Prevention of Ischemic Stroke

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1 Prevention of Ischemic Stroke Jesse Weinberger, MD Address Department of Neurology, Box 1052, The Mount Sinai School of Medicine, 1 Gustav Levy Place, New York, NY 10029, USA. jesse.weinberger@mssm.edu Current Cardiology Reports 2002, 4: Current Science Inc. ISSN Copyright 2002 by Current Science Inc. The primary risk factors for stroke are known, and attention to primary care of these disorders should reduce the incidence of stroke significantly. Control of hypertension, diabetes, and hyperlipidemia have all been shown to reduce the rate of stroke. Identification of potential cardioembolic sources of stroke, particularly atrial fibrillation, can prevent stroke with appropriate application of anticoagulation. Duplex Doppler B-mode sonography can establish the extent of carotid artery disease in patients with cervical bruit or risk factors for atherosclerosis, and indicate which conditions should be managed medically or surgically. Patients with a history suggestive of transient ischemic attacks can also be screened noninvasively with duplex sonography to determine if they have a critical carotid stenosis and require carotid endarterectomy. New advances in platelet antiaggregant therapy with ticlopidine, clopidegril, and the combination of aspirin with dipyridamole have also reduced the rate of stroke to a greater degree than standard treatment with aspirin. The incidence of this devastating illness could possibly be reduced by 50% with attentive primary care management. The cardiologist is often involved in the treatment of patients at risk for stroke, and is in an ideal position to provide this care. Introduction Stroke is the third leading cause of death in the United States, and over 500,00 people are afflicted with stroke each year. Cerebral ischemia accounts for 85% of strokes, and 15% are hemorrhagic. The three major categories of ischemic stroke are cardioembolic, atherothrombotic large vessel occlusive disease, and lacunar stroke from small vessel occlusive disease. Ischemic stroke patients carry many of the same risk factors as patients with coronary artery disease, and coronary artery disease patients are at risk for ischemic stroke [1]. The primary reversible risk factors for stroke are hypertension, diabetes, atherosclerotic carotid artery disease, atrial fibrillation, and smoking. The cardiologist is in a position to identify and treat these reversible risk factors for ischemic stroke, so that the incidence of this devastating illness can be significantly reduced. Hypertension The most significant risk factor for ischemic stroke is hypertension [2]. Occlusive vascular disease of intracranial arterioles and small arteries produced by hypertension accounts for at least 33% of strokes. These lesions produce small infarcts in the deep structures of the brain, the basal ganglia and subcortical white matter. A recent case-controlled study compared control of hypertension in 595 patients who suffered a stroke with control of hypertension in 2966 aged-matched randomly selected stroke-free patients [3]. Blood pressure was adequately controlled in 78% of 460 ischemic stroke cases, and 85% of 95 hemorrhagic stroke cases. The authors estimated that 27% of the ischemic strokes and 57% of the hemorrhagic strokes among treated hypertensive patients were attributable to uncontrolled blood pressure, and that uncontrolled blood pressure accounted for 32% of the overall number of strokes [3]. Early diagnosis and control of modest hypertension in the range of 130/90 among young adults can significantly reduce the risk of stroke over a 10-year follow-up period [4]. The impact of blood pressure control increases over time. Unlike coronary artery disease, in which some antihypertensive agents may be more effective in preventing ischemic heart disease than others, it is the absolute quantitative reduction in blood pressure that accounts for the benefit, regardless of the agent employed [5]. In elderly subjects, treatment of patients with both combined systolic and diastolic hypertension, and patients with isolated systolic hypertension has also been shown to reduce the risk of stroke [6,7]. A large meta-analysis of antihypertensive drug trials involving over 40,000 patients was performed to detect differences in benefit between sexes. A strong and statistically significant reduction in the relative risk of total and fatal strokes was found in both men and women. Absolute risk reduction appeared to be dependent on baseline risk more than any other factor, and thus, the authors stressed a need to accurately predict individual patient cardiovascular risk in order to institute effective therapy [8]. The trials in this meta-analysis used thiazide diuretics and β-blocking agents as principle therapy for reducing blood pressure. The Hypertension Optimal Treatment (HOT) randomized trial [9 ] used the calcium channel blocker

