A review of STRIDE‐2 and STRIDE‐2X: the case for selective endothelin receptor blockade

Abstract

Pulmonary arterial hypertension remains incurable and has previously required difficult parenteral therapy. Endothelin-1(ET-1) is an important mediator of pulmonary arterial hypertension. The recent availability of oral therapies, including endothelin receptor antagonists, has improved ease of use for patients, but most patients remain symptomatic to a significant degree. Two classes of ET-1 receptors have been described, ET(A) and ET(B). It has previously been unclear whether both receptors must be blocked in pulmonary arterial hypertension, or only the ET(A) receptor. The Sitaxsentan To Relieve ImpaireD Exercise-2 (STRIDE-2) study followed by STRIDE-2X exposed patients with pulmonary arterial hypertension to the highly selective ET(A) antagonist sitaxsentan (n = 145), or to bosentan (n = 84), a nonselective ET(A) and ET(B) antagonist. The total exposure duration and follow-up period was 1 year. Pre-specified comparisons included time to discontinuation of monotherapy, time to clinical worsening, incidence of elevated hepatic transaminase levels > 3 x upper limit of normal and survival. Sitaxsentan therapy showed significant benefit over bosentan with respect to discontinuation of monotherapy at 1 year (24% vs. 43%, P = 0.002), clinical worsening at 1 year (28% vs. 39%, P = 0.0425), elevated hepatic transaminases at 1 year (4% vs. 14%, P = 0.014) and 1-year survival (96% vs. 88%, P = 0.028). STRIDE-2 and its extension, STRIDE-2X, suggest significant benefit of sitaxsentan compared with bosentan, in terms of efficacy and reduced hepatotoxicity. The former may be related to the high ET(A) receptor selectivity of sitaxsentan.