Endothelin receptor antagonists for aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update

Endothelin is considered to be a key mediator of vasospasm after subarachnoid hemorrhage. A meta-analysis of randomized trials on the effectiveness of endothelin receptor antagonists in subarachnoid hemorrhage has been published previously, but since then new major trials have been published. We present the results of a systematic review and meta-analysis update.

We searched the Cochrane Library, the Cochrane Central Register of Controlled Trials, and PubMed with the following terms: subarachnoid hemorrhage AND (endothelin receptor antagonist OR clazosentan OR TAK-044 OR bosentan). All randomized, placebo-controlled trials investigating the effect of any endothelin receptor antagonists in patients with subarachnoid hemorrhage were included. Primary outcome was poor functional outcome (defined as death or dependency). Secondary outcomes were vasospasm, cerebral infarction as defined by investigators, and case fatality during follow-up. Data were pooled and effect sizes were expressed as risk ratio (RR) estimates with 95% confidence intervals (CI). We also calculated RR for several common complications.

in 5 trials with 2601 patients, endothelin receptor antagonists did not affect functional outcome (RR, 1.06: 95% CI, 0.93-1.22) despite a decreased incidence of angiographic vasospasm (RR, 0.58; 95% CI, 0.48-0.71). No effect was observed on vasospasm-related cerebral infarction (RR, 0.76; 95% CI, 0.53-1.11), any new cerebral infarction (RR, 1.04; 95% CI, 0.91-1.19), or case-fatality (RR, 1.04; 95% CI, 0.78-1.39). Endothelin receptor antagonists increased the risk of lung complications (RR, 1.79; 95% CI, 1.52-2.11), pulmonary edema (RR, 2.12; 95% CI, 1.32-3.39), hypotension (RR, 2.42: 95% CI, 1.78-3.29), and anemia (RR, 1.47; 95% CI, 1.19-1.83).

These results argue against the use of endothelin receptor antagonists in patients with subarachnoid hemorrhage.