2 Prevention of Ischemic Stroke Weinberger 165 felodipine to reduce blood pressure. Nearly 20,000 patients were followed for an average of 3.8 years, and were assigned to a target diastolic pressure using felodipine with addition of up to four other agents to achieve target diastolic blood pressures. A significant reduction of blood pressure was observed, but this was in relation to baseline values rather than a placebo group. The lowest risk of stroke was observed at systolic pressures less than 142 mm Hg and diastolic pressures below 80 mm Hg. Treatment of isolated systolic hypertension has been shown to reduce the risk of stroke in the elderly. The Systolic Hypertension in the Elderly program [10 ] showed a significant reduction in the incidence of both lacunar and hemorrhagic stroke in elderly patients treated with a thiazide class diuretic and additional atenolol 25 mg or 0.05 mg reserpine as needed to reduce systolic blood pressure by 20 mm Hg, to below 160 mm Hg. The Systolic Hypertension in Europe Trial [11] showed a significant reduction in the incidence of stroke in elderly patients treated with the long-acting calcium channel blocker nitrendipine. However, caution must be applied in treating elderly patients, because aggressive lowering of diastolic blood pressure below 65 mm Hg may actually increase the risk of stroke [12]. The risk of stroke also increased with elevated diastolic blood pressure, and the lowest risk for stroke for elderly patients was in the range of 140/80 mm Hg [13]. Diabetes Diabetes is a significant risk factor for stroke that can contribute to both small vessel occlusive disease and atherosclerotic disease of large vessels [14]. Although it has never been directly demonstrated that strict control of blood sugar is effective in preventing cerebrovascular disease, it has been documented to be effective in the prevention of diabetic retinopathy, which occurs on a similar basis to small artery occlusive disease [15]. It has also been shown that high blood glucose at the time of stroke is deleterious to the preservation of neurons in the ischemic area [16], so that strict control of glucose in diabetics may reduce the severity of infarction once cerebral ischemia occurs. The angiotensin-converting enzyme (ACE) inhibitor ramipril has been used primarily to reduce the complications of diabetic nephropathy. Treatment with ramipril 10 mg/d reduced the risk of stroke by 33% over a 4.5-year period in 3577 diabetic patients over age 55 with at least one other risk factor for cardiovascular disease [17,18 ]. Ramipril has also been shown to reduce the risk of stroke with a relative risk of 0.68 in high-risk patients with evidence of vascular disease or diabetes plus one other cardiovascular risk factor who had no reduction in cardiac ejection fraction or heart failure [18 ]. Hyperlipidemia and Atherosclerosis Serum lipids are not as great an independent risk factor for stroke as for coronary artery disease [19]. The Prospective Studies Collaboration [20] of 45 prospective trials involving over 450,000 patients was conducted to clearly delineate the relation of cholesterol, blood pressure, and stroke. There was no association between serum cholesterol level and stroke, but a positive relationship with ischemic stroke and a negative relationship with hemorrhagic stroke and increasing cholesterol levels may have been obscured. It has been suggested by several previous observational studies that a J-shaped curve exists for the relationship of cholesterol and stroke mortality, where ischemic stroke increases at high cholesterol levels and hemorrhagic stroke risk increases at low cholesterol levels [21,22]. Low cholesterol may also be a risk factor for ischemic stroke [23]. In a study of Japanese men, patients with stroke from large vessel atherosclerotic disease had an increased serum total cholesterol (mean 200 mg/dl), but patients with lacunar-type stroke from small vessel disease had a low serum total cholesterol (mean 177 mg/dl). Even though it is not clear that cholesterol is an independent risk factor for stroke, treatment of coronary artery disease patients having elevated serum cholesterol with the 3-hydroxy-3-methylglutaryl (HMG) co-reductase inhibitors causes a significant reduction of stroke as well as myocardial infarction. The Scandinavian Simvastatin Survival Study (4S) [24] analyzed 4444 patients with coronary artery disease and high cholesterol. A post hoc analysis of the data showed significant reduction in transient ischemic attack (TIA) and stroke by 30%, although for stroke alone it was not statistically significant. The Cholesterol and Recurrent Events (CARE) trial [25,26 ] of over 4000 post-myocardial infarction (MI) patients with average cholesterol levels demonstrated a similar significant risk reduction in stroke among men and women treated with pravastatin. Meta-analyses have been conducted on clinical trials of cholesterol reduction with HMG-CoA reductase inhibitors to determine their effect on stroke. A strong and statistically significant effect on stroke reduction among secondary prevention trials was noted in all four analyses; although, only a mild and nonsignificant trend toward reduction was observed in primary or mixed primary-secondary trials [27]. Reduction of low-density lipoprotein (LDL) cholesterol with both lovastatin and pravastatin reduces the degree of carotid artery intimal medial thickness (IMT) measured by B-mode ultrasonography. IMT is a marker for atherosclerosis that has been found to correlate both with pathologically demonstrable atherosclerosis and symptomatic coronary artery disease [28 ]. It has been suggested that non lipid-lowering properties of statins such as plaque stabilization, fibrinolytic effects, and alteration of endothelial function may have a greater effect on stroke incidence than their direct effect on cholesterol.

