A RANDOMIZED TRIAL OF INTRAOPERATIVE, INTRACISTERNAL TISSUE-PLASMINOGEN ACTIVATOR FOR THE PREVENTION OF VASOSPASM

A MULTICENTER, RANDOMIZED, blinded, placebo-controlled trial was conducted to study the possible role of intracisternally administered fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) in preventing delayed onset cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The target population was patients with ruptured saccular aneurysms causing severe SAH, placing them at high risk for vasospasm, Treatment consisted of a single 10 ml intraoperative injection of either vehicle buffer solution or rt-PA (1 mg/ml) into the opened basal subarachnoid cisterns immediately following aneurysm clipping. The major efficacy endpoint in this trial was angiographic vasospasm, and the major safety concern was intracranial hemorrhage. One hundred patients were randomized, 49 to placebo and 51 to rt-PA treatment, Baseline population characteristics were similar between the two groups. Severity of intracranial hemorrhage on computed tomographic scans was also similar between groups: 87.2% of both placebo and rt-PA treated patients had thick subarachnoid clots, and the rates for intracerebral and intraventricular hemorrhage were, respectively, 16.3% and 22.5% for placebo and 23.5% and 21.6% for rt-PA, Nine randomized patients did not receive treatment in the operating room, and in 8 this was due to conditions felt unsafe for the administration of a fibrinolytic agent. The overall incidence of angiographic vasospasm measured between the seventh and eleventh day following SAH was similar between the two groups, with arterial narrowing detected in 74.4% of dosed placebo patients and 64.6% of rt-PA treated patients. However, there was a trend toward lesser degrees of vasospasm in the rt-PA treated group. The rates for no or mild, moderate, and severe vasospasm were 69%, 16% and 15% in the rt-PA treated group, versus 42%, 35% and 23% in the placebo group (P = 0.07). When only those patients with thick subarachnoid clots were considered at the treating centers, there was a 56% relative risk reduction of severe vasospasm in the rt-PA treated group, which was significant (P = 0.02). Other trends in the rt-PA treated group (not reaching statistical significance) included less hypervolemic and hypertensive treatment, lower mean velocities on transcranial Doppler, reduced delayed neurological worsening, a lower 14 day mortality rate, and improved 3 month outcome rate. Considering just the dosed patients with thick clot, 56% made a good recovery and 12% died in the rt-PA group, versus 38% making a good recovery and 22% dying in the placebo group (P = 0.17). Overall bleeding complication rates did not differ between the two groups. Two treatment-related severe hemorrhages resulted from incompletely secured aneurysms that rebled shortly following treatment. Although the fibrinolytic treatment used in this study may reduce angiographic vasospasm, its efficacy in preventing clinical vasospasm and its ischemic consequences require reexamination in a larger randomized trial.