Endothelin Receptor Antagonist Therapy Less Effective for SSc-related PH

Initial oral therapy with an endothelin receptor antagonist (ERA) in patients with systemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) resulted in significantly worse time to clinical worsening, compared with those who received initial treatment with a phosphodiesterase 5 (PDE5) inhibitor, according to research published in Arthritis & Rheumatology.¹

Researchers used data from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry to examine SSc patients who received initial therapy with ERA, PDE5, or a combination of the 2 agents. The study included 24 patients who received initial therapy for 6 months with ERA, 59 who received PDE5 inhibitors, and 15 who received ERA and PDE5 combination therapy.

The time to clinical worsening (TTCW) was significantly shorter among patients receiving ERA monotherapy compared with patients receiving PDE5 or a combination of ERA and PDE5. Ten patients (41.6%) from the ERA group died during the 3-year follow-up period, compared to only 4 patients (6.8%) in the PDE5 inhibitor group, and 1 patient (6.7%) in the combination therapy group.  Initial treatment with an ERA was independently associated with shorter TTCW (hazard ratio [HR] 2.63 [P<.009]).

“Our analysis could not provide answers to any mechanistic questions, but pharmacologic factors could explain the worse outcomes seen in the patients initially treated with ERAs,” the authors wrote. “Fluid retention is a common side effect of ERAs, occurring in 6-28% of patients in clinical studies, and has even been severe enough to cause drug continuation. This potential for fluid retention may have driven TTCW events such as PAH-related hospitalization and prostacyclin initiation.”

The researchers also noted other factors associated with a shorter TTCW, including lower diffusing capacity for carbon monoxide (HR: 0.69 per 10% of predicted change; P=.04) and higher pulmonary vascular resistance (HR: 1.10 per Wood unit change; P=.007).

“This study highlights the need for randomized controlled trials performing head-to-head comparisons between PAH-specific medications specifically in patients with SSc as well as registry studies with long-term clinical follow-up to properly define ‘real world’ outcomes,” the authors noted.

Summary and Clinical Applicability

In this study, researchers sought to compare TTCW after initiating different oral therapies, including ERA and PRE5, for patients with SSc-related PAH. They found that initial therapy with an ERA was associated with significantly worse TTCW when compared to PDE5 inhibitor monotherapy or PDE5 inhibitor-ERA combination therapy.

The authors note that the unexpected results were not explained by differences in measured baseline variables between the groups. Even after adjustment for prognostic variables, initial ERA was associated with more than a 2.5-fold increased risk of clinical worsening. Although the results of the study were not definitive, and further research is required to determine the optimal initial oral therapy for this patient population.

 Of clinical note, peripheral edema is the most common adverse effect seen with ERA use.  Mild cases of peripheral edema can be managed with oral diuretics, however severe cases may warrant ERA discontinuation.²  Additionally, ERAs are potent teratogens (FDA category X) and are absolutely contraindicated in pregnancy.³

Reference

1.       Lammi MR, Mathai SC, Saketkoo LA, et al. Association between initial oral therapy and outcomes in systemic sclerosis—related pulmonary arterial hypertension. Arthrit Rheum. 2016; 68(3):740-748. doi: 10.1002/art39478.

2.       Aversa M, Porter S, Granton J. Comparative safety and tolerability of endothelin receptor antagonists in pulmonary arterial hypertension. Drug Saf. 2015;38(5):419-35.

3.       Liu C, Chen J, Gao Y, et al. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2013; 2:CD004434.