Key result
Combination therapy with endothelin receptor antagonists and PDE5 inhibitors significantly reduced the risk of clinical failure compared to ERA monotherapy (OR 0.54; 95% CI 0.32-0.90; P=.02).
Why the study?
CTD-PAH is characterized by poorer clinical outcomes than other PAH subtypes, and information on the effectiveness of endothelin receptor antagonists in this population was limited.
Does endothelin receptor antagonist therapy, alone or combined with PDE5 inhibitors, improve clinical failure endpoints and 6-minute walk distance in patients with connective tissue disease-pulmonary arterial hypertension?
Meta-Analysis (n=784)
Does endothelin receptor antagonist therapy, alone or combined with PDE5 inhibitors, improve clinical failure endpoints and 6-minute walk distance in patients with connective tissue disease-pulmonary arterial hypertension?
Combination therapy with endothelin receptor antagonists and PDE5 inhibitors significantly reduces clinical failure endpoints in patients with connective tissue disease-associated pulmonary arterial hypertension compared to monotherapy.
ERA monotherapy fails to cut clinical failure events in CTD-PAH; challenges monotherapy and supports combination regimens in this high-risk population.
INTRODUCTION: There is limited information regarding the effectiveness of endothelin receptor antagonists (ERA) in patients with connective tissue disease-pulmonary arterial hypertension (CTD-PAH), a condition that is characterized by poorer clinical outcomes compared to other PAH subtypes. OBJECTIVE: To conduct a systematic review and meta-analysis of the effectiveness and safety of ERA in CTD-PAH. METHODS: A literature search, using MEDLINE, COCHRANE, CINAHL and EMBASE databases was conducted, from inception to May 2019 to identify randomized control studies of ERA, as monotherapy or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in CTD-PAH. A protocol was registered in PROSPERO (CRD42019136956). Efficacy outcomes, including the 6-minute walk distance (6MWD) and composite clinical failure endpoints (CFE), and safety outcomes were evaluated. RESULTS: A total of 13 studies, including 784 CTD-PAH participants, were identified. ERA, as monotherapy, did not reduce the risk of CFE compared to placebo (odds ratio [OR] 0.77, 95% CI 0.50-1.19, P = .25). By contrast, combination therapy (ERA + PDE5i) significantly reduced the risk of developing CFE vs monotherapy (OR 0.54, 95% CI 0.32-0.90, P = .02). 6MWD did not improve when comparing monotherapy vs placebo (+17.41 m; 95% CI -19.83-54.66) P = .36) or combination therapy vs monotherapy (+13.17 m; 95% CI -16.44-42.78, P = .38). ERA-related adverse events rates in CTD-PAH and general PAH cohorts were comparable. CONCLUSIONS: ERA, when used in combination with PDE5is, are associated with reduced risk of CFE, but no significant changes in 6MWD, in CTD-PAH. This warrants further studies investigating early combination therapy as a standard of care in this group.
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Shivakumar et al. (2020) conducted a meta-analysis in Connective tissue disease-pulmonary arterial hypertension (CTD-PAH) (n=784). Endothelin receptor antagonists (ERA) in combination with PDE5 inhibitors vs. ERA monotherapy was evaluated on Composite clinical failure endpoints (CFE) (OR 0.54, 95% CI 0.32-0.90, p=.02). Combination therapy with endothelin receptor antagonists and PDE5 inhibitors significantly reduced the risk of clinical failure compared to ERA monotherapy (OR 0.54; 95% CI 0.32-0.90; P=.02).
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