Endothelin antagonists in subarachnoid hemorrhage: what next?

In the previous issue of Critical Care, Ma and colleagues perform a meta-analysis of five randomized, clinical trials of endothelin antagonists in patients with aneurysmal subarachnoid hemorrhage. There are four trials using clazosentan and one trial with TAK-044. These studies show that endothelin plays an important role in the genesis of angiographic vasospasm. The benefit of these drugs is less on delayed cerebral ischemia and nonexistent on overall clinical outcome. Why the drugs reduce vasospasm but do not improve outcome could be because of side effects such as hypotension and pulmonary complications that are more common in patients treated with endothelin antagonists or because rescue therapy, which is used more in the placebo groups, improves outcome in these patients to the same extent as the endothelin antagonists. As the authors conclude, future studies of these drugs will need to consider these and other factors in their design.