Vasospasm after aneurysmal subarachnoid hemorrhage: need for further study.
Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing. A phase 2b clinical trial (CONSCIOUS-1) demonstrated marked prevention of vasospasm with the endothelin antagonist, clazosentan, yet patient outcome was not improved. The most likely explanation is that the study was underpowered to detect the relatively small improvements in outcome that would be seen with prevention of vasospasm, especially when assessed using relatively insensitive measures such as the modified Rankin and Glasgow outcome scales. Other possible explanations for this result are that adverse effects of treatment affected the beneficial effects of the drug. It also is possible that alternative causes of neurological deterioration and poor outcome after SAH, including delayed effects of acute global cerebral ischemia, thromboembolism, microcirculatory dysfunction, and cortical spreading depression, play a role. Clazosentan reduced angiographic vasospasm in a dose-dependent manner in patients with aneurysmal SAH following coiling or clipping of the aneurysm. Reducing the incidence of vasospasm should have an important effect on clinical outcome. A phase 3 clinical trial (CONSCIOUS-2) will focus on quantifying this outcome in patients undergoing aneurysm clipping receiving placebo or 5 mg/h of clazosentan.
Pearl
J D
JD
Division of Neurosurgery and Keenan Research Centre, St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Macdonald
R L
RL
D017322:Clinical Trials, Phase II as Topic; D004146:Dioxanes / Q000627:therapeutic use; D016232:Endothelins / Q000037:antagonists & inhibitors; D006801:Humans; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013449:Sulfonamides / Q000627:therapeutic use; D013777:Tetrazoles / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology
D004146:Dioxanes; D016232:Endothelins; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan