Medical prevention of stroke, 2003. (Featured CME Topic: Stroke).

Abstract: Stroke is a preventable tragedy for nearly 750,000 people each year. Primary stroke prevention measures applicable to the general public include a healthy diet containing fruits, vegetables, fish, and low fat; exercise; smoking cessation; limiting alcohol to moderate use; and perhaps avoidance of stress. Screening for hypertension, cholesterol, heart disease, and carotid artery stenosis can lead to even more effective stroke prevention in high-risk patients. Specific antihypertensive drugs such as angiotensin-converting enzyme inhibitors and angiotensin-converting enzyme receptor blockers may be especially protective against stroke. Secondary stroke prevention in patients who have already had a stroke or transient isehemic attack is even more effective in preventing more serious strokes. Measures include antihypertensive and cholesterol-lowering agents, carotid endarterectomy, anticoagulation for atrial fibrillation and other cardiac sources of embolic stroke, and antiplatelet therapy. Stroke preven tion depends on the application of these well-known and widely available treatments to a large number of patients.

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The prevention of stroke depends on two critical premises: stroke is one of the most preventable serious medical illnesses, and stroke prevention depends not on new medical breakthroughs, such as a cure for cancer, but rather on the application of readily available knowledge. The medical community simply has not succeeded in getting the message of stroke risk factors and warning signs across to the public. This review summarizes recent evidence for stroke prevention, with emphasis on blood pressure treatment, cholesterol reduction, and antiplatelet therapy.

Stroke is the third-leading cause of death in the United States, with as many as 730,000 new cases and 158,000 deaths each year. (1) A stroke occurs every minute in the United States. Stroke is the leading cause of neurologic disability in adults; over 4 million Americans have permanent disability from stroke. Magnetic resonance imaging (MRI) studies have suggested that as many as 22 million "silent strokes" may occur each year. (2) Such small, vascular lesions in the brain may contribute to dementia as well as physical disability. In the past, stroke has been regarded as an inevitable result of aging and little attention was paid to reduction of risk factors. Strokes occur at all ages, but even when they afflict the elderly, the risk factors begin much earlier in life, and preventive measures cannot begin too early. Surveys of the public have shown very little awareness of either stroke risk factors or warning signs. (3)

Primary and Secondary Prevention of Stroke: General Measures

"Primary stroke prevention," the first aspect of stroke prevention, is the treatment of risk factors in the population at large. It is here that the medical community can make the most impact in preventing the epidemic of strokes that occurs in later years. Secondary prevention, in patients who have already developed symptoms of transient ischemic attack (TIA) or stroke, is applicable to a smaller number of patients, but these patients have a greatly increased risk of stroke. Johnston et al (4) found that patients who were discharged from emergency departments with a diagnosis of TIA had a 10.5% risk of presenting back with a stroke within 90 days, and half of the strokes occurred within the first 48 hours. TIA and minor stroke are major warning signs for a serious stroke within days.

Gorelick et al (5) reviewed available literature regarding the prevention of a first stroke and came up with the following four lifestyle factors: cigarette smoking, alcohol use, physical activity, and diet; as well as six risk factors: hypertension, MI, atrial fibrillation, diabetes mellitus, hyperlipidemia, and asymptomatic carotid artery stenosis.

Lifestyle factors have been recent subjects of investigation in stroke prevention. The Nurses' Health Study (6) reported that nurses who ate fish containing [omega]-3 fatty acids had a lower risk of stroke, by as much as 52%, for those who ate fish five or more time per week compared with those who did not eat fish. Intake of fruits, folic acid, potassium, and low levels of homocysteine have also been associated with lower evidence of cardiovascular events and stroke. (7) One study reported an association between whole grain intake and reduced stroke incidence. (8) Specific evidence for prevention of stroke with dietary manipulations, however, has not been established. (5) Much previous evidence has favored exercise for the prevention of both heart attack and stroke. The Nurses' Health Study (9) found a specific reduction in stroke incidence in women who exercise. Walking, particularly at a "brisk or striding walking pace" for 30 minutes at least 3 times per week, was adequate. Smoking clearly increases strok e risk, by as much as 1.5- to 2-fold, (5,10)." and smoking cessation likely reduces this risk. Alcohol may be protective of ischemic stroke in moderate drinkers, but hemorrhages are more likely with any intake of alcohol. (5,10,12) Stress is universally recognized as a precipitant of strokes by stroke patients and their families. The Caerphilly Study in Wales (13) reported a specific association between life stresses and incidence of stroke, particularly fatal stroke (risk ratio [RR], 3.36).