3 166 Stroke Analysis of stroke prevention in the Long-Term Intervention with Pravastatin in Ischemic Disease Study (LIPID) [29] demonstrated a 23% risk reduction for ischemic stroke and a 19% risk reduction for overall stroke, including hemorrhage. There was no increase in the risk of hemorrhage with pravastatin [29]. Analysis of the etiology of stroke suggested that the risk reduction may have been due to prevention of cardioembolic events from atrial fibrillation and ventricular thrombus secondary to myocardial infarction, rather than from reduction in atherothrombotic strokes [29]. Angiotensin II is a critical growth factor for propagation of smooth muscle atherosclerotic plaque. ACE inhibitors with a high affinity for binding to vessel walls with atherosclerotic plaque reduce the extent of proliferation of plaques, and may play a clinical role in plaque stabilization [30]. This may be why the ACE inhibitor ramipril has been effective in reducing the incidence of stroke in highrisk patients with cardiovascular disease [18 ]. Dietary factors, particularly antioxidants, may also play a role in reducing the risk of stroke. Antioxidants inhibit the oxidation of LDL, converting liquid cholesterol esters to crystalline cholesterol. This stabilizes atherosclerotic plaque and prevents plaque rupture [28 ]. In a clinical study of asymptomatic postmenopausal women, patients with higher dietary content of the antioxidant vitamin E, particularly nuts and seeds, as well as fat-containing products such as margarine and mayonnaise, had a reduce incidence of coronary deaths, even without the use of vitamin supplements [28 ]. High dietary content of beta carotene has also been shown to reduce the risk of stroke [31]. However, beta carotene and the antioxidant alpha-tocopherol have no effect on the risk of stroke in smokers [31]. Plasma homocysteine levels have been found to be elevated to 20 to 40 µmol/l in patients with cerebrovascular disease [32]. Homocysteine levels can be reduced by treatment with folic acid 200 µg/d, and although there have been no trials to document that reduction in homocysteine with folic acid lowers the risk of stroke, it is recommended in patients with homocysteine levels greater than 15 µmol/l. Smoking Smoking has been identified as an independent risk factor for stroke. Elimination of smoking can reduce carotid artery IMT and reverse propagation of atherosclerotic plaque visualized with B-mode ultrasonography [28 ]. Therefore, cessation of smoking should be encouraged as part of the primary prevention of atherothrombotic stroke from carotid artery disease. Asymptomatic Atherosclerotic Disease Asymptomatic carotid artery stenosis can be identified by auscultation of a bruit near the angle of the jaw. The management of patients with asymptomatic carotid artery stenosis is still controversial. One controlled trial indicated that asymptomatic patients with greater than 60% stenosis have a 10% risk of stroke over 5 years on medical therapy with aspirin, and a 5% risk of stroke with surgical therapy [33]. Patients with asymptomatic cervical bruit can be screened noninvasively to assess the degree of carotid stenosis with duplex Doppler ultrasonography. Patients with severe stenosis can be considered for surgical management if there are no significant medical risks to surgery. Studies of the morphology of atherosclerotic plaque at the carotid artery bifurcation with pathologic examination and sequential ultrasound examinations have indicated that cerebral ischemic events are associated with acute plaque rupture and thrombus formation [28,34]. In coronary artery disease, the thrombus occludes the artery, whereas in carotid artery disease, the thrombus can also embolize to occlude intracranial vessels. Therefore, patients who have a moderate stenosis or are not surgical candidates should be treated with platelet antiaggregant therapy and reduction of elevated cholesterol in an attempt to stabilize the plaque. Patients with asymptomatic carotid stenosis are followed with sequential carotid ultrasound examinations, and when significant progression of stenosis is identified, carotid endarterectomy may be indicated. With the advent of transesophageal echocardiography (TEE), atherosclerotic plaque at the arch of the aorta has been identified in stroke patients [35 ]. Asymptomatic plaques at the arch of the aorta are seen during TEE, or with a new technique utilizing noninvasive B-mode sonography. Therapy with warfarin is often recommended for treatment of aortic arch plaque in stroke patients, but there is no evidence from controlled trials that warfarin is superior to platelet antiaggregant