This proposal is an investigator-initiated, randomized, double-blind, multicenter, clinical trial designed to test the primary null hypothesis that warfarin therapy will not reduce the frequency of death or ischemic stroke recurrence by 30%, compared with platelet antiaggregant therapy, The trial will also test four secondary null hypotheses, not by sample size criteria, that the rate of death and recurrent stroke with warfarin will not be 50% lower in one year compared with platelet antiaggregant therapy; there will be no differences between the two therapies in the frequency of recurrence by stroke severity or subtype, race or sex, nor by the initial CT scan lesion size and location for infarct, and the rate of complications will not differ. After thorough search for the cause of stroke, patients will be randomized within 30 days after stroke and treated for at least two years, followed monthly by phone and quarterly in person to regulate the hematologic effects of medication and to detect the primary endpoints of death and symptomatic stroke recurrence, and to detect complications of therapy. Transient ischemic attacks and myocardial infarction will be recorded but treated as secondary events. The principal investigator statistician at the Data Management Center will have access to treatment status but all other participants will be blinded. To maintain blinding, the laboratory data will be sent to the Data Monitoring Center and there entered into the patient's electronic record before being made available to the local investigator. The results made available will be correct for tests monitoring active study medication but falsified for the placebo agent. An emergency notification system will be included to help maintain patient safety. To meet the 1,920 patient sample size, all forms of ischemic stroke will be included except those diagnosed as cardiogenic embolism. Over 30 experienced centers have been recruited and their stroke populations estimated using DRG 14 data. Ticlopidine will be used as the platelet antiaggregant assuming it receives sufficient FDA approval, aspirin otherwise. Warfarin dose will be adjusted to keep the prothrombin time at 14-18 secs. If chosen as the platelet antiaggregant, ticlopidine will be given 250 mg b.i.d., while aspirin will be given at 650 mg b.i.d., the regimen with the best clinical trial record.
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