TIA is a unique, important type of cerebral ischemia characterized by substantial instability, in which acute treatment is potentially highly consequential and has never been properly studied. Currently, the treatment choice ranges from immediate hospitalization and initiation of intravenous antiplatelet agents or heparin to outpatient evaluation and treatment with aspirin. TIAs are common, with an estimated 250,000-350,000 occurring each year in the US, an incidence about 30-40% that of stroke. Rapid recovery of cerebral ischemia is a defining characteristic of TIA and distinguishes it from completed stroke. This recovery defines a distinct pathophysiologic feature that generally indicates the presence of previously ischemic tissue still at risk: a characteristic that may be responsible for greater instability. The same is true for patients with minor ischemic strokes. The distinction between minor ischemic stroke and TIA is unimportant in terms of prognosis. Both groups are at high short-term risk for new ischemic stroke. In fact, numerous studies have shown that short-term risk of stroke is high after TIA and minor ischemic stroke, particularly in the first few days, even in patients treated with aspirin, the current standard of care. Antithrombotic therapy may play a distinct role in this acute pathophysiology. Effective therapies in those with TIA could significantly reduce the overall burden of stroke if initiated immediately. However, no large-scale trial has evaluated an acute intervention in these patients. Platelet aggregation is an important contributing factor in cerebral ischemia, as in other forms of ischemia. Antiplatelet agents reduce the risk of ischemic stroke in a variety of settings with distinct pathophysiologies (e.g., atrial fibrillation, small-vessel stroke, and large-vessel atherothrombosis). Aspirin given to patients with a history of stroke or TIA reduces subsequent risk of stroke. Furthermore, aspirin initiated as an acute intervention after stroke reduces risk of death and recurrent stroke. Trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination reduces risk of stroke but increases risk of major hemorrhage. However, the risk of thrombosis is extremely high in the acute period after TIA and risk of hemorrhage is expected to be lower than after a completed stroke, so the combination may be particularly effective and relatively safe in this setting. Even more compelling, clopidogrel combined with aspirin reduced the 90-day risk of stroke by 36% compared to aspirin alone in a pilot trial of 392 patients treated acutely after minor stroke or TIA, and it was well tolerated. Nonetheless, antiplatelet therapy has never been tested in a pivotal trial as an acute intervention after TIA, a setting with distinct pathophysiology that may favor the use of this class of agents.
Survivors of a transient ischemic attack (TIA), or stroke, have an increased risk of another stroke in spite of the best available treatments; of the 800,000 strokes in the US alone, 200,000 are in individuals with a recurrent event. In this randomized, blinded, multicenter trial, we will evaluate clopidogrel, a drug that blocks blood clotting, as a treatment to reduce risk of stroke and heart attack after a stroke or TIA in patients also prescribed aspirin. If the trial is positive, treatment with clopidogrel could reduce stroke burden and substantially reduce costs of care.
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