This Article Free upon publication Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldstein, L. B. Articles by Members Search for Related Content PubMed PubMed Citation Articles by Goldstein, L. B. Articles by Members, Pubmed/NCBI databases Medline Plus Health Information Stroke Related Collections Lipids Cerebrovascular disease/stroke Thrombosis risk factors Other diabetes AHA Statements and Guidelines Carotid Stenosis Primary and Secondary Stroke Prevention Risk Factors for Stroke Anticoagulants Antiplatelets Other Stroke Treatment - Medical Carotid endarterectomy Transient Ischemic Attacks

(Circulation. 2001;103:163.)
© 2001 American Heart Association, Inc.

AHA Scientific Statement

Primary Prevention of Ischemic Stroke

A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

Larry B. Goldstein, MD, Chair; Robert Adams, MD; Kyra Becker, MD; Curt D. Furberg, MD; Philip B. Gorelick, MD; George Hademenos, PhD; Martha Hill, PhD, RN; George Howard, PhD; Virginia J. Howard, MSPH; Bradley Jacobs, MD; Steven R. Levine, MD; Lori Mosca, MD; Ralph L. Sacco, MD; David G. Sherman, MD; Philip A. Wolf, MD; Gregory J. del Zoppo, MD; Members

Key Words: AHA Scientific Statements • stroke • prevention • risk factors • arrhythmia • hypercholesterolemia • smoking

Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.^{1 2} The economic burden of stroke was estimated by the American Heart Association to be $51 billion (direct and indirect costs) in 1999.³ Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.^{4 5} High-risk or stroke-prone individuals can be identified and targeted for specific interventions.⁶ This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.^{7 8}

The Stroke Council of the American Heart Association formed an ad hoc writing group to provide a clear and concise overview of the evidence regarding various established and potential stroke risk factors. The writing group was chosen based on expertise in specific subject areas, and it used literature review, reference to previously published guidelines, and expert opinion to summarize existing evidence and formulate recommendations (Table 1).

View this table: [in this window] [in a new window]   Table 1. Levels of Evidence and Grading of Recommendations

As given in Tables 2 through 4, risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).⁵ The tables give the estimated prevalence, population attributable risk, relative risk, and risk reduction with treatment for each factor when known. Population attributable risk reflects the proportion of ischemic strokes in the population that can be attributed to a particular risk factor and is given by the formula 100x[prevalence(relative risk-1)/prevalence(relative risk-1)+1]).⁹ Well-documented modifiable risk factors (Table 3) were considered as those with clear, supportive epidemiological evidence in addition to evidence of risk reduction with modification as documented by randomized trials. Less well-documented or potentially modifiable risk factors were those with either less clear epidemiological evidence or without evidence from randomized trials demonstrating a reduction of stroke risk with modification. Gaps in current knowledge are indicated by question marks in the tables.

View this table: [in this window] [in a new window]   Table 2. Nonmodifiable Risk Factors

View this table: [in this window] [in a new window]   Table 3. Well-Documented Modifiable Risk Factors

View this table: [in this window] [in a new window]   Table 4. Less Well-Documented or Potentially Modifiable Risk Factors

Table 5 summarizes guideline or consensus statement management recommendations where available. Other recommendations are indicated in the text. Based primarily on an individual patient’s risk assessment profile (the Framingham Heart Study risk profile⁶ is an easy-to-use and valuable tool for identifying persons at risk of stroke) and overall medical condition, interventions involving appropriate lifestyle behavior changes and surgical and pharmacological treatments can be implemented to treat, control, or modify specific risk factors with the goal of reducing the risk of a first stroke.

View this table: [in this window] [in a new window]   Table 5. Guideline or Consensus Statement Management Recommendations

Nonmodifiable Risk Factors

Although these factors are nonmodifiable, they identify individuals at highest risk of stroke and those who may benefit from rigorous prevention or treatment of modifiable risk factors.⁵ (See Table 2.)

Age
The cumulative effects of aging on the cardiovascular system and the progressive nature of stroke risk factors over a prolonged period of time substantially increase stroke risk. The risk of stroke doubles in each successive decade after 55 years of age.^{8 10}

Sex
Stroke is more prevalent in men than in women.⁸ Overall, men also have higher age-specific stroke incidence rates than women.¹¹ Exceptions are in 35- to 44-year-olds and in those over 85 years of age in whom women have slightly greater age-specific incidence than men.¹¹ However, stroke-related case-fatality rates are higher in women than men. In 1997, females accounted for 60.8% of stroke fatalities.² Overall, 1 in 6 women will die of stroke, compared with 1 in 25 who will die of breast cancer.¹² Circumstances such as oral contraceptive use and pregnancy uniquely contribute to the risk of stroke in women.^{13 14 15}

Race/Ethnicity
Blacks^{1 11 16} and some Hispanic Americans^{16 17} have high stroke incidence and mortality rates compared with whites. For example, in the Atherosclerosis Risk In Communities (ARIC) study, blacks had a 38% greater incidence of strokes than whites.¹⁸ Possible reasons for the high incidence and mortality rate of strokes in blacks include a higher prevalence of hypertension, obesity, and diabetes mellitus within the black population.^{19 20 21} However, a higher incidence of these other risk factors does not explain all of the excess risk.¹⁹ Epidemiological studies have also shown an increase in stroke incidence among self-identified Hispanic populations.^{22 23 24} Chinese and Japanese populations generally have high stroke incidence rates as well.²⁵

Family History
Both paternal and maternal history of stroke may be associated with increased stroke risk.^{26 27} This increased risk could be mediated through a variety of mechanisms, including genetic heritability of stroke risk factors, the inheritance of susceptibility to the effects of such risk factors, familial sharing of cultural/environmental and lifestyle factors, and the interaction between genetic and environmental factors.²⁸ Studies with twins provide strong data suggesting familial inheritance of stroke. Concordance rates for strokes are markedly higher in monozygotic than in dizygotic twins.²⁹ There is a nearly 5-fold increase in stroke prevalence among monozygotic versus dizygotic twins.³⁰

Well-Documented Modifiable Risk Factors

Several well-documented modifiable risk factors for stroke exist. (See Table 3.)

Hypertension
Hypertension is a major risk factor for both cerebral infarction and intracerebral hemorrhage.³¹ The incidence of stroke increases in proportion to both systolic and diastolic blood pressures. This relationship is "direct, continuous, and apparently independent."³² Blood pressure, particularly systolic blood pressure, increases with age.³³ Elevated systolic pressure, with or without an accompanying elevation in diastolic pressure, has been shown to increase stroke risk. Isolated systolic hypertension is an important risk factor for stroke in the elderly (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg).³⁴

There has been compelling evidence for more than 30 years that the control of high blood pressure contributes to the prevention of stroke as well as to the prevention or reduction of other target-organ damage, including congestive heart failure and renal failure.^{35 36} A meta-analysis of 18 long-term randomized trials found that both ß-blocker therapy (relative risk 0.71; 95% CI 0.59 to 0.86) and treatment with high-dose diuretics (relative risk 0.49; 95% CI 0.39 to 0.62) were effective in preventing stroke.³⁷ In the past 10 years, the importance of controlling isolated systolic hypertension to prevent stroke in the elderly has been underscored in clinical trials.³⁸ For example, in the Syst-Eur Trial, 4695 patients with isolated systolic hypertension were randomized to active treatment (nitrendipine and possibly enalapril or hydrochlorothiazide to lower systolic blood pressure 20 mm Hg) or to placebo.³⁸ The trial was stopped when stroke reduction reached 42% in the actively treated group. The Systolic Hypertension in the Elderly Program (SHEP) trial demonstrated a 36% reduction in the incidence of total stroke with antihypertensive treatment (chlorthalidone or atenolol).³⁹ Despite extensive education efforts, a significant proportion of the population has undiagnosed or inadequately treated hypertension.^{34 40 41} This is particularly true in high-risk race/ethnic groups.⁴²

Recommendation
Regular screening for hypertension (at least every 2 years in adults) and appropriate management, as summarized in the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, are recommended (Table 5).³⁴ (Level of Evidence I, Grade A)

Smoking
Active (current) cigarette smoking has been long recognized as a major risk factor for stroke. Pathophysiological effects of smoking are multifactorial, affecting both the systemic vasculature and blood rheology. Smoking causes reduced blood vessel distensibility and compliance by leading to increased arterial wall stiffness.⁴³ Smoking is also associated with increased fibrinogen levels, increased platelet aggregation, decreased high-density lipoprotein (HDL) cholesterol levels, and increased hematocrit.⁴⁴

A meta-analysis of 22 studies indicates an approximate doubling of the relative risk of cerebral infarction among smokers versus nonsmokers.⁴⁵ A prospective estimate of a 1.8-fold increase in stroke risk associated with smoking (after control for other stroke risk factors) from the Framingham Heart Study confirms this substantial increase in risk.⁴⁶ Currently, 25% of adults are active smokers.⁴⁷ Therefore, 18% of strokes are attributable to active cigarette smoking. This estimated population attributable risk is only slightly higher than the estimated 12% population attributable risk associated with active smoking in the Rochester, Minn, population.⁹

To the extent that former smoking may also place individuals at increased risk of stroke, efforts to prevent the initiation of smoking are important to the primary prevention of stroke. The relative risk of stroke among former smokers (compared with nonsmokers) was 1.34 in the Nurses’ Health Study⁴⁸ and 1.26 in the Physicians’ Health Study.⁴⁹ Currently, the Centers for Disease Control and Prevention estimate that 23% of the adult population are former smokers,⁴⁷ implying a population attributable risk for former smoking of 6%. However, the stroke risk associated with former smoking has been shown to substantially decrease with increasing time since cessation. As such, in the Physicians’ Health and Nurses’ Health studies, the 6% population attributable risk estimate is a function of the distribution of time since quitting. The Framingham Heart Study found stroke risk to be at the level of nonsmokers at 5 years from cessation.⁵⁰ A second study reported that stroke risks disappeared from 2 to 4 years after smoking cessation and that the benefits of cessation were independent of the age at starting and the number of cigarettes smoked per day.⁴⁸ Wannamethee et al⁵¹ concluded that smoking cessation is associated with a considerable and rapid benefit in decreased risk of stroke, particularly in light smokers (<20 cigarettes/d). However, switching to pipe or cigar smoking confers little benefit, emphasizing the need for complete cessation of smoking.⁵¹

