Medical Treatment for Stroke Prevention

(Note that sections in this review are numbered so that they can be identified with cross-references as supporting evidence in the article Guidelines for Medical Treatment for Stroke Prevention, published in the Clinical Guideline section of this issue; see pages 54-55.The Editor) 1. Selecting management strategies for patients at high risk for stroke must involve both an understanding of the best scientific evidence and a realization that other issues beyond stroke reduction should be considered. A treatment that decreases the risk for stroke may introduce the risk for serious complication or adversely affect the patient's usual activities. We review the available literature on the medical treatment for stroke prevention in patients at elevated risk for stroke. We first review briefly the context in which medical treatment decisions are made. We highlight areas in which single studies or multiple studies reviewed simultaneously can lead to strongly supported recommendations. For areas of continued controversy, we attempt to go beyond the analytical issues to consider the clinical implications of various treatment options. Our goal is to build on previous efforts to review this literature and to understand the content and the limits of available studies [1-7]. 2. Rationale 2.1 Who Is at Elevated Risk for Stroke? 2.1. 1 General Factors Therapeutic interventions directed at general modifiable risk factors should be part of any effort to reduce the risk for stroke, regardless of whether the patient receives more specific medical or surgical treatment. Potentially modifiable risk factors include hypertension (including isolated systolic hypertension), heart disease, cigarette smoking, diabetes mellitus, heavy alcohol use, and, perhaps, hypercholesterolemia. Hypertension is the most potent contributor to the incidence of stroke. According to data from the Framingham Study [8], patients with definite hypertension (blood pressure greater than 160/95 mm Hg) have a relative risk for stroke that is approximately four times that of patients who do not have hypertension. Several randomized clinical trials of antihypertensive therapy have shown the value of blood pressure reduction in preventing stroke. A 5 mm Hg decrease in diastolic blood pressure is associated with a 42% decrease in cerebrovascular events [9, 10]. A meta-analysis of prospective observational studies showed that larger reductions in blood pressure (10 mm Hg) are associated with an even greater decrease in cerebrovascular events, over 50% fewer strokes [11]. Isolated systolic hypertension is an independent risk factor for development of stroke, and patients with this condition who receive effective therapy experience a two- to four-fold decrease in the number of strokes [8]. 2.1. 2 Symptom Status For persons with asymptomatic carotid artery stenosis, the degree of carotid narrowing is the single most important factor in determining risk for stroke. A 75% or greater carotid artery cross-sectional area reduction (a diameter reduction of approximately 50%) as shown by ultrasound is associated with a 2.5% annual risk for ipsilateral stroke and a 6.5% risk for fatal myocardial infarction [12]. Approximately 10% of patients who do not have symptoms but have carotid arteriosclerotic lesions have been found on computed tomography to have lesions that are compatible with cerebral infarction, known as silent brain infarctions [13, 14]. Estimates of the annual risk for unheralded stroke among patients with asymptomatic carotid bruits range from 1.5% to 4%. However, carotid bruits are associated with carotid stenosis greater than 70% in no more than half of cases. Strokes are as likely to be on the contralateral as the ipsilateral side and are often heralded by a transient ischemic episode. In general, atrial fibrillation is a predictor of stroke. This association is present whether the atrial fibrillation is persistent or paroxysmal. It exists even when no evidence suggests valvular heart disease (nonvalvular atrial fibrillation) or any type of cardiac disease (lone atrial fibrillation). The likelihood of stroke increases further if atrial fibrillation occurs with specific clinical or echocardiographic risk factors. Clinical risk factors include hypertension, previous thromboembolism (transient ischemic attack [TIA], ischemic stroke, or systemic embolism), and recent congestive heart failure [15]. Left ventricular dysfunction and a left atrial size greater than 2.5 cm/m2 are echocardiographic abnormalities associated with thromboembolism [16]. Patients with none of these risk factors have a much better outlook than those with a high-risk profile. Patients younger than 60 years who have a normal echocardiogram and no risk factors have an extremely low risk for stroke (1% per year) [16]. Patients who have recently had TIA or stroke have a substantially increased annual risk for subsequent stroke, from 4.5% to 6.6% [17, 18]; the risk is even higher