Risk of Death Differs for Elderly Patients With PAH Taking Endothelin Receptor Antagonists

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The mortality risk differs for the 3 endothelin receptor antagonists approved to treat pulmonary arterial hypertension (PAH) in elderly patients; however, a direct comparison in a controlled trial is still needed to confirm results.

There are 3 endothelin receptor antagonists (ERAs) approved to treat elderly patients with pulmonary arterial hypertension (PAH), and the mortality rate differs, according to a study published in Pulmonary Circulation. However, there were variables that independently increased the risk of mortality.

There has been an increasing prevalence of elderly patients with PAH being treated in clinical practice, and these patients have a higher rate of comorbid conditions and run the risk of drug–drug interactions.

“Although research has indicated that comorbidities negatively affect outcomes in patients with PAH, there is limited information regarding the effect of comorbidities on survival in elderly patients,” the authors explained. “Evidence is also sparse on the mortality benefit of PAH therapy in elderly patients…”

Elderly patients with PAH are often treated similar to younger patients, and ERAs (bosentan, ambrisentan, and macitentan) are most commonly used and are recommended for use by clinical guidelines. Differences between the ERAs could be associated with different outcomes, but none of the pivotal trials for the 3 agents were powered to detect survival benefit and they have not been compared in any head-to-head randomized controlled trials (RCTs). “Therefore, the relative treatment effect of the three ERAs on mortality remains unknown,” the researchers wrote.

They conducted a retrospective database study to examine the risk of mortality among elderly patients with PAH treated with ERAs. They used data from January 1, 2013, to December 31, 2016, from the CMS national Medicare database.


A patient’s index date was their first date of a claim for bosentan, ambrisentan, or macitentan. There was a ≥12-month baseline period prior to index date and a ≥12-month follow-up before the end of a study period. All deaths during the follow-up period were counted and the mortality rate was calculated as events per 100 person-years.

A total of 6452 patients were included in the study: 1628 treated with macitentan, 2852 treated with ambrisentan, and 1972 treated with bosentan. The macitentan cohort had the highest number of ERA-naïve patients (1055), meaning they were not prescribed ERAs during the baseline period, followed by 871 in the ambrisentan cohort, and only 91 in the bosentan cohort.

In the baseline period, the most common (45%) PAH medications were phosphodiesterase type 5 (PDE-5) inhibitors. Since macitentan was the most recently approved ERA (2013 compared with 2007 for ambrisentan and 2001 for bosentan), patients with macitentan as their index ERA were more likely to be ERA-naïve.

The macitentan cohort had a slightly, but significantly, higher proportion of women, and in the macitentan cohort the patients were also slightly, but significantly, older than in the ambrisentan cohort. The proportion of non-White patients was 7% higher among patients taking ambrisentant compared with those taking macitentan.

During the follow up, 1994 patients died and the independent risk factors for increased risk of death were increasing age, higher Charlson Comorbidity Index, and inpatient hospitalization. Patients considered ERA-naïve during baseline had an increased risk of mortality associated with increasing age, coronary artery disease, renal insufficiency, pneumonia, portopulmonary hypertension, and chronic obstructive pulmonary disease.

While the unadjusted mortality rate was similar between the 3 ERAs for the overall patient population, macitentan had a significantly lower unadjusted mortality rate than ambrisentan for ERA-naïve patients (17.37 vs 20.62 per 100-person years, respectively, P = .04).

After adjusting for confounders in the overall patient population, the risk for mortality was 18% lower for macitentan compared with ambrisentan (hazard ratio [HR] 0.82, 95% CI 0.72–0.93; P = .0026) and 39% lower for macitentan compared with bosentan (HR 0.61, 95% CI 0.53–0.71; P < .0001). In addition, ambrisentan was associated with a 26% lower mortality risk than bosentan (HR, 0.74, 95% CI 0.67–0.83; P <.0001). Among the ERA-naïve patients, macitentan still had a lower mortality risk than the other 2 agents, but there was no significant difference between ambrisentan and bosentan.

The authors noted that unmeasured confounders and other sources of unrecognized bias could impact the results of the study. In addition, the claims used only provide information on prescriptions and no data on whether the prescriptions were taken as prescribed. Finally, as a retrospective database study, they warn against drawing “firm conclusions regarding causality of the association found in this study.”

“Direct comparison of these agents in a prospective, controlled trial is the only way to definitively answer the question of whether one of the available ERAs confers a survival advantage over the others,” the authors concluded. “Therefore, we advocate conducting an event-driven head-to-head RCT in an elderly and appropriately risk-enriched PAH population.”


Benza RL, Lickert CA, Xie L, et al. Comparative effectiveness of endothelin receptor antagonists on mortality in patients with pulmonary arterial hypertension in a US Medicare population: a retrospective database analysis. Pulm Circ. Published online October 20, 2020. doi:10.1177/2045894020954158