Avoidance of exposure to environmental tobacco smoke may also play a role in the primary prevention of stroke. Nearly 90% of nonsmokers have been shown to have detectable levels of serum cotinine, assumed to be present through exposure to environmental tobacco smoke.⁵² Because of the high population prevalence of exposure, even a small increase in the relative risk of stroke associated with exposure to environmental tobacco smoke may have a substantial population attributable risk. However, the increase in relative risk may not be small. It has been suggested that exposure to environmental tobacco smoke increases the risk for coronary events from 20% to 70%. An estimated 62 000 coronary heart disease deaths in 1985 were attributable to exposure to environmental tobacco smoke.⁵²

Because atherosclerosis can lead to both stroke and coronary heart disease, it is reasonable to suspect environmental tobacco smoke as a cause for some strokes. After adjusting for potential confounders (age, sex, history of hypertension, heart disease, and diabetes), Bonita and colleagues⁵³ found a 1.82-fold increase (95% CI 1.34 to 2.49) in the risk of stroke among nonsmokers and long-term ex-smokers exposed to environmental tobacco smoke. The risk was significant in both men and women. An increase of 1.82 is surprisingly large; however, even a more modest 1.20-fold increase in relative risk (the lower limit of the estimated effect on coronary heart disease) is associated with an estimated population attributable risk of 12% (based on a 67.5% population exposure, calculated as 90% prevalence of exposure in the 75% of the nonsmoking population).

In summary, these data suggest that the population attributable risk associated with all forms of exposure to cigarette smoke is substantial, with current smoking contributing to approximately half of the stroke events (population attributable risk of 18% for current smoking, 6% for former smoking, and 12% for exposure to environmental tobacco smoke).

Recommendation
Smoking cessation for all current smokers is recommended (Table 5).³⁴ (Level of Evidence III, Grade C; note that the evidence level reflects a lack of prospective randomized trials of smokers compared with nonsmokers. However, the data from cohort and epidemiological studies are consistent and overwhelming.)

Diabetes, Hyperinsulinemia, and Insulin Resistance
Insulin-dependent diabetics have both an increased susceptibility to atherosclerosis and an increased prevalence of atherogenic risk factors, notably hypertension, obesity, and abnormal blood lipids. A constellation of metabolic risk factors, termed syndrome X, has also been identified in some type 2 diabetics.^{54 55} The main characteristics of syndrome X are hyperinsulinemia and insulin resistance. These result in the secondary features of the syndrome, including hyperglycemia, increased very-low-density lipoprotein cholesterol, decreased HDL cholesterol, and hypertension.

Case-control studies of stroke patients and prospective epidemiological studies have confirmed an independent effect of diabetes on ischemic stroke, with an increased relative risk in diabetics ranging from 1.8- to nearly 6-fold. In the United States, from 1976 to 1980, a history of stroke was 2.5 to 4 times more common in diabetics than in persons with normal glucose tolerance. Among Hawaiian Japanese men in the Honolulu Heart Program, those with diabetes had twice the risk of thromboembolic stroke as nondiabetics, an increase in risk that was independent of other factors.⁵⁶ In the Framingham Heart Study, although the impact of diabetes was greatest on peripheral arterial disease with intermittent claudication, for which the relative risk was increased 4-fold, coronary and cerebral artery territories were also affected. For brain infarction, the impact of glucose intolerance was greater in women than men, reaching significance as an independent contributor only in older women. Overall, persons with glucose intolerance have double the risk of brain infarction compared with nondiabetics.⁵⁷

High blood pressure is common in patients with type 2 diabetes, with a prevalence of 40% to 60% in adults. The combination of hyperglycemia and hypertension has long been believed to increase the frequency of diabetic complications, including stroke. Several recent trials examining stroke and other cardiovascular outcomes compared the benefit of tight control of blood glucose and blood pressure in type 2 diabetics with less stringent management.⁵⁸ For combined fatal and nonfatal stroke, tight blood pressure control (mean blood pressure achieved 144/82 mm Hg) resulted in a convincing 44% relative risk reduction compared with more liberal control (mean blood pressure achieved 154/87 mm Hg).⁵⁹ This 44% benefit in stroke risk reduction is above and beyond the 20% risk reduction with antihypertensive treatment found in diabetics in SHEP.⁶⁰ However, improved glycemic control did not produce a significant reduction in stroke incidence over 9 years of follow-up.⁶¹

The conclusion reached from these studies and in a recent review is that tight control of hypertension in diabetics significantly reduces stroke incidence.⁶² Current measures to achieve tight glycemic control are less effective for stroke prevention. Nevertheless, intensive therapy to achieve tight control of hyperglycemia with 3 doses per day of insulin in patients with recent-onset insulin-dependent (type 1) diabetes mellitus was shown to reduce microvascular complications, nephropathy, and retinopathy, as well as peripheral neuropathy.⁵⁹

The report of the Heart Outcomes Prevention Evaluation (HOPE) study represents an exciting development in prevention of cardiovascular disease. In this placebo-controlled, randomized clinical trial, the addition of the angiotensin-converting enzyme (ACE) ramipril was compared with the current medical regimen of high-risk patients. The substudy of 3577 diabetic patients (of a total population of 9541 participants in the HOPE study) showed a reduction of the primary combined outcome of myocardial infarction, stroke, and cardiovascular death by 25% (95% CI 12% to 36%, P=0.0004) and a reduction of stroke by 33% (95% CI 10% to 50%, P=0.0074).⁶³ This benefit was present even after adjustment for the minor decrease in blood pressure in the ramipril group. There was also a reduction in diabetic complications (overt nephropathy, dialysis, or need for laser therapy).

These new reports provide long-sought evidence for stroke prevention in diabetics. Control of hypertension in diabetics and treatment of high-risk diabetic patients with the ACE inhibitor ramipril prevent stroke.

Recommendations
Careful control of hypertension in both type 1 and type 2 diabetics is recommended. (Level of Evidence I, Grade A) Glycemic control is recommended to reduce microvascular complications (Table 5).^{64 65}

Asymptomatic Carotid Stenosis
In the Cardiovascular Health Study, carotid stenoses >50% were detected in 7% of the men and 5% of the women 65 years of age.⁶⁶ Similarly, stenoses of 50% were detected in 7% of women and 9% of men aged 66 to 93 years in the Framingham cohort.⁶⁷ Therefore, it seems likely between 7% and 10% of men and between 5% and 7% of women above age 65 have carotid stenoses >50%.

Several studies have attempted to identify subgroups of patients with asymptomatic carotid artery stenosis who may be at particularly elevated risk of stroke. The Toronto Asymptomatic Cervical Bruit Study followed a cohort of 500 patients for a mean of 23 months.⁶⁸ Overall, cerebral ischemic events (transient ischemic attack [TIA] or stroke) were more frequent in patients with severe (>75%) carotid artery stenosis, progressing carotid artery stenosis, or heart disease and in men. A total of 8 patients (1.6%) had an unheralded stroke; however, only 2 (0.4%) were ipsilateral to a high-grade extracranial carotid artery stenosis as demonstrated by Doppler ultrasonography. In another study, 38 asymptomatic patients with >90% stenosis of the internal carotid artery were followed up for a mean period of 48 months.⁶⁹ Each year, 1.7% of the patients had an unheralded ipsilateral stroke. More recently, the NASCET (North American Symptomatic Carotid Endarterectomy Trial) investigators have retrospectively reviewed their data regarding the risk of stroke in the territory of an asymptomatic carotid artery stenosis contralateral to the side of the symptomatic vessel.^{70 71} The annual risk of stroke was 3.2% (over 5 years of observation) in patients with 60% to 99% stenosis. The average annual risk of ipsilateral stroke increased from 3.0% for those with 60% to 74% stenosis to 3.7% for those with 75% to 94% stenosis and decreased to 2.9% for those with 95% to 99% stenosis, with a rate of 1.9% for those with complete occlusion. Overall, 45% of ipsilateral strokes in patients with asymptomatic stenosis contralateral to a symptomatic stenosis may be attributable to lacunes or cardioembolism, underscoring the need to fully evaluate these patients for other treatable causes of stroke.

Taken together, these and other observational studies suggest that the rate of unheralded stroke ipsilateral to a hemodynamically significant extracranial carotid artery stenosis is 1% to 2% annually. This represents a significant factor on a population basis. Some studies suggest that the rate of stroke may be higher in those patients with progressing stenosis than in those with stable disease and higher in those with more severe stenosis. As with asymptomatic carotid bruit, an asymptomatic stenosis of the carotid artery is an important indicator of concomitant ischemic cardiac disease.^{68 69 72}

There have been 4 published randomized controlled trials that were designed to address the benefit of carotid endarterectomy in patients with asymptomatic carotid artery stenosis. The CASANOVA (Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin) study was inconclusive.⁷³ The Mayo Clinic Asymptomatic Carotid Endarterectomy (MACE) study included 71 randomized and 87 nonrandomized patients.⁷⁴ Surgically treated patients were not given aspirin. There were no major strokes or deaths in either group. However, the study was stopped because myocardial infarction occurred in 26% of those in the surgical arm (no aspirin) versus 9% of those in the aspirin-treated medical arm (P=0.002), reflecting the high incidence of concomitant coronary artery disease in patients with asymptomatic carotid artery stenosis.

The Veterans Affairs Cooperative Study of carotid endarterectomy for patients with asymptomatic carotid artery stenosis included 444 men followed up for a mean of 48 months.⁷⁵ Two hundred eleven patients received best medical therapy plus carotid endarterectomy, and 233 received medical therapy alone (including 650 mg of aspirin twice daily). Patients had >50% stenosis of the extracranial carotid artery demonstrated by angiography. Combined perioperative and angiographic risk was 4.7%. There was a 38% risk reduction for the combined end points of ipsilateral TIA, transient monocular blindness, and stroke over 2 years (P<0.001). Although the rate of fatal and nonfatal stroke was reduced in the surgical group (4.7% versus 9.4%, or 1.2% per year versus 2.4% per year), the difference was not significant (P=0.08). However, the study was not powered to detect differences in outcome subgroups.

