Induced Suppression of Platelet Activity in Aneurysmal SAH Management-2 (iSPASM-2)

Duke University, Durham NC

Investigators

Linked publications, trials & patents

Abstract

Intracranial aneurysm (IA) is a prevalent disease affecting ~2–5% of the population. Aneurysm rupture leads to aneurysmal subarachnoid hemorrhage (aSAH), which accounts for 2–5% of all new strokes and affects 21,000 to 33,000 patients each year in the United States (US). It poses an extremely high rate of mortality (~60%) and morbidity, with a large proportion (30–40%) of survivors rendered functionally dependent. Tragically, compared with others forms of stroke, aSAH disproportionately affects people of color, women, and young people. Delayed cerebral ischemia (DCI) is a prevalent and serious complication of aSAH, occurring in 30–40% of cases. It is the most consistent treatable predictor of morbidity, and plays an essential role in the persistent cognitive, social, emotional, and functional morbidity of survivors. Despite the complex pathophysiology of DCI, prior investigation has been almost exclusively focused on a narrow conception of DCI arising from narrowing of the arteries within the brain (arterial vasospasm). Our group has focused on arterial microthrombosis as a potential substrate for DCI after aSAH and has generated robust pre-clinical data supporting a role for anti-platelet therapy in ameliorating the devastating consequences of DCI. We completed an FDA-IND approved, single-center, double-blinded, randomized, clinical trial which aimed to determine the feasibility of delivering a continuous intravenous (IV) infusion of tirofiban or matched saline placebo to patients with aSAH. Thirty subjects with aSAH who were treated by external ventricular drain (EVD) then endovascular coiling were enrolled and treated with continuous IV tirofiban or placebo for 7 days post- treatment. There was no significant difference in hemorrhage associated with EVD and adverse events between groups. However, tirofiban-treated patients had a lower incidence of DCI compared with placebo- treated patients. Tirofiban also reduced the incidence of clinical vasospasm. The study was limited by its single center design and the fact that the EVD was placed in the operative room (OR) rather than bedside. A logical next step is to deploy IV tirofiban in a pragmatic, multi-center setting and to determine the maximum tolerated treatment dosage in advance of a fully-powered efficacy trial. Our primary objective is to determine the maximum tolerated treatment dosage for IV infusion of tirofiban in patients with aSAH who status post successful endovascular coiling are. Secondarily, we will examine the pharmacology of tirofiban in the setting of aSAH to better inform dosage schedules in a future clinical trial. To accomplish these objectives, we propose a pragmatic, randomized (2:1), double- blinded, placebo-controlled, multi-center clinical trial. Participants with aSAH (with and without EVD placement) will be randomized to IV tirofiban (at an infusion duration of 1, 3, 5, or 7 days) or saline placebo. Two large-volume endovascular centers (Duke University and University of Texas-Houston) will recruit and enroll subjects. The primary end point is dosage-limiting toxicity (any intracranial hemorrhage, major bleeding, thrombocytopenia, or serious adverse event due to tirofiban). Exploratory end points will include DCI, clinical vasospasm, and functional outcome as measured by the modified Rankin Scale (mRS) score at 90 days. Rigorously-ascertained data from this study will be used to select the appropriate dosage of IV tirofiban in this context. These data will be tested against explicitly-defined “Go-No Go” criteria to determine whether progression to the next phase is warranted.