Reassessment of defibrase in treatment of acute cerebral infarction: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of defibrase in patients with acute cerebral infarction by a large sample, multicenter, randomized, double-blind, placebo-controlled clinical trial.

METHODS: Patients with acute cerebral infarction within 12 hours of stroke onset were randomly assigned to receive either an initial intravenous infusion of defibrase 15 U plus normal saline 250 mL or 250 mL of normal saline only. Subsequent infusions of defibrase 5 U or placebo (normal saline) were given on the 3rd, 5th, 7th, and 9th day, respectively. Both groups received standard care of acute cerebral infarction. The primary efficacy outcome was functional status (Barthel Index) at 3 months after treatment. Safety outcome were bleeding events and mortality rate. Secondary outcome included Chinese Stroke Scale (CSS) score at 14 days and recurrence rate of stroke at 1 year.

RESULTS: A total of 1053 patients were enrolled at 46 centers from September 2001 to July 2003, and 527 patients were randomly assigned to receive defibrase and 526 to receive placebo. A similar proportion of patients in both groups completed a full course of treatment. There was a significantly greater proportion of favorable functional status (Barthel Index > or = 95) in defibrase group than in placebo group at 3 months (52.2% vs. 42.8%, P < 0.01), and the proportion of dependent functional status (Barthel Index < or = 60) was a little lower in defibrase group compared with placebo group (27.7% vs. 32.4%). These differences were more obvious among patients who were treated within 6 hours of stroke onset. Patients in defibrase group had better improvement with respect to CSS score than those in placebo group at 14 days (P < 0.05). Recurrence rate of stroke at 1 year was lower in the defibrase group compared with placebo group (6.2% vs. 10.1%, P = 0.053). Patients in defibrase group had higher risk of extracranial bleeding events (4.7% vs. 1.5%, P < 0.01) and a tendency of higher risk of symptomatic intracranial hemorrhage. The hemorrhage incidence was higher in patients with fibrinogen level < 130 mg/dL than > or = 130 mg/dL (10.6% vs. 3.8%, P < 0.05). Mortality rate at 3 months were slightly higher in defibrase group than placebo group (5.9% vs. 4.2%).

CONCLUSIONS: The defibrase is effective to improve neurological function and function of daily living for patients with acute cerebral infarction within 12 hours of symptom onset. The efficacy was even better for acute cerebral infarction within 6 hours of onset. The increased risks of intra- and extracranial hemorrhage during defibrase administration were related to the plasma fibrinogen level.