The Asymptomatic Carotid Atherosclerosis Study (ACAS) was a randomized trial investigating the efficacy of carotid endarterectomy in patients with asymptomatic high-grade (>60% diameter reduction) carotid artery stenosis.⁷⁶ Patients (n=1662) were randomized to surgery plus medical therapy (n=828) or to medical therapy without carotid endarterectomy (n=834). There was a 1.2% risk of angiography-related complications among the 424 patients undergoing postrandomization angiograms and a 2.3% aggregate perioperative stroke risk. The study was halted after a median follow-up of 2.7 years (4465 patient-years) because a significant benefit of surgery was found. The aggregate rate of ipsilateral stroke, any perioperative stroke, or death in surgically treated patients was estimated at 5% over 5 years; in medically treated patients, the corresponding rate was 11% (53% risk reduction, 2% per year event rate reduced to 1% per year; P=0.004). There was no relationship between benefit and the degree of carotid artery stenosis. Women did not benefit (17% nonsignificant risk reduction in women [95% CI -0.96 to 0.65] versus 66% risk reduction in men [95% CI 0.36 to 0.82]), a difference ascribed to a higher rate of perioperative complications in women (3.6% versus 1.7%). Other studies have also noted an increased risk of perioperative complications after endarterectomy in asymptomatic women compared with men.⁷⁷ However, as with the Veterans Affairs trial, the study was not powered to detect differences among subgroups of patients.

It should be noted that the benefit of endarterectomy in the setting of asymptomatic carotid artery stenosis is highly dependent on surgical risk. Yet, most physicians are not aware of the complication rates of the surgeon to whom they refer patients for the operation.^{78 79}

Recommendation
Endarterectomy may be considered in patients with high-grade asymptomatic carotid stenosis performed by a surgeon with <3% morbidity/mortality rate. (Level of Evidence I, Grade A) Careful patient selection, guided by comorbid conditions, life expectancy, and patient preference, as well as other individual factors, including sex, and followed by a thorough discussion of the risks and benefits of the procedure, is required. It is important that patients with asymptomatic carotid artery stenosis be fully evaluated for other treatable causes of stroke. (See Table 5.)

Atrial Fibrillation
Atrial fibrillation is a common arrhythmia and an important risk factor for stroke, with established effective therapy for stroke prevention. The annual risk of stroke in unselected patients with nonvalvular atrial fibrillation is 3% to 5%, with the condition responsible for 50% of thromboembolic strokes.⁸⁰ It is estimated that approximately two thirds of the strokes that occur in patients with atrial fibrillation are cardioembolic. The median age of patients with atrial fibrillation is 75 years. The Framingham Heart Study noted a dramatic increase in stroke risk associated with atrial fibrillation with advancing age, from 1.5% for those 50 to 59 years of age to 23.5% for those 80 to 89 years of age.⁸¹ In addition, atrial fibrillation was associated with an OR for death of 1.5 (95% CI 1.2 to 1.8) in men and 1.9 (95% CI 1.5 to 2.2) in women after adjustment for other risk factors.

Five placebo-controlled trials investigating the efficacy of warfarin in the primary prevention of thromboembolic stroke included the Copenhagen Atrial Fibrillation Aspirin and Anticoagulation (AFASAK) trial,⁸² Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF),⁸³ Stroke Prevention in Atrial Fibrillation I (SPAF I),⁸⁴ Veterans Affairs Stroke Prevention in Atrial Fibrillation trial (SPINAF),⁸⁵ and the Canadian Atrial Fibrillation Anticoagulation (CAFA) trial.⁸⁶ The efficacy of aspirin was studied in 2 of these trials (AFASAK and SPAF I). Combined analysis of these 5 trials showed that the relative risk of thromboembolic strokes for patients treated with warfarin was reduced by 68%.

An important observation arising from the randomized treatment trials is that there are a limited number of predictors of high stroke risk within the population of patients with atrial fibrillation. The predictors of high risk include advancing age, prior TIA or stroke, systolic hypertension (systolic blood pressure >160 mm Hg), a history of hypertension, impaired left ventricular function, diabetes mellitus, and women over the age of 75 years.⁸⁷ Long-term oral anticoagulation of patients with these high-risk features reduces the risk of stroke by 68% based on results of the intention-to-treat analysis of the randomized trials and by as much as 80% when the on-treatment effect is noted.⁸⁸

Recommendation
Antithrombotic therapy (warfarin or aspirin) should be considered for patients with nonvalvular atrial fibrillation based on an assessment of their risk of embolism and risk of bleeding complications (Tables 4 and 5).⁸⁷ (Level of Evidence I, Grade A)

Other Cardiac Disease
Other types of cardiac disease that contribute a small yet finite risk to thromboembolic stroke include dilated cardiomyopathy, valvular heart disease (eg, mitral valve prolapse, endocarditis, and prosthetic cardiac valves), and intracardiac congenital defects (eg, patent foramen ovale, atrial septal defect, and atrial septal aneurysm). Overall, an estimated 20% of ischemic strokes are due to cardiogenic embolism. Potential cardiac sources of emboli are associated with up to 40% of cryptogenic strokes in some series involving the younger population.⁸⁹

The presence of cerebrovascular disease is strongly associated with the presence of symptomatic^{90 91 92 93} and asymptomatic^{94 95 96 97 98} cardiac disease. Conversely, based on the Framingham Heart Study, 8% of men and 11% of women will have a stroke within 6 years after acute myocardial infarction. In addition, myocardial infarction is associated with the development of atrial fibrillation and is a common source of cardiogenic emboli.⁸¹ However, acute myocardial infarction is infrequently associated with stroke, occurring in 0.8% of patients.^{99 100 101} The majority of these strokes (in 0.6% of patients) are ischemic.¹⁰¹

Perioperative stroke occurs in 1% to 7% of patients undergoing cardiac surgical procedures (predominantly coronary artery bypass procedures and open heart surgery). A history of prior neurological events, increasing age, diabetes, and atrial fibrillation have been identified as risk factors for early and delayed stroke after cardiac surgery.^{102 103 104 105 106 107 108 109 110 111 112} Other factors associated with perioperative stroke include duration of cardiopulmonary bypass and the presence of aortic atherosclerosis.^{113 114}

Sickle Cell Disease
Sickle cell disease (SCD) is a genetic disorder with autosomal dominant inheritance in which the abnormal gene product is an altered ß-chain in the structure of hemoglobin. Although the clinical manifestations are highly variable, typically SCD manifests early in life as a severe hemolytic anemia punctuated by bouts of painful episodes involving the extremities and bones ("vaso-occlusive crises"), bacterial infections, and organ infarctions, including stroke. In addition, there are systemic effects including impaired growth and possibly cognitive developmental retardation.¹¹⁵

Stroke prevention is most important for patients with homozygous SS disease. The prevalence of stroke by age 20 in these patients is at least 11%,¹¹⁶ and a substantial number of patients also have "silent" strokes on brain MRI.¹¹⁷ The highest stroke rates occur in early childhood. Recent advances in detection of risk with transcranial Doppler have made primary prevention of stroke a high priority in children with SCD.^{118 119} The risk of stroke during childhood is 1% per year, but patients with transcranial Doppler evidence of high cerebral blood flow velocity rates (time-averaged mean velocity of 200 cm/s) have stroke rates in excess of 10% per year.

A recently completed randomized trial (Stroke Prevention Trial in Sickle Cell Anemia; the STOP study) compared periodic blood transfusion with standard care in 130 children with SCD ranging in age from 2 to 16 years (mean 8 years).¹²⁰ Blood transfusions were given an average of 14 times per year for >2 years in the treatment group, with a target reduction of Hb S from a baseline of 90% to 95% of total hemoglobin to <30%. The trial was halted 16 months early at the point at which 11 strokes had occurred in the standard-care arm compared with 1 stroke in the transfusion-treated group. The risk of stroke was reduced from 10% per year to <1%. Given these results, a Clinical Alert issued by the National Heart, Lung, and Blood Institute of the National Institutes of Health has recommended screening all children with SCD who have no history of stroke, with consideration of transfusion for those with 2 abnormal transcranial Doppler studies.

At present, the duration of transfusion needed has not been determined. Long-term transfusion is always associated with iron toxicity that must be treated with chelation.¹²¹ In the STOP study, there was no evidence of transfusion-related infection, but this and alloimmunization remains a transfusion risk.¹²⁰ The role of other therapies such as bone marrow transplantation or hydroxyurea, which reduce the number of painful crises but have an uncertain effect on organ damage, including stroke, requires further study.^{122 123} The roles of anticoagulation and antiplatelet agents have not been evaluated. The use of methods other than transcranial Doppler, such as MRI or magnetic resonance angiography, to predict stroke sufficient to trigger prophylactic transfusion has not been well studied. There are no systematic data on prevention of stroke in adults with SCD, and improvements in care have increased expected longevity well beyond 40 years of age, making stroke in older SCD patients a more common clinical problem. Preventive therapies other than transfusion and the development of a prevention strategy in adults should be explored.

Recommendation
Children with SCD should be screened with transcranial Doppler ultrasonography at 6-month intervals to determine their level of stroke risk. Those at elevated risk should be considered for transfusion therapy. (Level of Evidence I, Grade A)

Hyperlipidemia
Abnormalities of serum lipids (triglycerides, cholesterol, low-density lipoprotein [LDL], and HDL) have traditionally been regarded as a risk factor for coronary artery disease but not for cerebrovascular disease. However, recent studies have helped clarify the relationship between lipids and stroke, as well as showing that the risk of stroke and amount of carotid atheroma can be reduced with cholesterol-lowering medications.

In a large meta-analysis of 45 prospective observational cohorts involving 450 000 individuals, no association was found between cholesterol and stroke rate.¹²⁴ However, these epidemiological studies of the relationship between total cholesterol and stroke are confounded by reports of an inverse association between total cholesterol and cerebral hemorrhage, with a greater mortality from hemorrhagic stroke among those with serum cholesterol levels <160 mg/dL.^{125 126 127} In the studies included in the meta-analysis, most of the strokes were fatal, and there was not a clear differentiation between ischemic and hemorrhagic strokes.