Lowering Blood Pressure

Blood pressure management is the liveliest area in current stroke prevention research. Hypertension is the most common stroke risk factor, occurring in approximately 50 million Americans. Epidemiologic studies have uniformly confirmed a relationship between hypertension and stroke. (5) A meta-analysis of studies of antihypertensive therapy (14) reported that a modest, 5- to 6-mm Hg blood pressure reduction resulted in a 42% reduction in stroke incidence. The Systolic Hypertension in the Elderly Program (SHEP) (15) showed a 37% reduction in ischemic stroke in elderly patients treated with one of three antihypertensive regimens. Two recent trials (16,17) have suggested that angiotensin-converting enzyme (ACE) inhibitors may be especially effective, and a comparison study of an ACE receptor blocker (ARB) suggested a similar effect of the ARB losartan. (18) In the HOPE trial (16) of high-risk patients older than 55 years of age, the ACE inhibitor ramipril reduced the incidence of stroke, myocardial infarction (M I), and vascular death by 22% more than placebo; strokes were 32% less frequent in ramipril-treated patients. The LIFE trial, (18) also a primary stroke prevention study in high-risk patients, found better stroke prevention with the ACE receptor blocker losartan than the [beta]-blocker atenolol.

Secondary prevention of stroke in patients who have already suffered a TIA or stroke has been studied in the PROGRESS trial. (17) In this study, 6,105 patients were randomized to active treatment with the ACE inhibitor perindopril, with or without the diuretic indapamide, versus placebo. The "active treatment" arm had a 28% reduction in stroke compared with the placebo arm, and reductions also occurred in MI and cerebral hemorrhage. The average blood pressure reduction was 9/4 mm Hg, but both hypertensive and normotensive subjects benefited. On the other hand, the subgroup of patients who received perindopril alone had only a 5/3 mm Hg blood pressure reduction and did not show statistically significant stroke reduction, whereas the combination therapy group had a 12/5 mm Hg blood pressure reduction and even greater benefit in reducing stroke incidence.

We can conclude from these clinical trials on antihypertensive therapy that blood pressure reduction definitely helps prevent strokes. The "neuroprotective" effect of ACE inhibitors or ACE receptor blockers remains unproved. The LIFE trial (18) suggests that ARBs are superior to [beta]-blockers for stroke prevention, and the PROGRESS trial suggests that combined ACE inhibitor/diuretic therapy may be better than ACE inhibitor alone. All stroke patients should likely be placed on antihypertensive therapy and probably an ACE inhibitor or ARB with a diuretic, unless there is hypotension or another contraindication to treatment.

Lipid Lowering in Stroke Prevention

Cholesterol was long neglected as a stroke risk factor because the correlation of hyperlipidemia with stroke is not as close as that with MI. In the Framingham Study, (19) for example, most of the association between hyperlipidemia and stroke disappeared when the "big three" associations--hypertension, diabetes, and heart disease--were factored out. The "MRFIT" analysis (20) of serum cholesterol levels and stroke found increases in stroke mainly with severely elevated low-density lipoprotein (LDL) cholesterol levels. A stroke preventive effect of cholesterol-lowering agents in healthy populations remains unproved; the West of Scotland Study, (21) reported a 10% reduction in stroke, but the small number of events precluded statistical significance.

In contrast to these unimpressive correlations between cholesterol and stroke or stroke reduction in healthy patients, studies on the effect of HMG-CoA reductase inhibitors ("statins") in patients with coronary artery disease have shown significant stroke preventive effects. The first such study, the Scandinavian 4S study, (22) did not include stroke as a preplanned end point; when stroke data was analyzed, a greater than 30% reduction in TIA and stroke was found with simvastatin. A recalculation of the data (23) placed the relative stroke reduction at 28%. Likewise, the CARE trial (24) of patients with MI, many of whom had normal plasma lipids, showed a similar degree of stroke preventive effect with pravastatin. The Food and Drug Administration (FDA) has included stroke prevention as an indication for the use of both simvastatin and pravastatin. Most recently, the LIPID trial (25) reported a 19% stroke reduction with pravastatin.

