*Required hospital admission, and transfusion if major bleeding event
Efficacy Endpoints: Primary - death or dependence greater than 30 days after stroke; Secondary – death from any cause at < 30 days (treatment period) or > 30 days (follow-up period), evidence of DVT, symptomatic pulmonary embolus during the treatment period, recurrent stroke during the treatment period (ischemic or unknown), any recurrent stroke, and complete recovery from stroke
Harm Endpoints: Symptomatic intracranial hemorrhage during treatment period and major extracranial hemorrhage during the treatment period (resulting in a fatal bleed or requiring a transfusion or operation).
Narrative: Ischemic stroke is thought to occur by one of two processes - the activation of platelets leading to thromboembolic events, or plaque rupture in the cerebral arterial circulation leading to the formation of a clot. Interventions that prevent the clotting of platelets and thus the formation of thrombi or progression of ruptured plaques have been proposed to reduce the incidence and severity of acute ischemic stroke.
The Cochrane review included twelve randomized trials encompassing 43,041 stroke patients and, in aggregate, the review clearly suggests a benefit. Included trials compared an antiplatelet agent to control (placebo or no therapy with adequate blinding) for acute stroke, initiated within 14-days of onset. Antiplatelet medications evaluated by the included trials in the Cochrane review included: COX-2 inhibitors, thienopyridine derivatives, phosphodiesterase inhibitors, thromboxane A2 antagonists, and GP IIb/IIIa receptor antagonists. 94% of the data came from two trials, CAST and IST, which evaluated 160mg and 300mg of once daily aspirin for acute stroke continued for either four or two-weeks, respectively.
The OR for death or dependence was 0.95 (95% CI 0.91 – 0.99, p = 0.008), NNT = 79.The OR for death from all causes at 6-months was 0.93 (95% CI 0.87 – 0.99, p = 0.01), NNT = 108.The OR for symptomatic PE during the first 30-days was 0.71 (95% CI 0.52 – 0.95, p = 0.02), NNT 693. The OR for recurrent stroke in the first 30-days was 0.77 (95% CI 0.68 – 0.86, p < 0.00001), a reduction of 7 events per 1000 treated, NNT = 140. The OR for complete recovery was 1.06 (95% 1.02 – 1.11, p = 0.006), a benefit of 11 per 1000, NNT = 89.
Intracranial hemorrhage increased with antiplatelet agents at a rate of 2 per 1000 patients, NNH (number needed to harm) = 574. Major extracranial hemorrhage occurred in 4 per 1000 patients, NNH = 245.
Caveats: 94% of the available data came from the two largest trials, CAST and IST, and unlike some of the other included trials in this meta-analysis, not all of these patients had a CT scan to exclude hemorrhagic stroke prior to randomization. Thus, some patients may have had intracranial hemorrhage rather than ischemic stroke at the time of treatment, which would lead to an underestimate of benefit when compared to a setting where imaging is generally secured before therapy is started.
Not all included trials in the meta-analysis used aspirin as the antiplatelet agent to be studied; however aspirin was the study drug used in CAST and IST, and it is likely the cheapest and most feasible medication to be used in a broad array of settings. Because of the small scale of the other trials included in the meta-analysis, there is limited evidence to recommend the use of other antiplatelet agents other than aspirin in patients who cannot tolerate aspirin. Finally, a significant interaction between aspirin and streptokinase was noted in the MAST-I trial, leading to an increase in early and late mortality, in-hospital death from all causes, neurologic cause, and increase in intracranial hemorrhage. Thus, it is unclear what role antiplatelet agents may play and when they should be administered in those patients who receive thrombolytic therapy for acute ischemic stroke.
Author: Paul Roszko, MD and Anthony M. Napoli, MD FACEP
Published/Updated: July 17, 2011
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