For ischemic stroke, some studies have found a weak association between serum cholesterol and an increasing risk of cerebral infarction.¹²⁸ For example, the Multiple Risk Factor Intervention Trial demonstrated increased mortality among men with high cholesterol levels.¹²⁹ The adjusted risk ratio was 1.8 for those with serum cholesterol 240 to 279 mg/dL and 2.6 for those with cholesterol levels 280 mg/dL. In the Honolulu Heart Program, there was a continuous and progressive increase in both coronary heart disease and thromboembolic stroke rates with increasing levels of cholesterol. An inverse relationship between HDL and stroke risk was demonstrated in both the Oxfordshire Community Study and the Northern Manhattan Stroke Study.^{130 131 132} More recent studies utilizing ultrasound technology have established an association between lipid levels and extracranial carotid atherosclerosis and intimal-media plaque thickness.^{66 67 133 134 135}

Older clinical trials did not confirm a reduction in stroke risk with the use of lipid-lowering therapies.¹³⁶ However, more recent clinical trials using serial ultrasound measurements showed that reductions of elevations of LDL with ß-hydroxy-ß-methylglutaryl-CoA (HMG-CoA) reductase inhibitors ("statins") can modestly retard the progression of asymptomatic carotid atherosclerosis.^{67 137 138 139 140}

Trials using these agents have demonstrated consistent benefits in reduction of stroke risk among individuals with coronary artery disease and elevated cholesterol levels, as well as among those with only mild to borderline elevations of cholesterol.^{141 142 143 144 145 146} For example, the Simvastatin Survival Study (4S) evaluated the effects of lowering cholesterol on 4444 patients with elevated total cholesterol levels and coronary heart disease.¹⁴¹ The simvastatin-treated group experienced 51% and 35% reductions in ischemic nonembolic stroke and TIAs, respectively. In 1998, the Food and Drug Administration (FDA) approved simvastatin to reduce the risk of first stroke or TIA in people with high total cholesterol and coronary heart disease. The West of Scotland Primary Prevention (WOSCOPS) trial found a nonsignificant 11% reduction in stroke in men with coronary heart disease and hypercholesterolemia who were treated with pravastatin.¹⁴⁷ The Cholesterol And Recurrent Events (CARE) study investigated the efficacy of lowering cholesterol with pravastatin in 4159 patients who had suffered a heart attack in the previous 2 years and showed a reduction in stroke or TIA risk by 32%.¹⁴⁸ Pravastatin was also approved by the FDA in 1998 for use in reducing risk of stroke or TIA in patients who have had a heart attack and have normal cholesterol levels (total cholesterol <240 mg/dL).

The benefits of statin agents in stroke prevention in patients with coronary heart disease have been supported by several meta-analyses.^{146 149 150} Exactly how statins provide stroke protection is uncertain. Although some of the stroke reduction may be due to lipoprotein alterations, statins may also act through mechanisms unrelated to their lipid-lowering properties, such as improved endothelial function, plaque stabilization, and antithrombotic, anti-inflammatory, and neuroprotective properties.^{151 152 153 154 155}

Lipoprotein(a) [Lp(a)], an apolipoprotein homologous with plasminogen,¹⁵⁶ is a known risk factor for the development of coronary heart disease.^{157 158} A study performed in Japan found that Lp(a) was also an independent risk factor for ischemic stroke, especially in young adults.¹⁵⁹ However, a population-based prospective study in the United States found that Lp(a) was only a weak risk factor for cerebrovascular disease in men and was not a significant predictor of stroke risk in women.¹⁵⁸ One case-control study revealed no relationship between Lp(a) concentrations and either stroke, TIA, or carotid atheromata in men,¹⁶⁰ whereas a second found that serum Lp(a) levels were associated with stroke risk independent of other factors.¹⁶¹ There was no association between elevated Lp(a) levels and future stroke risk in a study in which patients with ischemic stroke were compared with matched controls.¹⁶²

Recommendations
Management of patients with elevated cholesterol according to National Cholesterol Education Program II guidelines is recommended (Table 5).³⁴ Patients with known coronary heart disease and elevated LDL cholesterol levels should be considered for treatment with a statin. (Level of Evidence I, Grade A) Additional data are required to elucidate the role of Lp(a) as an independent risk factor for stroke.

Less Well-Documented or Potentially Modifiable Risk Factors

Less well-documented or potentially modifiable risk factors are given in Table 4.

Obesity
Obesity (defined as a body mass index [BMI] 30 kg/m²) predisposes to cardiovascular disease in general and to stroke in particular. However, obesity prevalence increases with advancing age, and obesity is associated with increased blood pressure, blood sugar, and blood lipids. On the basis of these associations alone, it is not surprising that obesity would be related to an increased risk of stroke. However, several large studies suggest abdominal obesity, rather than BMI or general obesity, is more closely related to stroke risk. The age-adjusted relative risk of stroke was 2.33 in a comparison of the extreme quintiles of waist-hip ratios in American men participating in the Health Professionals Follow-Up Study.¹⁶³

In women, obesity was associated with an increased risk of ischemic stroke with increasing levels of BMI. The relative risk ranged from 1.75 (95% CI 1.17 to 2.59) for BMI of 27 to 28.9 kg/m², 1.90 (95% CI 1.28 to 2.82) for BMI of 29 to 31.9 kg/m², and 2.37 (95% CI, 1.60 to 3.50) for BMI of 32 kg/m². Weight gain after the age of 18 years was also related to ischemic stroke, with increasing weight associated with increasing stroke risk.¹⁶⁴ Thus, recent evidence supports abdominal obesity in men and obesity and weight gain in women as independent risk factors for stroke.

Recommendation
Weight reduction in overweight persons is recommended on the basis of the associated increase in comorbid conditions that can lead to stroke. Reduction in stroke risk with weight loss has not been established on the basis of existing prospective randomized studies. (Level of Evidence IV, Grade C)

Physical Inactivity
Regular physical activity has well-established benefits for reducing the risk of premature death and cardiovascular disease. The beneficial effects of physical activity have also been documented for stroke.^{165 166 167 168 169 170 171 172 173} The Framingham Heart Study, Honolulu Heart Program, and Oslo Study have shown the protective effect of physical activity for men.^{166 167 168} For women, the Nurses’ Health Study and Copenhagen City Heart Study demonstrated an inverse association between level of physical activity and stroke incidence.^{169 170} The protective effects of leisure-time physical activity have also been found for blacks and Hispanics in the National Health and Nutrition Examination Survey (NHANES) I Follow-Up Study and the Northern Manhattan Stroke Study.^{171 172}

Dose-response relationships have sometimes been difficult to demonstrate, with no to deleterious effects of vigorous physical activity compared with lower levels of physical activity.^{167 173 174} In the Northern Manhattan Stroke Study, intensive forms of physical activity provided additional benefits compared with light-to-moderate activities. Additional protection was observed with increasing duration of exercise; however, the prevalence of such activities in the elderly was quite low.¹⁷² The protective effect of physical activity may be mediated in part through its role in controlling various known risk factors for stroke, such as hypertension,¹⁷⁵ cardiovascular disease,¹⁷⁶ diabetes,¹⁷⁷ and body weight. Other biological mechanisms are also associated with physical activity, including reductions in plasma fibrinogen and platelet activity, as well as elevations in plasma tissue plasminogen activator activity and HDL concentrations.^{178 179 180 181}

Currently available data support the benefits of physical activity. Guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health recommend that Americans should exercise moderately for at least 30 minutes on most, and preferably all, days of the week.^{182 183} For stroke, the benefits are apparent even for light-to-moderate activities, such as walking, and the data support additional benefit from increasing the level and duration of one’s recreational activity. Physical activity is a modifiable behavior that requires greater emphasis in stroke prevention campaigns.

Recommendation
As per guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health, regular exercise (30 minutes of moderate-intensity activity daily) is part of a healthy lifestyle and helps to reduce comorbid conditions that may lead to stroke (Table 5).¹⁸³ (Level of Evidence III, Grade C)

Poor Diet/Nutrition
Data regarding the effects of general nutritional status on stroke risk are limited. There is no evidence that the use of dietary vitamin E or C supplements or the use of specific carotenoids substantially reduces the risk of stroke.¹⁸⁴ There may be a protective relationship between stroke and consumption of fruits and vegetables, especially cruciferous and green leafy vegetables and citrus fruit and juice.¹⁸⁵ An analysis of data from the Nurses’ Health Study and the Health Professionals’ Follow-Up Study that included individuals free of cardiovascular disease at baseline found that the relative risk of stroke was 0.69 (95% CI 0.52 to 0.92) for persons in the highest quintile of fruit and vegetable intake.¹⁸⁵ An increment of 1 serving per day was associated with a 6% lower risk of stroke. However, it cannot be certain whether the effect was specifically due to diet or a reflection of a generally more healthy lifestyle in these individuals.

Recommendation
A healthy diet containing at least 5 daily servings of fruits and vegetables may decrease the risk of stroke (Table 5). (Level of Evidence III, Grade C)

Alcohol Abuse
The effect of alcohol as a risk factor for ischemic stroke is controversial and likely dose dependent. For hemorrhagic stroke, cohort studies have shown that alcohol consumption has a direct dose-dependent effect.^{186 187 188} For cerebral infarction, chronic heavy drinking and acute intoxication have been associated with an increased risk among young adults.¹⁸⁹ In older adults, risk is increased among heavy-drinking men. No effect is present among men and women after controlling for other confounding risk factors, and there is a protective effect for moderate alcohol consumption.^{186 187 190 191 192 193 194 195}

Some studies have supported a J-shaped dose-response curve between alcohol intake and ischemic stroke risk, with protection for those drinking up to 2 drinks per day and an increased risk for those drinking >5 drinks per day compared with nondrinkers.^{196 197 198} The dose-response relationship between alcohol and stroke is consistent with the observed deleterious and beneficial effects of alcohol. The deleterious effects of alcohol for stroke may occur through various mechanisms, including increasing hypertension, hypercoagulable states, and cardiac arrhythmias and reducing cerebral blood flow. However, there is also evidence that light-to-moderate alcohol intake can reduce the risk of coronary artery disease, increase HDL cholesterol, and increase endogenous tissue plasminogen activator. Although it is difficult to consider recommending alcohol to those who are nondrinkers, elimination of heavy drinking and reduction to moderate levels of alcohol intake (no more than 2 drinks per day) for those who are currently drinking will probably do no harm and may reduce the incidence of stroke.

