Randomised Trial of Clazosentan, an Endothelin Receptor Antagonist, in Patients with Aneurysmal Subarachnoid Hemorrhage Undergoing Surgical Clipping (CONSCIOUS-2)

Abstract

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

Natural course of subarachnoid hemorrhage is worse in elderly patients

“…It impairs several physiologic patterns related to cerebrovascular hemodynamics and homeostasis 6,7,8,9,10,11,12 . There is a decline in cerebral blood flow velocity with age, which may be associated with certain changes as: decreased cerebral blood flow (CBF) or metabolic demands; vessel changes like progressive kinking, calcifications (Figure 4), elongation, stenosis and lower cardiac output 1,2,3,11,13,14,15 . It is also associated with a 20% to 30% decrease in CBF in healthy individuals between the ages of 20 and 80 years and with dilatation of major extracranial arteries and reduction of flow within parenchymal vessels 1,13,14,15 .…”

“…There is a decline in cerebral blood flow velocity with age, which may be associated with certain changes as: decreased cerebral blood flow (CBF) or metabolic demands; vessel changes like progressive kinking, calcifications (Figure 4), elongation, stenosis and lower cardiac output 1,2,3,11,13,14,15 . It is also associated with a 20% to 30% decrease in CBF in healthy individuals between the ages of 20 and 80 years and with dilatation of major extracranial arteries and reduction of flow within parenchymal vessels 1,13,14,15 . All those statements justify that elderly usually present with more severe SAH than younger patients, characterized by higher Fisher and Hunt Hess grades.…”

“…Although it is associated with hypercholesterolemia, chronic hypertension and atherosclerosis, there is lower incidence of VSP in older patients, probably secondary to the age-related impairment of contractility and elasticity of the muscle wall of small arteries and arterioles. However, the severity of VSP in such patients is pronounced as the margin between adequate CBF and the ischemic threshold may become especially narrow 13,14,15 . Several limitations should be pointed out.…”

Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage

“…While the hemorrhage itself and associated global cerebral hypoxia induce fatal brain injury in some patients, clinical outcome in patients surviving the initial hemorrhagic event is thought to be largely determined by cerebral hypoperfusion and large vessel vasospasm (CV) [1][2][3][4][5][6], which occur in the days and weeks following the bleeding event due to pathophysiological events induced by the subarachnoid hematoma [4]. However, more recent clinical studies have reported discrepancies between CV, cerebral hypoperfusion, and neurological outcome [7][8][9][10][11], attenuating the association of CV with an unfavorable outcome.…”

Drug treatment of cerebral vasospasm after subarachnoid hemorrhage following aneurysms

“…The results showed that clazosentan treatment after aneurysmal SAH significantly reduced the incidence of the vasospasm-related DINDs and DCI. However, subsequently a randomized, double-blind, placebo-controlled study [69] claimed that clazosentan did not significantly decrease mortality/ vasospasm-related morbidity and increase poor functional outcomes in patients with aneurysmal SAH undergoing surgical clipping.…”