Aptiganel Hydrochloride in Acute Ischemic Stroke: A Randomized Controlled Trial
2001
ContextTissue plasminogen activator is the only thrombolytic agent approved
in the United States for treatment of acute ischemic stroke, and has limitations.
Aptiganel hydrochloride is a novel and selective ligand for the ion-channel
site of the N-methyl-D-aspartate receptor-channel
complex and a promising neuroprotective agent in animal models of focal brain
ischemia.ObjectiveTo determine whether aptiganel improves the clinical outcome for acute
ischemic stroke patients.DesignNested phase 2/phase 3 randomized controlled trial conducted between
July 1996 and September 1997.SettingOne hundred fifty-six medical centers in the United States, Canada,
Australia, South Africa, England, and Scotland.ParticipantsA total of 628 patients with hemispheric ischemic stroke (50.3% male;
mean age, 71.5 years).InterventionsPatients were randomly assigned within 6 hours of stroke to receive
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 MeasuresThe primary efficacy end point was the Modified Rankin Scale score at
90 days after stroke onset. Secondary end points included mortality and change
in National Institutes of Health (NIH) Stroke Scale score at 7 days after
stroke.ResultsThe 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 aptiganel
(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 = .31). At 7 days, placebo-treated patients exhibited slightly greater
neurological 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 with high-dose aptiganel was higher than that
in patients who received placebo (26.3% vs 19.2%; P
= .06). Mortality in the low-dose aptiganel group was 22.5% (P = .39 vs placebo).ConclusionsAptiganel was not efficacious in patients with acute ischemic stroke
at either of the tested doses, and m ay be harmful. The larger proportion
of patients with favorable outcomes and lower mortality rate in the placebo
group suggest that glutamate blockade with aptiganel may have detrimental
effects in an undifferentiated population of stroke patients.
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