Recommendation
No more than 2 drinks per day for men and 1 drink per day for nonpregnant women, as reflected in the US Preventive Services Task Force report (Table 5), is recommended.⁶⁴ (Level of Evidence IV, Grade C)

Hyperhomocysteinemia
Although the definition of hyperhomocyst(e)inemia has not been standardized across epidemiological studies, fasting plasma levels of homocyst(e)ine between 5 and 15 µmol/L are generally considered normal,^{96 199 200} and levels 16 µmol/L are generally classified as indicating hyperhomocyst(e)inemia (although the risk is likely continuous).^{199 201} In the Framingham Heart Study original cohort (aged 67 to 96 years), Selhub and colleagues²⁰² found 19% had homocysteine concentrations >16.4 µmol/L. Homocysteine concentrations increase with age, with men having higher levels than women, especially at younger ages.²⁰³ From NHANES III, Selhub and colleagues²⁰⁴ recently identified population references for total homocysteine concentrations. For men aged 40 to 59 years and those aged 60 years, the prevalence of high homocyst(e)ine (defined as >11.4 µmol/L) is 28.6% and 43.2%, respectively. For women aged 40 to 59 years and those aged 60 years, the prevalence of high homocyst(e)ine (defined as >10.4 µmol/L) is 21.1% and 46.5%, respectively.²⁰⁴

Numerous case-control studies have shown an association between hyperhomocyst(e)inemia and stroke. Based on a change of 5 µmol/L in homocysteine level, a meta-analysis found a summary OR for cerebrovascular disease of 1.5 (95% CI 1.3 to 1.9).²⁰⁵ From the NHANES III data, the OR comparing the top quartile with the bottom 3 quartiles is 2.25 (95% CI 1.59 to 3.18).²⁰⁶ In the Framingham Study, the relative risk for stroke, comparing the lowest quartile with the highest, was 1.82 (95% CI 1.14 to 2.91).²⁰⁷ Although the association between plasma homocyst(e)ine and cerebrovascular risk is biologically plausible, it is more consistently present in case-control studies than in prospective studies, so further confirmatory evidence is required.^{199 207 208 209 210}

The OR from NHANES III, when coupled with the prevalence estimates from Selhub et al,²⁰² gives a population attributable risk of 26% for men aged 40 to 59 years, 35% for men aged >60 years, 21% for women aged 40 to 59 years, and 37% for women aged >60 years. These population attributable risk estimates must be interpreted with caution, because no data are available that would permit the estimation of population attributable risk after adjustment for other cerebrovascular risk factors that are positively correlated with homocyst(e)ine levels.

Folic acid, together with vitamins B₆ and B₁₂, has been shown to be effective in reducing elevated plasma homocyst(e)ine levels,²¹¹ but no randomized trials have as yet been completed to determine whether lowering elevated homocyst(e)ine levels will subsequently reduce stroke. Secondary prevention trials are in progress.^{199 212}

Recommendations
An emphasis should be placed on meeting current recommended daily amounts of folate (400 µg/d), vitamin B₆ (1.7 mg/d), and vitamin B₁₂ (2.4 µg/d) by intake of vegetables, fruits, legumes, meats, fish, and fortified grains and cereals (nonpregnant, nonlactating individuals).²⁰¹ Specific recommendations regarding treatment of patients without cerebrovascular or cardiovascular disease are deferred pending completion of ongoing clinical trials. In the interim, given their safety and low cost, use of folic acid and B vitamins may be considered for patients with known elevated homocysteine levels. (Level of Evidence IV, Grade C)

Drug Abuse
Illicit drug abuse, particularly involving the use of amphetamines, "crack" cocaine, and heroin, has emerged as a serious public health threat. Although the available data are derived primarily from limited epidemiological studies focusing on minority populations with low socioeconomic status, a consistent increase in the risk of both ischemic and hemorrhagic stroke has been demonstrated.^{213 214 215 216 217 218 219 220} Adjusting for other potential stroke risk factors, some studies have found an 7-fold increase in stroke risk among drug abusers.^{213 220} However, another study²¹⁷ found no significant association between illicit drug abuse and stroke. The pathogenesis of stroke in illicit drug abuse is likely multifactorial, possibly involving sudden surges in blood pressure, vasculitis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation.^{221 222}

Recommendation
History of illicit drug abuse should be sought during routine medical evaluations and the patient referred for appropriate counseling (US Preventive Services Task Force report; Table 5).⁶⁴

Hypercoagulability
Although the results of certain blood tests have been associated with hypercoagulable states characterized by venous thrombosis, many have not been clearly proven to be associated with cerebrovascular arterial thrombosis. The presence of antiphospholipid antibodies (aPL) has been shown in several case-control studies and one prospective study to be associated with ischemic stroke. The 2 most frequent tests used to detect aPL are anticardiolipin antibodies (more prevalent, but less specific) and lupus anticoagulants (less prevalent, but more specific).

Unfortunately, the definition of a significant positive result on testing for aPL has not been uniformly delineated. For example, the isotype of anticardiolipin antibody (IgG, IgM, or IgA) tested and the definition of a significantly elevated level varies among studies. As a result, it is difficult to give accurate prevalence data or risk of stroke associated with the presence of aPL. Although empirical treatments have been given for secondary stroke prevention in persons with aPL, evidence supporting the efficacy of this approach is limited.^{223 224} The Antiphospholipid Antibodies and Stroke Study (APASS) and Warfarin-Aspirin Recurrent Stroke Study (WARSS) results may help to shed light on the best treatment for secondary stroke prevention. However, further studies may then be needed to investigate primary prevention in persons with aPL.

Many case reports and case-control studies have been published related to the association of other coagulation abnormalities and stroke (eg, factor V Leiden, prothrombin 20210 mutation, protein C deficiency, protein S deficiency, and antithrombin III deficiency; Table 3). However, many have been poorly adjusted for other stroke risk factors. More recent case-control and prospective studies of these abnormalities have cast doubt on their importance as independent risk factors for ischemic stroke. Therefore, hypercoagulable states are presently difficult to categorize as targets for primary stroke prevention.

Even if only a small increased risk of ischemic stroke exists with some of these hypercoagulable states, they may be important to consider in the overall risk profile of patients. Because some of the identified factors underlying hypercoagulable states are relatively common, these patients may also have other risk factors for stroke. These disorders may eventually be a target for more aggressive primary stroke prevention; however, further studies are needed to confirm whether these are indeed risk factors for stroke and whether populations who more frequently have these coagulation abnormalities should be targeted for testing and more aggressive primary prevention.

Recommendation
Specific recommendations regarding treatment of patients without cerebrovascular or cardiovascular disease or a history suggestive of a clinical coagulopathy are deferred pending further study.

Hormone Replacement Therapy
The impact of postmenopausal hormone replacement therapy on stroke risk appears to be neutral, but owing to a lack of control studies, definitive conclusions cannot be reached. Since 1980, there have been at least 18 studies published on this subject.²²⁵ With the exception of the Framingham Heart Study, none detected a large increase in stroke risk, and several reported a slight (but often nonsignificant) decrease in risk. The Framingham Heart Study found a 2.60-fold increase in the relative risk of atherothrombotic stroke among women receiving hormone replacement therapy compared with nonusers.²²⁶ In other studies, the relative risk of stroke among hormone replacement therapy users varied from 0.23 to 1.46, with the relative risk of fatal stroke ranging from 0.30 to 1.40.^{170 192 227 228 229 230 231 232 233 234 235 236 237 238 239} A review indicated a neutral effect of postmenopausal hormone replacement therapy, with a relative risk of 0.96.²⁴⁰ However, the studies conducted to date have had methodological limitations.²²⁵ These limitations include nonspecific end points, lack of control for prior hormone replacement use or specific regimens, a lack of sufficient numbers of women from minority race-ethnic groups, and possible confounding by a healthy-user effect.²²⁵ The benefits and risks in terms of stroke must also be balanced against other potential effects of hormone replacement, including osteoporosis and breast cancer. Further studies are required to clarify this important issue.

Recommendation
The risk of stroke associated with hormone replacement therapy appears low but requires further study. Until more data are available, the use of hormone replacement therapy should be guided by factors other than stroke risk.

Oral Contraceptive Use
Much of the perceived increased stroke risk associated with the use of oral contraceptives is based on early studies with high-dose preparations²²⁵ (ie, first-generation oral contraceptives containing 50 µg of estradiol^{241 242 243} ). The majority of studies of second-generation oral contraceptives containing lower doses of estrogens did not find an increased risk of stroke.^{242 243 244 245 246} However, one study did report an increased risk of stroke in women using first-, second-, or third-generation oral contraceptives.²⁴⁷ The reasons for this discrepancy are not certain. In addition, women who are cigarette smokers, are hypertensive, or have diabetes, migraine, or prior thromboembolic events may be at increased stroke risk if they use oral contraceptives.^{248 249}

A meta-analysis concluded that the risk of ischemic stroke is increased in oral contraceptive users but that the absolute increase in risk would be small because of the low stroke incidence in this population.²⁵⁰ The increase in risk was present even with the newer low-dose estrogen preparations. Methodological limitations limited definitive conclusions regarding the impact of additional risk factors such as hypertension and cigarette smoking in oral contraceptive users.

Recommendation
The risk of stroke associated with use of low-dose oral contraceptives in women without additional risk factors appears low. Oral contraceptives should be avoided in women with additional risk factors (eg, cigarette smoking or prior thromboembolic events).

Inflammatory Processes
Atherosclerosis, the most common cause of stroke, is now believed to be a disease of chronic inflammation. Its lesions typically occur at branch points and bifurcations in large and medium-sized elastic and muscular arteries. The extracranial internal carotid artery and the vertebral artery (at its origin and just distal to the posterior inferior cerebellar artery) are the cerebral vessels most commonly affected.

