Prolyse in Acute Cerebral Thromboembolism Trials I and II

Prolyse in acute cerebral thromboembolism trials (PROACT) I was a Phase 2, randomized, blinded trial that compared the safety and recanalization frequency in patients who presented in <6 hr of a clinically symptomatic MCA occlusion (26). After a CT scan excluded hemorrhage, all patients were taken for cerebral angiography. Patients demonstrating an occlusion in the M1 or M2 segment of the MCA were randomized in a 2:1 fashion to receive either a placebo or rpro-UK (6 mg) over 2 hr into the proximal-third of the thrombus face. All patients received IV heparin (bolus followed by infusion) for 4 hr after occlusion was confirmed. The primary efficacy endpoint was recanalization of the M1 or M2 at 120 min after initiation of infusion. The primary safety outcome was hemorrhagic transformation that caused neurologic deterioration within 24 hr. Out of 1314 patients screened, 40 were treated (26 with rpro-UK, 14 with placebo). During the study, the hemorrhage rate that caused neurologic worsening was 72.7% in the rpro-UK group and 20.0% in the placebo group. Consequently, the trial was continued with a decreased heparin dose. The recanalization rate for all patients receiving rpro-UK was 57.7% versus 14.3% ( p=0.017) for the placebo group. Although the numbers were too small for statistical significance, there appeared to be a 10% to 12% absolute increase in excellent neurologic outcome at 90 days in the rpro-UK group against placebo. The rate of mortality in the rpro-UK group was 26.9% versus 42.9% in the placebo group (p = 0.48).

In PROACT II, patient selection was similar, but the protocol differed from PROACT I in the following ways: more patients treated (180), higher rpro-UK dose (9 mg), and all patients were placed on low-dose heparin (2000 U bolus followed by a 4-hr infusion of 500 U). The primary outcome was based on the proportion of patients with slight or no neurologic disability at 90 days (mRS > 2). Although the hemorrhage rate with neurologic deterioration within 24-hr was higher in the rpro-UK group than in the placebo (10% vs. 2%; p= 0.06), patients in the rpro-UK group did better at three months. Forty percent of rpro-UK patients and 25% of placebo patients achieved an mRS of < 2 ( p=0.04). The recanalization rates were 66% for the rpro-UK group and 18% for the control group ( p < 0.001). The difference in mortality was insignificant (27).

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