Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

Abstract

ABSTRACT:Objective: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, has demonstrated efficacy and safety in treating patients with PAH due to a WHO Group I etiology. In this report, we describe the 3-year efficacy and safety of ambrisentan in patients with CTD associated PAH (CTD-PAH). Methods:Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-minute walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Categorical (30m) breakpoints for 6MWD were evaluated and additional analyses were conducted to determine any relationship between 6MWD and survival.Results: 124 patients with CTD-PAH were evaluated. Survival information at 3 years was available for 112 (90%) subjects; clinical worsening data was available for 68% of subjects at 3 years, and 6MWD results were available for 73%, 60%, and 44% of subjects at 1-, 2-, and 3-years, respectively. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3-years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Factors with prognostic relevance included: improving 6MWD ≥ 30m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222m. Conclusion:These analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed improved clinical worsening and survival compared to historical controls. Furthermore, several key exercise parameters were identified which appear important in guiding individual patient treatment.

Major lung complications of systemic sclerosis

“…Therapies have progressed from a time when only intravenous epoprostenol was available [144,145] and outcomes were very poor, to the current availability of multiple licensed treatments that can be used in combination ( Table 2). The early studies that led to the licensing of various PAH therapies, including bosentan and sildenafil, focused on short term gains in exercise capacity; in these studies, the response of patients with SSc-associated PAH or CTD-associated PAH was often less efficacious than patients with other forms of PAH, although most treatments seem to result in meaningful benefit in the majority of patients with SSc-associated PAH [146,147,148,149]. However, evidence in clinical practice suggests that these therapies have long-term benefits in SSc-associated PAH [142], which is supported by key eventdriven clinical trials published in the past 3 years [150,151,152]: the SERAPHIN trial (which tested the oral endothelin receptor antagonist macitentan), the GRIPHON trial (which tested the prostcyclinreceptor agonist selexipag) and the AMBITION trial (which tested a combination therapy of ambrisentan (endothelin receptor antagonist) and tadalafil (a PDE5 inhibitor)).…”

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension‐connective tissue disease subtype: A systematic review and meta‐analysis

“…3 From included studies in F I G U R E 4 Forest plot comparing Combination vs Monotherapy A, 6 min walk distance; B, clinical failure endpoint our analysis, the pattern of frequency of AEs appears similar to that of the idiopathic subtype. 3,31 Vasodilatory AEs, such as peripheral edema, were more common with initial combination therapy compared to monotherapy. 3 Choosing…”

“…However, CTD-specific data from 3 of these studies were reported in 3 subsequent publications. 3,30,31 The final analysis included a total of 3100 PAH patients, of whom 784 belonged to the CTD-PAH subgroup (25.3%). Characteristics of the included studies are summarized in Table 1 Five studies compared various forms of combination therapy to monotherapy.…”

<p>Management of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis</p>

“…74 In the ARIES-1/ARIES-2 trials, ambrisentan improved the 6MW distance and slowed clinical worsening in CTD-PAH, though survival was better in the IPAH population. 75,76 The SERAPHIN trial showed that macitentan reduced morbidity and mortality in PAH patients, after-which a meta-analysis showed similar outcomes between IPAH and CTD-PAH. 77,78 ERA side effects include elevated liver function tests (bosentan), peripheral edema and anemia (all).…”