Pharmacologic Therapy

Published studies to date overwhelmingly support the ability of aspirin to reduce stroke incidence and death in patients who present with TIA or CVA. Aspirin and other agents that affect platelet function are frequently used for long-term secondary stroke prevention. It therefore seems reasonable, after hemorrhage has been excluded by CT, to begin aspirin therapy in the setting of acute stroke, provided the patient does not have a contraindication to aspirin therapy. Aspirin doses between 50 and 1300 mg/day have been shown to be effective for stroke prevention. In the absence of convincing evidence favoring a specific dosage, most clinicians prescribe 81 or 325 mg/day. The FDA recommends that aspirin doses of 50 to 325 mg/day be used for stroke prevention.

Clopidogrel (Plavix) inhibits platelet function by irreversibly binding to adenosine diphosphate receptors. Compared with aspirin, clopidogrel significantly decreases the constellation of CVA, myocardial infarction (MI), and vascular death and has a toxicity comparable with that of aspirin. Thrombotic thrombocytopenic purpura (TTP) has been reported after the initiation of clopidogrel, often within the first 2 weeks of therapy (Bennett et al., 2000).

Dipyridamole (Persantine) was widely used in combination with aspirin in the early 1980s for the prevention of stroke until critical analysis cast doubt on its efficacy. A European study found high-dose sustained-release dipyridamole plus aspirin to be superior to aspirin alone for the prevention of stroke (Diener et al., 1996). The side effects of this therapy included headache and required discontinuation in approximately 6% of patients.

Selection of the appropriate antiplatelet agent for stroke prevention can become complicated, especially for patients with comorbid cardiovascular disease. Both extended-release dipyridamole plus aspirin (Aggrenox) and clopidogrel (Plavix) are reasonable first line antiplatelet agents for secondary stroke prevention, shown to be more effective than aspirin alone. Randomized controlled trials (RCTs) have shown no additional benefit of the combination of clopidogrel and aspirin, which only increase the risk of hemorrhage.

The use of heparin therapy for the prevention of recurrent TIA or stroke progression is limited. Progression of CVA is common, occurring in 15% to 20% of carotid-distribution strokes and 35% to 40% of vertebrobasilar CVAs. Even in patients with angiographically minimal or absent cerebral artery occlusion, clinical worsening of neurologic findings frequently occurs. Furthermore, heparin has not been shown in adequate clinical trials to improve clinical outcome among patients with stroke. The International Stroke Trial (IST, 1997) reported that patients receiving subcutaneous heparin had fewer recurrent ischemic strokes, but this improvement was offset by an increase in hemorrhagic strokes. There was no net benefit. Trials with heparinoids have also failed to demonstrate a clear benefit and have shown an increased risk of non-central nervous system (non-CNS) bleeding. Studies have also failed to demonstrate a clear benefit for low-molecular-weight (LMW) heparin.

Box 42-2 Cardiac Conditions Substantially Associated with Embolism

Atrial fibrillation Mitral stenosis Mechanical cardiac valves Recent myocardial infarction

Left ventricular thrombus, especially if mobile and protruding Atrial myxoma Infective endocarditis Dilated cardiomyopathy

Marantic (nonbacterial thrombotic) endocarditis

Currently, warfarin (Coumadin) cannot be recommended as initial therapy for most patients with stroke of primarily cerebrovascular origin. In two large-scale RCTs of warfarin compared with aspirin in the prevention of recurrent stroke (SPIRIT, WARSS), warfarin was not superior to aspirin for patients without cardioembolic disease or operable carotid stenosis (Sacco et al., 2006). Furthermore, the hemorrhagic risk with warfarin was higher than with aspirin. In contrast to ischemic stroke, there is good evidence that warfarin is beneficial for patients with several major cardiac disorders predisposing them to embolic stroke. Box 42-2 summarizes cardiac conditions that are substantially associated with cardioembolic stroke and often warrant prophylactic therapy with warfarin. Other cardiac conditions, such as mitral valve prolapse with or without myxomatous changes, severe mitral annular calcification, and calcific aortic stenosis, have a low or uncertain risk of embolism, and warfarin therapy is generally reserved for secondary prevention.

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