in symptomatic patients with high-degree carotid stenosis [19]. The risk for stroke is highest in the first several months after the initial TIA or stroke; in patients who do not have additional strokes in the next 5 to 10 years, the risk approximates that of the background population. Compared with hemispheric TIA, retinal TIA (amaurosis fugax) is associated with a substantially lower risk for ipsilateral stroke. Evidence that a difference exists in the outlook for carotid compared with vertebral basilar TIA is not convincing. Risk for stroke recurrence after an initial ischemic stroke is substantially higher in persons who have a high-risk profile or silent brain infarctions [20]. Embolic stroke occurs in 3% to 4% of patients who have myocardial infarction. The risk for embolic stroke is highest between 3 days and 3 weeks after the myocardial infarction. After 4 weeks, cerebral emboli resulting from myocardial infarction are uncommon, and strokes that occur are most likely attributable to other causes [21]. Mural thrombi develop almost exclusively with antero-apical infarctions. Because mural thrombi are infrequent in postero-inferior and subendocardial infarctions, efforts to detect them by echocardiography are probably unnecessary [22]. 2.2 Who Are Surgical Candidates? The question of medical treatment for stroke prevention must be considered in the context of surgical options, particularly carotid endarterectomy. Three recently completed studies indicate that surgery can be beneficial when done in a low-risk setting (that is, a total perioperative stroke and death rate lower than 6%) in symptomatic patients (those with anterior circulation TIAs or nondisabling strokes with a stable deficit [minor stroke]) who have carotid lesions greater than 70% (by strict measurement criteria) [19, 23, 24]. Symptomatic patients with stenosis less than 30% have been shown to have worse outcomes after surgery [23]. Two clinical trials are continuing to enroll patients to determine the efficacy of carotid endarterectomy for symptomatic patients with mid-range stenosis (30% to 69%) [19, 23]. The efficacy of surgery for stroke reduction among asymptomatic patients is another area of continuing investigation [25-27]. We focus on the medical management of patients not judged to be candidates for carotid endarterectomy. 3. Methods We reviewed the literature to identify and summarize the best available published evidence on the medical treatment for the prevention of stroke in persons at elevated risk. English-language studies published between 1977 and 1993 were identified from MEDLINE, a computerized bibliographic database of the National Library of Medicine, and Current Contents on Disk. The search strategy is described in Appendix Table 1. The computerized database searches were supplemented by articles cited in pertinent reviews, textbooks, and published guidelines. We also examined citations from the included articles. Articles were selected according to published rules of evidence for articles on efficacy [28]. We accepted only articles that used a randomized, controlled trial study design (level I or level II) to assess the efficacy of anticoagulant or platelet antiaggregant treatment in patients with symptomatic or asymptomatic cerebrovascular disease or cardioembolic risk factors for stroke. Level I studies are defined as randomized trials with low false-positive () or low false-negative () errors, or both. Level II studies are defined as randomized trials with high false-positive () and high false-negative () errors. Two investigators independently extracted data, and any differences were resolved by consensus. We compared the effects of various treatment regimens on three mutually exclusive end points: stroke, death from causes other than stroke, and nonfatal major complications. These end points were chosen because they capture the primary benefit of interest here, stroke reduction, as well as other benefits and harms (including changes in cardiac mortality and increases in fatal and nonfatal bleeding episodes). Transient ischemic attacks were not included as an end point. Complete definitions are provided in the Appendix. We counted events using the intention-to-treat principle; events were attributed to the treatment group to which the patient was initially assigned. In some cases, only combined outcomes (for example, stroke or death from stroke) or summary-effect measures (relative risks) could be determined. The number of patient-years at risk (that is, the mean duration of follow-up times the number of patients) was recorded or estimated from the follow-up information given. Studies dealing with similar patients and similar interventions were considered for meta-analysis. Where data were available to calculate a summary relative risk for several studies (that is, patient-years of follow-up and the number of outcome events for each group), the resulting relative risk estimates were tested for homogeneity. We calculated a relati