Intra-Arterial Prourokinase Effective for Acute Stroke Therapy

CLINICAL QUESTION: How effective and safe is intra-arterial prourokinase (proUK) in patients with acute stroke of less than 6 hours’ duration caused by middle cerebral artery occlusion?

BACKGROUND: Intravenous tissue-type plasminogen activator (tPA) benefits acute ischemic stroke patients if given within 3 hours. Most stroke patients present after 3 hours of symptoms and are not eligible for tPA. The authors of this study investigated whether this therapeutic window can be extended to 6 hours with the use of intra-arterial proUK in patients with middle cerebral artery ischemic strokes. The investigators chose middle cerebral artery stroke because it is the most frequent site of arterial occlusion in patients with a severe stroke of less than 6 hours’ duration.

POPULATION STUDIED: Fifty-four North American centers screened 12,323 patients who presented with symptoms consistent with acute stroke. Only 180 patients (2%) were eligible for randomization. Major inclusion criteria included symptoms of less than 6 hours’ duration, symptoms consistent with middle cerebral artery stroke, head computed tomography scan negative for hemorrhage or major infarction, and angiographically proven occlusion of the middle cerebral artery. The most common cause of exclusion was failure to make the 6-hour cutoff (4053 patients, 33% of those screened). The average age of participants was 64 years. Women made up 41% of the study, and 80% of participants were white.

STUDY DESIGN AND VALIDITY: This was a randomized trial comparing 9 mg of intra-arterial proUK plus heparin to a control group receiving only heparin. The proUK was infused into the middle cerebral artery through a microcatheter during a 2-hour period. Head computed tomography scans were done at baseline, 24 hours, and at 7 to 10 days to evaluate for parenchymal hemorrhage, and an angiogram was performed on study and control patients at 2-hours to access final vessel patency. A neurologist blinded to treatment assignment assessed patients clinically at 7 to 10 days, 30 days, and 90 days.

Although a small sample was randomized, the study and control groups were similar. Researchers were prevented from knowing to which group patients would be assigned before entering them in the trial (concealed allocation), which prevented selective enrollment of patients. A single-blinded study was chosen for ethical concerns about infusing a placebo into the middle cerebral artery with little chance of benefit. Intention-to-treat analysis was applied.

OUTCOMES MEASURED: The primary outcomes measured were patients achieving a modified Rankin stroke score of 2 or less (slight or no disability) at 90 days and hemorrhagic transformation causing neurologic deterioration within 24 hours of treatment. Secondary outcomes included intracranial hemorrhage with neurologic deterioration at 10 days, the 90-day mortality rate, the middle cerebral artery recanalization rate, and the procedural complication rates.

RESULTS: At 90 days, 40% of the proUK patients and 25% of the control patients had no or minimal disability (P=.04; number needed to harm [NNH]=7). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of proUK patients and 2% of control patients (P=.06; NNH=12). By day 10, intracranial hemorrhage with neurological deterioration remained at 10% in proUK patients and rose to 4% in control patients (P=.22; NNH=17). This probably signifies delayed recanalization with hemorrhagic transformation in the control group. There was no difference in the 90-day mortality rate. Procedural complications consisted of one proUK patient who had worsening of neurologic symptoms during treatment (1/121) and one patient in the proUK group who had anaphylaxis (1/121).