The outcome of trials for therapeutics directed at reversing vasospasm has been less than satisfactory. The mainstay of vasospasm treatment after SAH has been triple-H therapy (hemodilution, hypervolemia, and hypertension). First, it is unclear whether triple-H therapy has beneficial effects on CBF. In a recent review by Dankbaar et al,22 only hypertensive therapy demonstrated more consistent positive effects on CBF. In terms of clinical outcome, there is even a greater paucity of comparative trials studying triple-H therapy or any of its components. In a randomized controlled trial of hypervolemia by Lennihan et al,23 no difference in mean global CBF as measured by xenon-CT or clinical outcome at 3 months was detected. A small randomized controlled trial of prophylactic hypervolemia and hypertensive therapy found no difference in TCD vasospasm, clinical vasospasm, perfusion on SPECT, or clinical outcome at 1 year.24 A retrospective review of patients with SAH with symptomatic vasospasm who were treated with an algorithm of hypervolemia and hypertensive therapy showed that clinical responders to therapy did not show improvements in activities of daily living or cognitive function and had the same cerebral infarction rate as those who did not respond to therapy.25 The emerging second line of treatment for vasospasm has become endovascular interventions. Angioplasty and intra-arterially delivered vasodilators such as papaverine and verapamil have shown the ability to reverse angiographic vasospasm.1 However, there is no definitive evidence that the interventions have improved outcomes.26 A randomized study of prophylactic balloon angioplasty in patients with SAH with Fisher scale III hemorrhages demonstrated no difference in clinical outcomes between the treatment and control groups.27 To date, the 1 drug that has consistently decreased the risk of death, disability, and delayed ischemia after SAH is nimodipine.28 Initially thought to target vasospasm and therefore prevent DCI, it has subsequently been shown to have no effect on the development of vasospasm after SAH.29 Interestingly, nicardipine, another calcium channel blocker, appears to reduce vasospasm but has no effect on clinical outcome.28,29 Most recently, attention has been directed toward endothelin, a potent endogenous vasoconstrictor and has been implicated in the pathogenesis of vasospasm. In experimental models of SAH, endothelin receptor antagonists demonstrated the ability to reduce vasospasm.30 Although an initial trial with a nonselective endothelin receptor antagonist demonstrated no difference in cerebral infarction rates or clinical outcomes,31 it was suggested that the lack of effect could result from inhibition of both endothelin A and endothelin B receptors, which have opposing effects on vascular tone, endothelin A mediating vasoconstrictor and endothelin B vasodilatation. Therefore, it was hypothesized that a selective endothelin A receptor antagonist may have a benefit. Two trials were conducted using the endothelin A receptor antagonist clazosentan. The preliminary phase 2a study32 demonstrated reduction of angiographic vasospasm. In the follow-up CONSCIOUS-1 study,33 which involved 413 patients, a dose-dependent reduction of angiographic vasospasm was observed. In the highest-dose group, there was a 65% relative risk reduction of vasospasm. Despite this impressive efficacy in ameliorating vasospasm, no significant difference in mortality or morbidity was shown. Thus, effective reversal of vasospasm did not translate into reduction of DCI-related mortality or morbidity and brings to question the primary role of vasospasm in the development of DCI.