therapy. Studies with B- mode sonography have indicated that plaque morphology is a more significant risk factor for cerebral ischemic events than plaque size (Figs. 1 and 2) [36], and that plaques are relatively stable over time [37], suggesting that asymptomatic aortic arch plaque should be treated in the same manner as asymptomatic carotid artery plaque. Prevention of Cardioembolic Stroke Anticoagulation with warfarin has long been established for prevention of stroke in patients with atrial fibrillation and mitral stenosis [31,38]. Warfarin is also recommended for primary prevention of stroke in patients with nonvalvular atrial fibrillation [31,38]. The Stroke Prevention in Atrial Fibrillation Trial (SPAF) [31,38] demonstrated a beneficial effect of aspirin prophylaxis 325 mg/d for patients under age 75 who did not have associated cardiovascular risk factors such as ventricular hypertrophy. In patients over age 75, warfarin is superior to aspirin in preventing ischemic stroke. In the SPAF trial, the risk of hemorrhage in these elderly patients negated the beneficial effect of anticoagulation [31,38]. However, the level of anticoagulation in this

4 Prevention of Ischemic Stroke Weinberger Figure 1. A homogeneous echodense simple plaque (x) is seen on the arch of the aorta just below the origin of the innominate artery (arrow) using noninvasive B-mode imaging. 167 increasing age, hypertension, diabetes mellitus, congestive heart failure, and previous TIA. An INR of 2.0 to 3.0 should be achieved. A lower degree of anticoagulation with INR of 1.7 to 2.0 has been demonstrated to be effective in one trial, and this level of anticoagulation can be employed in elderly patients who are more at risk for hemorrhage [28,37]. For those patients without risk factors, aspirin at 325 mg/d is used [31,38]. Stroke prevention with warfarin is possible in other forms of cardiac disease. Patients with cardiac valve replacement are routinely treated with warfarin for prevention of embolic stroke [31]. Warfarin has also been beneficial in preventing stroke during the first 3 months after MI [31,39], although aspirin is more commonly used for long-term prophylaxis. A meta-analysis of five major trials that used warfarin in post-mi patients revealed that warfarin reduced the risk of stroke by 64%, but the benefit was unclear in patients older than 75 years. Current guidelines suggest warfarin should be used to prevent stroke after MI in patients with atrial fibrillation, left ventricle thrombi, or compromised left ventricular function [31,39]. Diagnosis and Management of Patients with Transient Ischemic Attacks Figure 2. A complex heterogeneous plaque with ulcer craters (arrows) and attached mobile low echodensity thrombus (arrowheads) is seen in the distal ascending aorta and aortic arch using noninvasive B-mode imaging. trial was higher than in the other three trials, as measured by the international normalized ratio (INR). In another trial, fixed minidose warfarin and aspirin, alone and in combination, were compared with the currently recommended warfarin only therapy (INR ) for patients with atrial fibrillation, but low level anticoagulation was not as effective as full anticoagulation in preventing stroke [31,38]. Recent guidelines for primary prevention of stroke in patients with atrial fibrillation indicate that warfarin should be used in patients with risk factors for stroke: Transient ischemic attacks are defined as episodes of transient focal neurologic dysfunction caused by temporary lack of blood supply to a region of the brain. Typical symptoms of cerebral transient ischemic attack would be a temporary inability to speak, weakness on one side of the body, or transient sensory disturbance. Patients with vertebrobasilar insufficiency may have symptoms of focal brainstem dysfunction, such as double vision or vertigo, which are often difficult to distinguish from other causes of dizziness. An equivalent symptom to TIA is transient visual loss in one eye, or amaurosis fugax, which is an indication of ipsilateral carotid artery atherosclerotic disease. It is critical to recognize the occurrence of TIAs because they are a highly significant warning sign of impending stroke. A completed stroke develops in 25% to 33% of patients with TIA, most commonly within the first 3 months after the initial transient event [1]. Atherosclerotic disease at the carotid artery bifurcation is responsible for 50% of cerebral TIAs, whereas the other potential sources of cerebral ischemia, including cardioembolic causes and intracranial small vessel disease, account for the remaining events. Evaluation of the cerebral vasculature with ultrasonography is an accurate and convenient noninvasive method for determining the extent of occlusive disease of the extracranial carotid artery bifurcation, the extracranial vertebral arteries, and both the anterior and posterior cerebral circulation. Duplex Doppler color flow ultrasonography can identify a stenosis of greater than 70% with an accuracy of 90% compared with angiography [40] (Figs. 3 and 4). Distal perfusion can be assessed by

