Aptiganel hydrochloride in acute ischemic stroke - A randomized controlledtrial

Context Tissue plasminogen activator is the only thrombolytic agent approve d in the United States for treatment of acute ischemic stroke, and has limi tations. Aptiganel hydrochloride is a novel and selective ligand for the io n-channel site of the N-methyl-D-aspartate receptor-channel complex and a p romising neuroprotective agent in animal models of focal brain ischemia. Objective To determine whether aptiganel improves the clinical outcome for acute ischemic stroke patients. Design Nested phase 2/phase 3 randomized controlled trial conducted between July 1996 and September 1997. Setting One hundred fifty-six medical centers in the United States, Canada, Australia, South Africa, England, and Scotland. Participants A total of 628 patients with hemispheric ischemic stroke (50.3 % male; mean age, 71.5 years). Interventions Patients were randomly assigned within 6 hours of stroke to r eceive 1 of 3 treatment regimens: high-dose aptiganel (5-mg bolus followed by 0.75 mg/h for 12 hours; n=214); low-dose aptiganel (3-mg bolus followed by 0.5 mg/h for 12 hours; n=200); or placebo (n=214). Main Outcome Measures The primary efficacy end point was the Modified Ranki n Scale score at 90 days after stroke onset. Secondary end points included mortality and change in National Institutes of Health (NIH)Stroke Scale sco re at 7 days after stroke. Results The trial was suspended by the sponsor and the independent data and safety monitoring board because of both a lack of efficacy and a potential imbalance in mortality. There was no improvement in outcome for either apt iganel (low-dose or high-dose) group compared with the placebo group at 90 days (median Modified Rankin Scale score for all 3 treatment groups=3; P=.3 1). At 7 days, placebo-treated patients exhibited slightly greater neurolog ical improvement on the NIH Stroke Scale than high-dose aptiganel patients (mean improvement for placebo group, -0.8 points vs for high-dose aptiganel , 0.9 points; P=.04). The mortality rate at 120 days in patients treated wi th high-dose aptiganel was higher than that in patients who received placeb o (26.3% vs 19.2%; P=.06). Mortality in the low-dose aptiganel group was 22 .5% (P=.39 vs placebo). Conclusions Aptiganel was not efficacious in patients with acute ischemic s troke at either of the tested doses, and may be harmful. The larger proport ion of patients with favorable outcomes and lower mortality rate in the pla cebo group suggest that glutamate blockade with aptiganel may have detrimen tal effects in an undifferentiated population of stroke patients.