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

A MULTICENTER, RANDOMIZED, blinded, placebo-controlled trial was condu cted to study the possible role of intracisternally administered fibri nolytic agent recombinant tissue plasminogen activator (rt-PA) in prev enting delayed onset cerebral vasospasm following aneurysmal subarachn oid 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 inject ion of either vehicle buffer solution or rt-PA (1 mg/ml) into the open ed 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 hundre d patients were randomized, 49 to placebo and 51 to rt-PA treatment, B aseline population characteristics were similar between the two groups . Severity of intracranial hemorrhage on computed tomographic scans wa s also similar between groups: 87.2% of both placebo and rt-PA treated patients had thick subarachnoid clots, and the rates for intracerebra l and intraventricular hemorrhage were, respectively, 16.3% and 22.5% for placebo and 23.5% and 21.6% for rt-PA, Nine randomized patients di d not receive treatment in the operating room, and in 8 this was due t o conditions felt unsafe for the administration of a fibrinolytic agen t. The overall incidence of angiographic vasospasm measured between th e seventh and eleventh day following SAH was similar between the two g roups, with arterial narrowing detected in 74.4% of dosed placebo pati ents and 64.6% of rt-PA treated patients. However, there was a trend t oward lesser degrees of vasospasm in the rt-PA treated group. The rate s 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 gr oup (P = 0.07). When only those patients with thick subarachnoid clots were considered at the treating centers, there was a 56% relative ris k 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 r eaching statistical significance) included less hypervolemic and hyper tensive treatment, lower mean velocities on transcranial Doppler, redu ced delayed neurological worsening, a lower 14 day mortality rate, and improved 3 month outcome rate. Considering just the dosed patients wi th thick clot, 56% made a good recovery and 12% died in the rt-PA grou p, versus 38% making a good recovery and 22% dying in the placebo grou p (P = 0.17). Overall bleeding complication rates did not differ betwe en the two groups. Two treatment-related severe hemorrhages resulted f rom incompletely secured aneurysms that rebled shortly following treat ment. Although the fibrinolytic treatment used in this study may reduc e angiographic vasospasm, its efficacy in preventing clinical vasospas m and its ischemic consequences require reexamination in a larger rand omized trial.