5 168 Stroke Figure 3. A normal carotid artery bifurcation is outlined with colorflow power spectral duplex Doppler B-mode sonography. A branch is seen originating from the external carotid artery (arrow), whereas the larger internal carotid artery has no branches. Figure 4. Spectral analysis of Doppler frequency shifts measures the velocity of blood flowing through the carotid artery. Flow velocity is being measured at the site of the cursor adjacent to a small homogenous plaque (arrow) at the origin of the internal carotid artery. The spectral analysis is shown below indicating normal flow velocity of 0.59 m/sec and no significant stenosis. Systolic peak velocity greater than 3.0 m/sec correlate with greater than 70% stenosis compared with angiography. transcranial Doppler to corroborate whether an internal carotid stenosis is hemodynamically significant [41]. Transcranial Doppler can detect whether a TIA is due to stenosis of an intracranial artery rather than stenosis at the carotid artery bifurcation. Ultrasonography of the cervical vertebral artery and transcranial Doppler study of the intracranial vertebrobasilar system are valuable in identifying occlusive disease of the vertebral or basilar arteries. When Doppler studies are suggestive of a hemodynamically significant lesion or if the Doppler study is technically not definitive a confirmatory imaging procedure is performed. Magnetic resonance angiography (MRA) is usually performed because it is also noninvasive. MRA has an accuracy of about 90% for identifying a hemodynamically significant 70% stenosis of the internal carotid artery, and the results of Doppler and MRA complement one another. The accuracy of the two studies combined provides a 95% correlation with the results of angiography [40]. However, some clinicians insist that intra-arterial contrast angiography be performed because the studies documenting the role of carotid endarterectomy in the management of TIA patients are based on criteria developed with intra-arterial contrast angiography. Patients with carotid artery TIA or amaurosis fugax have significantly better results with surgery than with medical therapy (aspirin 650 mg by mouth twice daily) when there is greater than 70% stenosis of the origin of the ipsilateral internal carotid artery [42]. The risk of stroke ipsilateral to a 70% carotid artery stenosis was 2% with surgical management, and 20% with medical management [42]. Selected patients with 50% to 70% stenosis also benefit from carotid endarterectomy, specifically nondiabetic men [43 ] (Fig. 5). Stenting of the internal carotid artery may prove to be of value in patients in whom the risk of surgery is too great, but the number of cerebrovascular complications with stenting is equal to the number with carotid endarterectomy and the long term outcome of stenting has not been established [44]. Medical therapy for patients with TIA is indicated for patients with nonsurgical lesions of the carotid artery, and patients without carotid artery stenosis or a cardioembolic source. The standard medical treatment for patients with TIA is the platelet antiaggregant aspirin. The Canadian Cooperative Study [45] demonstrated that aspirin 650 mg by mouth twice daily significantly reduced the incidence of subsequent stroke by 50% in men, although no statistically significant reduction was found in women. Several studies showed a significant reduction in patients with TIA treated with low dosages of aspirin from 30 to 283 mg/d [28 ]. However, a comparison of studies using doses of aspirin higher than 975 mg/d and those with doses of more than 975 mg/d showed a significantly greater reduction in stroke in the higher-dosage group [28 ]. Meta-analysis of these aspirin studies has also shown that there is a significant beneficial effect of aspirin therapy in preventing stroke in women symptomatic with TIA [46]. Ticlopidine was developed for patients with TIA who could not tolerate aspirin, and because of the possibility that aspirin was not as effective in women as it was in men. Ticlopidine binds to the platelet ADP receptor. Ticlopidine was found to be more effective in preventing stroke in patients with focal TIA and amaurosis fugax than aspirin 650 mg by mouth twice daily, with a relative risk reduction of 48% after 1 year of treatment, and 25% after 5 years of

