-II disease (low/intermediate risk).

Findings from this investigation were recently published in Pulmonary Circulation. The medical chart review comprised an overall 5654 patients (75.5% were female patients; median age, 62 years) from OPUS (n = 2670) and OrPHeUS (n = 2984), with an observation period from October 2013 through March 2017; 81.9% had diagnosed PAH, with the most common PAH subtypes being idiopathic disease (54.8%) and associated with connective tissue disease (26.8%); and the median 6-minute walk distance at study entry was 293 meters. All were new users of macitentan.

“The combined OPUS/OrPHeUS dataset is the largest new-users database for macitentan, describing a large population of patients who newly initiated macitentan in real-world clinical practice in the United States,” the study investigators wrote. “Importantly, this patient population reflects the full heterogeneity of the PAH disease state.”

Median (IQR) macitentan exposure was 14.5 (5.2-29.0) months in the PAH follow-up set and 13.6 (4.8-28.0) overall, for exposures of 7044 and 8322 person-years, respectively. The oral endothelin receptor antagonist (ERA) was most often prescribed as part of a doublet regimen (48.0%), followed by its use as monotherapy (37.9%) or in a triplet combination (14.1%).

Overall, at the 1-year mark, 59.9% (95% CI, 58.3%-61.5%) of patients had not required hospitalization and 90.4% (95% CI, 89.3%-91.3%) were still alive. Corresponding 3-year rates were 36% and 75%.

Hepatic and nonhepatic adverse events (AEs) were low, at just 17.1% and 0.3%, respectively; 9.9% of the cohort had more than 1 AE; and 6.2% had 1 or more hepatic events of special interest. According to previous research, the study authors noted, liver toxicity is a known risk from ERA drugs.

For OPUS, data were collected from macitentan initiation to study end or death, loss to follow-up, withdrawal of consent, or 30 days beyond macitentan discontinuation date; in OrPHeUS, data were collected from macitentan initiation through discontinuation, last patient data available in the medical chart, patient’s last day under the center’s care, death, or March 31, 2017.

Just 3.3% of patients overall had alanine aminotransferase or aspartate aminotransferase (AST) levels of 3 times or more the upper limit of normal (≥ 3 × ULN), and even fewer patients had both AST/ALT at least 3 × ULN and total bilirubin of at least 2 × ULN (0.9%).

By 6 months following treatment initiation, 30% of patients were receiving macitentan monotherapy (down from 37.9%), 50% were receiving it in a doublet combination (up from 48%), and 20%, in a triplet regimen (up from 14.1%). Overall, patients receiving macitentan as part of a combination treatment when the medication was initiated or by 6 months after that date rose from 60% and 66%, respectively, to 66% and 80% over the course of the study.

When emphasizing the strength of their findings, the investigators noted that in addition to the large patient cohort, the analysis included patients typically excluded from other clinical trials, such as persons who had portopulmonary hypertension or elevated baseline liver function tests. In addition, the patient demographics echo data seen in other real-world PAH registries, no new safety signals were identified, and the hospitalization and survival rates are similar to macitentan findings from the SERAPHIN trial, which investigated the efficacy and safety of long-term macitentan treatment.

“This analysis of real-world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients,” the study investigators concluded, “with overall and hepatic safety profiles consistent with previous macitentan clinical trials.”

Reference

McLaughlin VV, Kim N, Frantz R, et al. Safety of macitentan for the treatment of pulmonary hypertension: real-world experience from the OPsumit USers Registry (OPUS) and OPsumit Historical USers cohort (OrPHeUS). Pulm Circ. Published online October 21, 2022. doi:10.1002/pul2.12150