Patients with stroke and TIA who have not developed evidence of coronary artery disease or peripheral vascular disease do not have a definite indication for statin therapy. The ongoing SPARCL study (26) is designed to detect a stroke preventive effect of atorvastatin in patients with TIA and ischemic stroke but without evidence of coronary artery or peripheral vascular disease.

The rationale for the use of statin drugs in stroke prevention may not rest solely on the lipid-lowering effects of these drugs. Research has indicated "pleiotropic" effects of statin drugs, including plaque stabilization, reduction of free radical and inflammatory markers, and antiplatelet effects, among others. (21,28)

The National Cholesterol Education Program (NCEP) (29) released the third edition of its Adult Treatment Program (ATP III) recommendations for cholesterol-lowering treatment in 2001. In this guideline, the presence of diabetes is equal to that of coronary artery or peripheral vascular disease in indicating lowering of the LDL level below 100 mg/dl. Symptomatic carotid artery disease is also an indication, but this is the only indication related to stroke in the current guidelines. Patients with two or more risk factors should have a goal of less than 130 mg/dl; these risk factors include age greater than 45 in men and 55 in women, hypertension, smoking, family history of early coronary disease, and low high-density lipoprotein (HDL < 40 mg/dl).

Lowering cholesterol should clearly be a part of stroke prevention. For patients with coronary or peripheral vascular disease, or diabetes, the NCEP guidelines mandate aggressive therapy. The SPARCL trial (26) should provide useful information about the benefit of statin therapy in patients with TIA or stroke but no evidence of coronary or peripheral vascular disease.

Antiplatelet Therapy

Once patients have been screened for the need for antihypertensive and lipid-lowering medications, the stroke prevention depends on antithrombotic and antiplatelet medications. The effectiveness of these drugs in primary stroke prevention is uncertain except for anticoagulation for patients with cardiac sources of embolic stroke such as atrial fibrillation, MI with mural thrombus, prosthetic cardiac valves, and low output congestive heart failure. (30) Aspirin prevents MI in normal middle-aged persons as substantiated by both the British (31) and American (32) physicians health studies, but neither trial provided clear evidence of stroke prevention. The small event rates for stroke in healthy male physicians may explain these negative results.

The best-established evidence for secondary stroke prevention involves antiplatelet therapy. Several large, randomized trials have supported the use of aspirin to prevent stroke, although the optimal dose remains controversial. The Canadian study of 1978 (33) documented a nearly 50% reduction of stroke and/or death in males with TIA who were treated with 1300 mg/d of aspirin; females showed no benefit. This was the first "evidence-based medicine" for prevention of serious outcomes related to stroke. Controversy persists regarding the optimal dose of aspirin. Small doses (81 mg/d or less) have been advocated on the theoretical grounds of sparing the prostacyclin system of the vessel wall; since platelets have no nuclei, their ability to generate thromboxane A2 remains irreversibly blocked by aspirin. The UK Trial (34) found no difference in effectiveness between 325 and 1300 mg/d of aspirin, but both doses were superior to placebo in preventing the combined end point of stroke, MI, and vascular death. The Swed ish SALT study (35) reported a similar benefit with 75 mg aspirin over placebo. In the Dutch TIA Study, (36) patients on 30 mg of aspirin fared no differently than those on 270 mg of aspirin; there was no placebo group in this study. The ACE (After Carotid Endarterectomy Study) (37) showed lower incidence of stroke, MI, and vascular death in patients treated with 81 or 325 mg/d aspirin compared with those treated with 650 or 1,300 mg/d, for 3 months after carotid endarterectomy. Another source of information on antiplatelet therapy are the Antiplatelet Trialists (38,39) and Antithrombotic Trialists (40) publications, which document benefit from aspirin in multiple trials at a 20 to 25% relative risk reduction level. The Antithrombotic Trialists (40) endorsed low doses of aspirin, 75 to 160 mg/d. The current FDA guidelines recommend aspirin doses of 50 to 325 mg/d for stroke prevention.

