Tissue-type plasminogen activator (tPA) is known to improve outcomes after ischemic stroke, but its use is limited because it must be given within three hours of symptom onset. Furlan and the other investigators of the first Prolyse in Acute Cerebral Thromboembolism (PROACT) trial, conducted this study to determine if intra-arterial recombinant prourokinase (r-proUK) was safe and efficacious in patients with ischemic stroke of fewer than six hours' duration caused by middle cerebral artery (MCA) occlusion.

Adult patients 18 to 85 years of age were included if they had new neurologic signs in the MCA and could be treated within six hours. Each participant had to have a National Institutes of Health Stroke Scale score of at least four. Exclusion criteria included rapidly improving neurologic signs, recent history of previous stroke, history of an intracranial hemorrhage, recent head or other trauma, or recent lumbar puncture. All participants underwent diagnostic cerebral angiography of the MCA distribution in question.

Patients with complete occlusion or with contrast penetration with minimal perfusion were included. Arterial dissection and arterial stenosis were some of the exclusion criteria. Patients were then randomized to receive intravenous (IV) heparin or IV heparin plus 9 mg of intra-arterial r-proUK over a two-hour period. The IV heparin was given as a bolus infusion of 2,000 units followed by an infusion of 500 units per hour, starting at the time of the angiography. An infusion micro-catheter was placed in the MCA, and intra-arterial r-proUK was infused at a rate of 4.5 mg per hour. After one hour of infusion, a repeat angiogram was obtained. Regardless of the result, the remaining intra-arterial r-proUK was infused over the next hour. Computed tomographic (CT) scans were done at baseline, 24 hours and about one week after treatment started. Extent of recanalization was recorded, as was clinical efficacy at seven to 10 days, 30 days and 90 days after treatment. The primary outcome was the percentage of patients who had slight or no disability.

Of the 12,323 patients with acute stroke symptoms, 180 were determined to be eligible for randomization. There were 121 patients in the intra-arterial r-proUK group and 59 in the IV heparin-only group. The median time to initiation of intra-arterial r-proUK was 5.3 hours. One-quarter of the control group (heparin only) and 40 percent of the treatment group achieved ratings at 90 days consistent with slight or no disability (number needed to treat to benefit: seven). Patients in the treatment group regained independence in activities of daily living earlier than patients in the control group. Other secondary outcomes also showed benefit from intra-arterial r-proUK, although none of these achieved clinical significance. Although the intracranial hemorrhage rate within the first day of treatment was 35 percent for the treatment group and 13 percent for the control group, the intracranial hemorrhage rate after 10 days was 68 versus 57 percent, a nonsignificant difference. The intracranial hemorrhage was accompanied by neurologic deterioration within the first 24 hours in 10 percent of the treatment group and 2 percent of the control group (number needed to treat to harm: 12).

The authors conclude that by using other lytic agents (such as intra-arterial r-proUK) instead of tPA, the therapeutic window for acute ischemic stroke may be widened.

editor's note: The treatment of stroke is clearly advancing. Surprisingly, even the PROACT II study treated only one patient (out of 121 randomized to receive treatment) with intra-arterial r-proUK within three hours of the onset of stroke symptoms. This study underscores the need for primary care physicians to continue to educate their patients about the warning signs of a “brain attack,” so that these treatment advances are not for nothing.—g.b.h.