Endothelial cells of normal postcapillary venules express P-selectin, intercellular adhesion molecule-1 (ICAM-1), and E-selectin when exposed to cytokines, peroxides, and other stimuli associated with hypoxic injury. Their appearance mediates leukocyte adhesion and trafficking. The adhesion receptors ICAM-1 and VCAM-1 (vascular cell adhesion molecule-1) are also expressed by endothelium at sites predisposed to atherosclerosis²⁵¹ and continue to be expressed during the development of the atheroma. Shear stress and turbulence may contribute to adhesion receptor expression and may explain the localization of atherosclerotic plaques at vessel bifurcations.^{252 253 254}

Monocytes and T cells bind to the expressed adhesion molecules, become activated, and secrete products such as cytokines and proteolytic enzymes that contribute to vessel damage. Markers of inflammation, such as leukocyte adhesion receptors²⁵⁵ and cytokines,²⁵⁶ as well as activated T cells and macrophages,²⁵⁷ are present in carotid endarterectomy specimens of recently symptomatic patients, which suggests that acute inflammatory responses may predispose to plaque destabilization and symptoms. Elevated levels of soluble leukocyte adhesion receptors have been associated with carotid artery atherosclerosis.^{258 259 260}

Chronic infection may underlie atherosclerosis. Chlamydia pneumoniae, a Gram-negative obligate intracellular bacterium, has been identified in atherosclerotic carotid plaques^{261 262 263 264 265} and localizes to regions of altered plaque morphology.^{263 264} The fact that seropositivity to Chlamydia does not seem to correlate to carotid atherosclerosis, as measured by duplex ultrasonography,^{265 266} supports the notion that Chlamydia may participate in plaque progression and destabilization as opposed to initiation of atherosclerosis, which may be why there appears to be a relationship between serum antibody titers to C pneumoniae and stroke.^{267 268 269 270} The benefit of eradicating C pneumoniae from carotid plaques with antibiotic therapy remains unclear.²⁷¹ Data linking infection with other pathogens, such as cytomegalovirus and herpes simplex virus, with atherosclerosis are not as robust as those for C pneumoniae.^{267 272}

Several observational studies suggest that acute infection may be associated with ischemic stroke. C-reactive protein (CRP) and serum amyloid A, acute-phase reactants produced by the liver, are markers of systemic inflammation. CRP levels are increased in smokers^{273 274} and in apparently healthy men with vascular risk factors.²⁷⁴ There is a significant and positive association between plasma CRP levels and the risk of vascular events, including stroke.^{273 275 276}

Data from prospective randomized clinical trials suggest that the efficacy of common preventive agents such as aspirin and HMG-CoA reductase inhibitors may be related, at least in part, to their anti-inflammatory effects. In the Physicians’ Health Study, aspirin significantly reduced the risk of vascular events only among men in the highest quartile of CRP levels,²⁷³ although the direct effect of aspirin on CRP is unclear.^{277 278} Pravastatin use, which was shown to decrease the risk of vascular events and stroke in the CARE trial, led to a significant decrease in CRP levels over the 5-year follow-up, whereas CRP levels increased in patients who received placebo. This effect of pravastatin appears to be independent of its effect on lowering LDL cholesterol.¹⁵⁴ Whether CRP contributes to vascular disease or is merely a marker of vascular risk is unclear, but an inflammatory environment seems to predispose to the risk of stroke in experimental model studies.²⁷⁹

Recommendation
The currently available data do not provide sufficient evidence to support a specific management recommendation.

Management Strategies

Table 5 summarizes strategies for risk factor management based on published guidelines and/or consensus statements. Details of the various recommendations can be found in the original references. Risk factors for which specific guidelines have not been previously adopted have not been included in the Table.^{280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330}

Future Research

As can be readily appreciated by inspection of the tables and in the accompanying text, significant gaps exist in current knowledge of the impact of specific factors on stroke risk. Moreover, the possible impact of treatment of many of the potentially modifiable factors on subsequent stroke risk is uncertain. Whether the focus of management of specific risk factors should be modified in different race-ethnic groups requires further study. Additional study is also necessary to develop a fuller understanding of differences in risks between men and women. Despite recent advances in acute stroke management and promising new approaches to improving poststroke recovery, prevention remains the cornerstone of therapy for these devastating diseases.

Footnotes

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in September 2000. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0197. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or

This statement is being published simultaneously in the January 2001 issue of Stroke.

References

1. 1. Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998;29:415–421.[Abstract/Free Full Text]

2. American Heart Association. Stroke Statistics. Dallas, Tex: American Heart Association; 2000. Available at: http://www.americanheart.org/Heart_and_Stroke_A_Z_Guide/strokes.html. Accessed September 2000.

3. American Heart Association. Economic Cost of Cardiovascular Diseases. Available at: http://www.americanheart.org/statistics/10econom.html. Accessed September 2000.

4. Gorelick PB. Stroke prevention. Arch Neurol. 1995;52:347–355.[Abstract/Free Full Text]

5. Sacco RL, Benjamin EJ, Broderick JP, et al. American Heart Association Prevention Conference IV: prevention and rehabilitation of stroke: risk factors. Stroke. 1997;28:1507–1517.[Free Full Text]

6. D’Agostino RB, Wolf PA, Belanger AJ, et al. Stroke risk profile: adjustment for antihypertensive medication: the Framingham Study. Stroke. 1994;25:40–43.[Abstract]

7. Gillum RF, Sempos CT. The end of the long-term decline in stroke mortality in the United States? Stroke. 1997;28:1527–1529.[Free Full Text]

8. Brown RD, Whisnant JP, Sicks JD, et al. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke. 1996;27:373–380.

9. Whisnant JP. Modeling of risk factors for ischemic stroke: the Willis Lecture. Stroke. 1997;28:1840–1844.[Free Full Text]

10. Wolf PA, D’Agostino RB, O’Neal MA, et al. Secular trends in stroke incidence and mortality: the Framingham Study. Stroke. 1992;23:1551–1555.[Abstract/Free Full Text]

11. Sacco RL, Boden-Albala B, Gan R, et al. Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study. Am J Epidemiol. 1998;147:259–268.[Abstract/Free Full Text]

12. Bousser M-G. Stroke in women: the 1997 Paul Dudley White International Lecture. Circulation. 1999;99:463–467.[Free Full Text]

13. Kittner SJ, Stern BJ, Feeser BR, et al. Pregnancy and the risk of stroke. N Engl J Med. 1996;335:768–774.[Abstract/Free Full Text]

14. Qureshi AI, Giles WH, Croft JB, et al. Number of pregnancies and risk for stroke and stroke subtypes. Arch Neurol. 1997;54:203–206.[Abstract/Free Full Text]

15. Mosca L, Manson JE, Sutherland SE, et al. Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association Writing Group. Circulation. 1997;96:2468–2482.[Free Full Text]

16. Gorelick PB. Cerebrovascular disease in African Americans. Stroke. 1998;29:2656–2664.[Free Full Text]

17. Howard G, Anderson R, Sorlie P, et al. Ethnic differences in stroke mortality between non-Hispanic whites, Hispanic whites, and blacks: the National Longitudinal Mortality Study. Stroke. 1994;25:2120–2125.[Abstract]

18. Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke. 1999;30:736–743.[Abstract/Free Full Text]

19. Giles WH, Kittner SJ, Hebel JR, et al. Determinants of black-white differences in the risk of cerebral infarction: the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Arch Intern Med. 1995;155:1319–1324.[Abstract/Free Full Text]

20. Gillum RF. Secular trends in stroke mortality in African Americans: the role of urbanization, diabetes and obesity. Neuroepidemiology. 1997;16:180–184.[Medline] [Order article via Infotrieve]

21. Gillum RF. Stroke mortality in blacks: disturbing trends. Stroke. 1999;30:1711–1715.[Abstract/Free Full Text]

22. Sheinart KF, Tuhrim S, Horowitz DR, et al. Stroke recurrence is more frequent in blacks and Hispanics. Neuroepidemiology. 1998;17:188–198.[Medline] [Order article via Infotrieve]

23. Deleted in proof.

24. Frey JL, Jahnke HK, Bulfinch EW. Differences in stroke between white, Hispanic, and Native American patients: the Barrow Neurological Institute stroke database. Stroke. 1998;29:29–33.[Abstract/Free Full Text]

25. He J, Klag MJ, Wu Z, et al. Stroke in the People’s Republic of China, I: geographic variations in incidence and risk factors. Stroke. 1995;26:2222–2227.[Abstract/Free Full Text]

26. Welin L, Svardsudd K, Wilhelmsen L, et al. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med. 1987;317:521–526.[Abstract]

27. Kiely DK, Wolf PA, Cupples LA, et al. Familial aggregation of stroke: the Framingham Study. Stroke. 1993;24:1366–1371.[Abstract/Free Full Text]

28. Liao D, Myers R, Hunt S, et al. Familial history of stroke and stroke risk: the Family Heart Study. Stroke. 1997;28:1908–1912.[Abstract/Free Full Text]

29. Hrubec Z, Robinette CD. The study of human twins in medical research. N Engl J Med. 1984;310:435–441.[Medline] [Order article via Infotrieve]

30. Brass LM, Isaacsohn JL, Merikangas KR, et al. A study of twins and stroke. Stroke. 1992;23:221–223.[Abstract/Free Full Text]

31. Wolf PA. Cerebrovascular risk. In: Izzo JL Jr, Black HR, Goodfriend TL, et al. Hypertension Primer: The Essentials of High Blood Pressure. Baltimore, Md: Lippincott Williams & Wilkins; 1999.

32. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease, part 1: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–774.[Medline] [Order article via Infotrieve]

33. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension. 1995;25:305–313.[Abstract/Free Full Text]

34. Joint National Committee. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413–2446.[Abstract/Free Full Text]

35. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension, II: results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213:1143–1152.[Abstract/Free Full Text]

36. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202:1028–1034.[Abstract/Free Full Text]

37. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277:739–745.[Abstract/Free Full Text]

38. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension: the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–764.[Medline] [Order article via Infotrieve]

39. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255–3264.[Abstract/Free Full Text]

40. Burt VL, Culter JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population: data from the health examination surveys, 1960 to 1991. Hypertension. 1995;26:60–69.[Abstract/Free Full Text]

41. Klungel OH, Stricker BH, Paes AH, et al. Excess stroke among hypertensive men and women attributable to undertreatment of hypertension. Stroke. 1999;30:1312–1318.[Abstract/Free Full Text]

42. Friday GH. Antihypertensive medication compliance in African-American stroke patients: behavioral epidemiology and interventions. Neuroepidemiology. 1999;18:223–230.[Medline] [Order article via Infotrieve]

43. Kool MJ, Hoeks AP, Struijker Boudier HA, et al. Short- and long-term effects of smoking on arterial wall properties in habitual smokers. J Am Coll Cardiol. 1993;22:1881–1886.[Abstract]

44. Cruickshank JM, Neil-Dwyer G, Dorrance DE, et al. Acute effects of smoking on blood pressure and cerebral blood flow. J Hum Hypertens. 1989;3:443–449.[Medline] [Order article via Infotrieve]

45. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ. 1989;298:789–794.