Ticlopidine, a thienopyridine agent that blocks adenosine diphosphate-dependent platelet aggregation, has shown substantial benefit. In the Ticlopidine Aspirin Stroke Study (TASS) (41) study of TIA or mild stroke, ticlopidine reduced the rate of stroke by 21% compared with aspirin at the end of 3 years. Ticlopidine has largely been abandoned because of its toxicity, including diarrhea, rash, and occasional neutropenia. Clopidogrel (Plavix; Bristol-Myers Squibb Co., New York, NY), a thienopyridine similar in structure to ticlopidine, has a more favorable side effect profile and similar in vitro properties. The CAPRIE trial (42) studied 19,000 patients with stroke, MI, or peripheral vascular disease and showed only a modest, 8.7% relative risk reduction of clopidogrel over aspirin. The group with stroke showed a 7.4% relative risk reduction, not statistically significant. Clopidogrel thus appears only minimally more effective than aspirin, and current applications of the drug are largely in combination with asp irin. The CURE trial (43) in acute coronary syndrome suggested greater efficacy of Plavix when combined with aspirin, though with an increased bleeding risk. There is currently no evidence for combined use of aspirin and clopidogrel in stroke patients; the MATCH trial, in progress, compares clopidogrel plus aspirin against clopidogrel alone in secondary stroke prevention. The most recently approved oral antiplatelet agent is the combination of extended release dipyridamole and aspirin. In the European Stroke Prevention Study II, (44) aspirin plus dipyridamole (Aggrenox 25/200 mg bid) prevented 19% more strokes than aspirin alone, 37% more than placebo.

Warfarin is still used in stroke prevention, sometimes empirically in patients who fail antiplatelet regimens. The Warfarin Aspirin Recurrent Stroke Study, (45) showed no significant difference between aspirin and waffarin in the secondary prevention of stroke in patients who have had an ischemic stroke without evidence of either significant carotid stenosis or a definite cardiac source of embolus. This study should reduce the routine use of warfarin in nonembolic stroke patients. Patients with carotid dissections, venous sinus thrombosis, intracranial vascular stenosis, low cardiac ejection fraction, and hypercoagulable states may benefit from warfarin, but large trials have not addressed these relatively uncommon indications for warfarin. Only atrial fibrillation in primary (30) and secondary (46) prevention has be en adequately tested to prove a benefit of warfarin.

These data on antiplatelet and antithrombotic therapy do not permit a single drug recommendation for secondary stroke prevention. The widely quoted guidelines of the American College of Chest Physicians (47) recommend that aspirin, dopidogrel, or aspirin/dipyridamole are all acceptable first-line options for secondary stroke prevention. The guidelines state that aspirin/dipyridamole "may be" more effective than aspirin and has a similar side effect profile. The use of combined aspirin and clopidogrel for stroke prevention remains unproved, at least until the results of the MATCH trial become available.

This review has not discussed the surgical prevention of stroke with carotid endarterectomy, angioplasty and stenting, or vascular bypass surgery. We have seen that patients with TIA and stroke are at greatly increased risk of stroke compared with the general population. In the same way, patients with atrial fibrillation are about four times as likely to have a stroke if they have previously had a stroke or TIA (approximately 12%/yr) (46) than if they are asymptomatic (approximately 3%/yr). (30) Similarly, patients with greater than 70% internal carotid stenosis are at least six times as likely to have a stroke if they have had TIA or stroke symptoms on the appropriate side (48) than if they are asymptomatic. (49) In our approach to the patient at risk for stroke, therefore, the importance of a careful history for stroke warning signs (TIA or stroke) cannot be overemphasized.

Afterword

After the original preparation of this article, the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (50) compared the effects of a calcium channel blocker, amlodipine, an ACE inhibitor, lisinopril, and an [alpha]-blocker (doxazocin) versus a thiazide diuretic (chlorthalidone) in the prevention of heart attack and stroke in a population of 33,357 patients older than 55 years of age with hypertension and at least one other vascular risk factor. The chlorthalidone group did at least as well as the other groups, and chlorthalidone was associated with a trend toward a lower incidence of stroke as compared with lisinopril. The explanation of the apparent benefit of chlorthalidone is unclear, but the diuretic did lower blood pressure more than lisinopril. Whether a different ACE-inhibitor--one with greater tissue penetration such as ramipril or perindopril--would have fared better against chlorthalidone is an unanswered question. The authors of the trial recommended chlorthalido ne as the first-line treatment for hypertension.

Accepted November 7, 2002.

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RELATED ARTICLE: Key Points

* Stroke is one of the most preventable serious medical illnesses.

* Stroke prevention depends on public education and application of already available medical knowledge.

* Hypertension is the most common modifiable risk factor for stroke.

From the Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN.

Reprint requests to Howard S. Kirshner, MD, Department of Neurology, Vanderbilt University School of Medicine, 362 Vanderbilt Medical Center S., 2100 Pierce Avenue, Nashville, TN 37212. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9604-0354