6 Prevention of Ischemic Stroke Weinberger 169 Figure 5. A large heterogeneous plaque extending from the bifurcation (arrow) through the internal carotid artery (arrowhead at distal end) in a patient with transient ischemic attack (TIA. The degree of stenosis was 50% to 69%. Symptomatic patients with heterogeneous plaque are more prone to recurrent TIA and stroke, and may represent the subset of patients that would benefit from carotid endarterectomy, even though the stenosis is less than 70%. Ingelheim, Ridgefield, CT). This dosage was equivalent to low-dose aspirin 50 mg/d in reducing the relative risk of stroke by 18%. The combination of time release Persantine 400 mg/d with aspirin 50 mg/d resulted in a 37% risk reduction of stroke [49]. When a patient with TIA who does not have an atherosclerotic or hypertensive etiology for the event is identified, echocardiography is generally performed. Patients with mitral valve prolapse may present with TIA. Although aspirin has been shown to be effective in preventing stroke in most patients with mitral valve prolapse [28], those patients with large redundant valves with myxomatous changes may require warfarin for stroke prophylaxis. Patients with TIA with ventricular wall abnormalities or dilated cardiomyopathy should also be treated with warfarin. Transesophageal echocardiography is performed in patients with no clear source for TIA to identify occult sources such as aortic arch plaque, patent foramen ovale, or atrial septal aneurysm. Prophylactic therapy with warfarin to prevent stroke is indicated in TIA patients with patent foramen ovale or atrial abnormalities. Warfarin has been shown to be more effective than aspirin in preventing recurrence in stroke patients with large vessel intracranial vascular occlusive disease who are not controlled with aspirin [50]. treatment [47]. Ticlopidine is equally as effective as aspirin in preventing stroke from carotid artery disease, but is more effective than aspirin in patients with intracranial vascular disease, women, and black patients. Ticlopidine has been associated with a significant incidence of neutropenia, thrombotic thrombocytopenic purpura, and hepatitis. Clopidogrel is a platelet antiaggregant with a similar mechanism of action as ticlopidine, but without the adverse events. Clopidogrel 75 mg/d significantly reduced the risk of ischemic events by 7.8% compared with aspirin 325 mg/d in patients with recent ischemic stroke, recent MI, or symptomatic peripheral vascular disease [48]. However, it has not been compared directly with aspirin in patients with TIA. The combination of clopidogrel 75 mg with aspirin 75 mg to 325 mg produces a 20% reduction in ischemic event rate in patients with unstable angina or non ST-segment elevation MI compared with clopidogrel alone. The stroke rate was reduced 14% with combination therapy over the 9-month period. Dipyridamole prevents platelet aggregation by inhibiting the enzyme phosphodiesterase. Inhibition of this enzyme may also have vasodilatory effects. Initial studies had not been effective for preventing strokes in patients with TIA when administered alone [28], nor was there an additive effect when administered with aspirin [28]. The European Stroke Prevention Study [49] employed a timerelease preparation of Persantine 400 mg/d (Boehringer Conclusions The significant risk factors for stroke have been established. Primary prevention of stroke can be achieved with control of hypertension, diabetes, and hyperlipidemia. Warfarin therapy has been proven effective in the prevention of cardioembolic stroke. Medical and surgical therapies exist to prevent stroke in TIA patients. The indications for carotid artery endarterectomy have become more clearly defined and new medical treatments that are more effective than aspirin have been developed. Carotid artery stenting holds promise for becoming a standard therapy in the treatment of carotid artery disease, but the efficacy has not yet been established. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Sherman DG, Dyken MJ, Gent M, et al.: Antithrombotic therapy for cerebrovascular disorders. An update. Chest 1995, 106:444S 456S. 2. Kannel WB, Dawber TR, Sorlie P, Wolf PA: Components of blood pressure and risk of atherothrombotic brain infarction: The Framingham Study. Stroke 1976, 7: Klungel OH, Kaplan RC, Heckbert SR, et al.: Control of blood pressure and risk of stroke among pharmacologically treated hypertensive patients. Stroke 2000, 31:

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