46. Wolf PA, D’Agostino RB, Belanger AJ, et al. Probability of stroke: a risk profile from the Framingham Study. Stroke. 1991;22:312–318.[Abstract/Free Full Text]

47. National Center for Health Statistics. Healthy People 2000 Review, 1989–1999. Hyattsville, Md: US Dept of Health and Human Services; 1999.

48. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA. 1993;269:232–236.[Abstract/Free Full Text]

49. Robbins AS, Manson JE, Lee I-M, et al. Cigarette smoking and stroke in a cohort of U.S. male physicians. Ann Intern Med. 1994;120:458–462.[Abstract/Free Full Text]

50. Wolf PA, D’Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke: the Framingham study. JAMA. 1988;259:1025–1029.[Abstract/Free Full Text]

51. Wannamethee SG, Shaper AG, Whincup PH, et al. Smoking cessation and the risk of stroke in middle-aged men. JAMA. 1995;274:155–160.[Abstract/Free Full Text]

52. Wells AJ. Passive smoking as a cause of heart disease. J Am Coll Cardiol. 1994;24:546–554.[Abstract]

53. Bonita R, Duncan J, Truelsen T, et al. Passive smoking as well as active smoking increases the risk of acute stroke. Tob Control. 1999;8:156–160.[Abstract/Free Full Text]

54. Baillie GM, Sherer JT, Weart CW. Insulin and coronary artery disease: is syndrome X the unifying hypothesis? Ann Pharmacother. 1998;32:233–247.[Abstract]

55. Garvey WT, Hermayer KL. Clinical implications of the insulin resistance syndrome. Clin Cornerstone. 1998;1:13–28.[Medline] [Order article via Infotrieve]

56. Burchfiel CM, Curb JD, Rodriguez BL, et al. Glucose intolerance and 22-year stroke incidence: the Honolulu Heart Program. Stroke. 1994;25:951–957.[Abstract]

57. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA. 1979;241:2035–2038.[Abstract/Free Full Text]

58. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713.[Abstract/Free Full Text]

59. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869–880.[Medline] [Order article via Infotrieve]

60. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension: Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA. 1996;276:1886–1892.[Abstract/Free Full Text]

61. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865.[Medline] [Order article via Infotrieve]

62. Tuomilehto J, Rastenyte D. Diabetes and glucose intolerance as risk factors for stroke. J Cardiovasc Risk. 1999;6:241–249.[Medline] [Order article via Infotrieve]

63. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259.[Medline] [Order article via Infotrieve]

64. Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. 2nd ed. Baltimore, Md: Williams & Wilkins; 1996.

65. American Diabetes Association. Clinical practice recommendations 1998. Diabetes Care. 1998;21(suppl 1):S1–S89.

66. O’Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study: the CHS Collaborative Research Group. Stroke. 1992;23:1752–1760.[Abstract/Free Full Text]

67. Fine-Edelstein JS, Wolf PA, O’Leary DH, et al. Precursors of extracranial carotid atherosclerosis in the Framingham Study. Neurology. 1994;44:1046–1050.[Abstract/Free Full Text]

68. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med. 1986;315:860–865.[Abstract]

69. Bogousslavsky J, Despland P-A, Regli F. Asymptomatic tight stenosis of the internal carotid artery: long-term prognosis. Neurology. 1986;36:861–863.[Abstract/Free Full Text]

70. Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA. 2000;283:1429–1436.[Abstract/Free Full Text]

71. Inzitari D, Eliasziw M, Gates P, et al. The causes and risk of stroke in patients with asymptomatic internal carotid artery stenosis. N Engl J Med. 2000;342:1693–1700.[Abstract/Free Full Text]

72. Autret A, Saudeau D, Bertrand P, et al. Stroke risk in patients with carotid stenosis. Lancet. 1987;1:888–890.[Medline] [Order article via Infotrieve]

73. The CASANOVA Study Group. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke. 1991;22:1229–1235.[Abstract/Free Full Text]

74. Mayo Asymptomatic Carotid Endarterectomy Study Group. Results of a randomized controlled trial of carotid endarterectomy for asymptomatic carotid stenosis. Mayo Clin Proc. 1992;67:513–518.[Medline] [Order article via Infotrieve]

75. Hobson RWI, Weiss DG, Fields WS, et al, for the VA Cooperative Study Group. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis: the Veterans Affairs Cooperative Study Group. N Engl J Med. 1993;328:221–227.[Abstract/Free Full Text]

76. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–1428.[Abstract/Free Full Text]

77. Goldstein LB, Samsa GP, Matchar DB, et al. Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis. Stroke. 1998;29:750–753.[Abstract/Free Full Text]

78. Goldstein LB, Bonito AJ, Matchar DB, et al. US national survey of physician practices for the secondary and tertiary prevention of ischemic stroke: design, service availability, and common practices. Stroke. 1995;26:1607–1615.[Abstract/Free Full Text]

79. Goldstein LB, Moore WS, Robertson JT, et al. Complication rates for carotid endarterectomy: a call for action. Stroke. 1997;28:889–890.[Free Full Text]

80. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–988.[Abstract/Free Full Text]

81. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946–952.[Abstract/Free Full Text]

82. Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet. 1989;1:175–179.[Medline] [Order article via Infotrieve]

83. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med. 1990;22:1505–1511.

84. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circulation. 1991;84:527–539.[Abstract/Free Full Text]

85. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992;327:1406–1412.[Abstract]

86. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991;18:349–355.[Abstract]

87. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest. 1998;114(suppl):579S-589S.

88. The Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449–1457.[Abstract/Free Full Text]

89. Di Pasquale G, Urbinati S, Pinelli G. Cardiac investigation in patients with cerebrovascular disease. In: Ginsberg M, Bogousslavsky J. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. Malden, Mass: Blackwell Science; 1998.

90. Rokey R, Rolak LA, Harati Y, et al. Coronary artery disease in patients with cerebrovascular disease: a prospective study. Ann Neurol. 1984;16:50–53.[Medline] [Order article via Infotrieve]

91. Hertzer NR, Lees CD. Fatal myocardial infarction following carotid endarterectomy: three hundred thirty-five patients followed 6–11 years after operation. Ann Surg. 1981;194:212–218.[Medline] [Order article via Infotrieve]

92. Shah S, Vanclay F, Cooper B. Predicting discharge status at commencement of stroke rehabilitation. Stroke. 1989;20:766–769.[Abstract/Free Full Text]

93. Komrad MS, Coffey CE, Coffey KS, et al. Myocardial infarction and stroke. Neurology. 1984;34:1403–1409.[Abstract/Free Full Text]

94. Chimowitz MI, Mancini GB. Asymptomatic coronary artery disease in patients with stroke: prevalence, prognosis, diagnosis, and treatment. Stroke. 1992;23:433–436.[Abstract/Free Full Text]

95. Chimowitz MI, Poole RM, Starling MR, et al. Frequency and severity of asymptomatic coronary disease in patients with different causes of stroke. Stroke. 1997;28:941–945.[Abstract/Free Full Text]

96. Urbinati S, Di Pasquale G, Andreoli A, et al. Frequency and prognostic significance of silent coronary artery disease in patients with cerebral ischemia undergoing carotid endarterectomy. Am J Cardiol. 1992;69:1166–1170.[Medline] [Order article via Infotrieve]

97. Di Pasquale G, Andreoli A, Pinelli G, et al. Cerebral ischemia and asymptomatic coronary artery disease: a prospective study of 83 patients. Stroke. 1986;17:1098–1101.[Abstract/Free Full Text]

98. Sen S, Oppenheimer SM. Cardiac disorders and stroke. Curr Opin Neurol. 1998;11:51–56.[Medline] [Order article via Infotrieve]

99. The TIMI IIIb Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non–Q-wave myocardial infarction: results of the TIMI IIIb trial: Thrombolysis In Myocardial Ischemia. Circulation. 1994;89:1545–1556.[Abstract/Free Full Text]

100. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335:775–782.[Abstract/Free Full Text]

101. Mahaffey KW, Harrington RA, Simoons ML, et al. Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial. Circulation. 1999;99:2371–2377.[Abstract/Free Full Text]

102. Gardner TJ, Horneffer PJ, Manolio TA, et al. Stroke following coronary artery bypass grafting: a ten-year study. Ann Thorac Surg. 1985;40:574–581.[Abstract]

103. Reed GL III, Singer DE, Picard EH, et al. Stroke following coronary-artery bypass surgery: a case control estimate of the risk from carotid bruits. N Engl J Med. 1988;319:1246–1250.[Abstract]

104. Frye RL, Kronmal R, Schaff HV, et al. Stroke in coronary artery bypass graft surgery: an analysis of the CASS experience. Int J Cardiol. 1992;36:213–221.[Medline] [Order article via Infotrieve]

105. Tuman KJ, McCarthy RJ, Najafi H, et al. Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg. 1992;104:1510–1517.[Abstract]

106. Ricotta JJ, Faggioli GL, Castilone A, et al. Risk factors for stroke after cardiac surgery: Buffalo Cardiac-Cerebral Study Group. J Vasc Surg. 1995;21:359–363; discussion 364.[Medline] [Order article via Infotrieve]

107. Newman MF, Wolman R, Kanchuger M, et al. Multicenter preoperative stroke risk index for patients undergoing coronary artery bypass graft surgery: Multicenter Study of Perioperative Ischemia (MCSPI) Research Group. Circulation. 1996;94(suppl II):II-74–II-80.

108. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery: Multicenter Study of Perioperative Ischemic Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med. 1996;335:1857–1863.[Abstract/Free Full Text]

109. Alexander KP, Anstrom KJ, Muhlbaier LH, et al. Outcomes of cardiac surgery in patients > or =80 years: results from the National Cardiovascular Network. J Am Coll Cardiol. 2000;35:731–738.[Abstract/Free Full Text]

110. Peterson ED, Cowper PA, Jollis JG, et al. Outcomes of coronary artery bypass graft surgery in 24,461 patients aged 80 years or older. Circulation. 1995;92(suppl II):II-85–II-91.

111. Hogue CW Jr, Murphy SF, Schechtman KB, et al. Risk factors for early or delayed stroke after cardiac surgery. Circulation. 1999;100:642–647.[Abstract/Free Full Text]

112. Almassi GH, Sommers T, Moritz TE, et al. Stroke in cardiac surgical patients: determinants and outcome. Ann Thorac Surg. 1999;68:391–397; discussion 397-398.[Abstract/Free Full Text]

113. Stern A, Tunick PA, Culliford AT, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J. 1999;138:746–752.[Medline] [Order article via Infotrieve]

114. Davila-Roman VG, Murphy SF, Nickerson NJ, et al. Atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic events and mortality. J Am Coll Cardiol. 1999;33:1308–1316.[Abstract/Free Full Text]

115. Adams RJ. Neurological complications. In: Embury S. Sickle Cell Disease: Scientific Principles and Clinical Practice. New York, NY: Raven Press; 1994:599–621.

116. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288–294.[Abstract/Free Full Text]

117. Armstrong FD, Thompson RJ Jr, Wang W, et al. Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease: Neuropsychology Committee of the Cooperative Study of Sickle Cell Disease. Pediatrics. 1996;97:864–870.[Abstract/Free Full Text]

118. Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992;326:605–610.[Abstract]

119. Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. 1997;42:699–704.[Medline] [Order article via Infotrieve]

120. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5–11.[Abstract/Free Full Text]

121. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood. 1993;81:1109–1123.[Free Full Text]

122. Walters MC, Sullivan KM, Bernaudin F, et al. Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. Blood. 1995;85:879–884.[Abstract/Free Full Text]

123. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia: investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332:1317–1322.[Abstract/Free Full Text]

124. Qizilbash N, Lewington S, Duffy S, et al. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts: Prospective Studies Collaboration. Lancet. 1995;346:1647–1653.[Medline] [Order article via Infotrieve]

125. Ueshima H, Iida M, Shimamoto T, et al. Multivariate analysis of risk factors for stroke: eight-year follow-up study of farming villages in Akita, Japan. Prev Med. 1980;9:722–740.[Medline] [Order article via Infotrieve]

126. Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men: the Honolulu Heart Study. Stroke. 1980;11:14–21.[Abstract/Free Full Text]

127. Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ. 1994;309:11–15.[Abstract/Free Full Text]

128. Benfante R, Yano K, Hwang LJ, et al. Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men: implications of shared risk. Stroke. 1994;25:814–820.[Abstract]

129. Iso H, Jacobs DR Jr, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989;320:904–910.[Abstract]

130. Qizilbash N, Jones L, Warlow C, et al. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ. 1991;303:605–609.

131. Kargman DE, Tuck C, Berglund LF, et al. High density lipoprotein: a potentially modifiable stroke risk factor: the Northern Manhattan Stroke Study. Neuroepidemiology. 1996;15:20S. Abstract.

132. Kargman DE, Tuck C, Berglund LF, et al. Elevated high density lipoprotein levels are more important in atherosclerotic ischemic stroke subtypes: the Northern Manhattan Stroke Study. Ann Neurol. 1998;44:442–443. Abstract.

133. Salonen R, Seppanen K, Rauramaa R, et al. Prevalence of carotid atherosclerosis and serum cholesterol levels in eastern Finland. Atherosclerosis. 1988;8:788–792.

134. Dempsey RJ, Diana AL, Moore RW. Thickness of carotid artery atherosclerotic plaque and ischemic risk. Neurosurgery. 1990;27:343–348.[Medline] [Order article via Infotrieve]

135. Heiss G, Sharrett AR, Barnes R, et al. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol. 1991;134:250–256.[Abstract/Free Full Text]

136. Atkins D, Psaty BM, Koepsell TD, et al. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med. 1993;119:136–145.[Abstract/Free Full Text]

137. Blankenhorn DH, Selzer RH, Crawford DW, et al. Beneficial effects of colestipol-niacin therapy on the common carotid artery: two- and four-year reduction of intima-media thickness measured by ultrasound. Circulation. 1993;88:20–28.[Abstract/Free Full Text]

138. Furberg CD, Adams HP Jr, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events: Asymptomatic Carotid Artery Progression Study (ACAPS) research group. Circulation. 1994;90:1679–1687.[Abstract/Free Full Text]

139. Crouse JR III, Byington RP, Bond MG, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol. 1995;75:455–459.[Medline] [Order article via Infotrieve]

140. Hodis HN, Mack WJ, LaBree L, et al. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med. 1996;124:548–556.[Abstract/Free Full Text]

141. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]

142. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events trial investigators. N Engl J Med. 1996;335:1001–1009.[Abstract/Free Full Text]

143. LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group. N Engl J Med. 1998;339:1349–1357.[Abstract/Free Full Text]

144. Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation. 1995;92:2419–2425.[Abstract/Free Full Text]

145. Hebert PR, Gaziano JM, Chan KS, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278:313–321.[Abstract/Free Full Text]

146. Blauw GJ, Lagaay AM, Smelt AH, et al. Stroke, statins, and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-Co-A reductase inhibitors. Stroke. 1997;28:946–950.[Abstract/Free Full Text]

147. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307.[Abstract/Free Full Text]

148. Plehn JF, Davis BR, Sacks FM, et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation. 1999;99:216–223.[Abstract/Free Full Text]

149. Deleted in proof.

150. Bucher HC, Griffith LE, Guyatt GH. Systematic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vasc Biol. 1999;19:187–195.[Abstract/Free Full Text]

151. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998;279:1643–1650.[Abstract/Free Full Text]

152. Delanty N, Vaughan CJ. Vascular effects of statins in stroke. Stroke. 1997;28:2315–2320.[Abstract/Free Full Text]

153. Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998;95:8880–8885.[Abstract/Free Full Text]

154. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein: the Cholesterol And Recurrent Events (CARE) Investigators.Circulation. 1999;100:230–235.[Abstract/Free Full Text]

155. Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999;30:1969–1973.[Abstract/Free Full Text]

156. McLean JW, Tomlinson JE, Kuang W-J, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987;300:132–137.

157. Dahlen GH, Guyton JR, Attar M, et al. Association of levels of lipoprotein(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation. 1986;74:758–765.[Abstract/Free Full Text]

158. Nguyen TT, Ellefson RD, Hodge DO, et al. Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women. Circulation. 1997;96:1390–1397.[Abstract/Free Full Text]

159. Nagayama M, Shinohara Y, Nagayama T. Lipoprotein(a) and ischemic cerebrovascular disease in young adults. Stroke. 1994;25:74–78.[Abstract]

160. Markus HS, Kapadia R, Sherwood RA. Relationship between lipoprotein(a) and both stroke and carotid atheroma. Ann Clin Biochem. 1997;34:360–365.

161. Peng DQ, Zhao SP, Wang JL. Lipoprotein(a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke. J Cardiovasc Risk. 1999;6:1–6.[Medline] [Order article via Infotrieve]

162. Glader CA, Stegmayr B, Boman J, et al. Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions: results from a nested case-control study in northern Sweden. Stroke. 1999;20:2013–2018.

163. Walker SP, Rimm EB, Ascherio A, et al. Body size and fat distribution as predictors of stroke among US men. Am J Epidemiol. 1996;144:1143–1150.[Abstract/Free Full Text]

164. Rexrode KM, Hennekens CH, Willett WC, et al. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA. 1997;277:1539–1545.[Abstract/Free Full Text]

165. Fletcher GF. Exercise in the prevention of stroke. Health Rep. 1994;6:106–110.[Medline] [Order article via Infotrieve]

166. Abbott RD, Rodriguez BL, Burchfiel CM, et al. Physical activity in older middle-aged men and reduced risk of stroke: the Honolulu Heart Program. Am J Epidemiol. 1994;139:881–893.[Abstract/Free Full Text]

167. Kiely DK, Wolf PA, Cupples LA, et al. Physical activity and stroke risk: the Framingham Study. Am J Epidemiol. 1994;140:608–620.[Abstract/Free Full Text]

168. Haheim LL, Holme I, Hjermann I, et al. Risk factors of stroke incidence and mortality: a 12-year follow-up of the Oslo Study. Stroke. 1993;24:1484–1489.[Abstract/Free Full Text]

169. Manson JE, Stampfer MJ, Willett WC, et al. Physical activity and incidence of coronary heart disease and stroke in women. Circulation. 1995;91(suppl):5. Abstract.

170. Lindenstrom E, Boysen G, Nyboe J. Lifestyle factors and risk of cerebrovascular disease in women: the Copenhagen City Heart Study. Stroke. 1993;24:1468–1472.[Abstract/Free Full Text]

171. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men: the NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1996;143:860–869.[Abstract/Free Full Text]

172. Sacco RL, Gan R, Boden-Albala B, et al. Leisure-time physical activity and ischemic stroke risk: the Northern Manhattan Stroke Study. Stroke. 1998;29:380–387.[Abstract/Free Full Text]

173. Wannamethee G, Shaper AG. Physical activity and stroke in British middle aged men. BMJ. 1992;304:597–601.

174. Shinton R, Sagar G. Lifelong exercise and stroke. BMJ. 1993;307:231–234.

175. Kokkinos PF, Narayan P, Colleran JA, et al. Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. N Engl J Med. 1995;333:1462–1467.[Abstract/Free Full Text]

176. Blair SN, Kampert JB, Kohl HW III, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996;276:205–210.[Abstract/Free Full Text]

177. Manson JE, Rimm EB, Stampfer MJ, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet. 1991;338:774–778.[Medline] [Order article via Infotrieve]

178. Lakka TA, Salonen JT. Moderate to high intensity conditioning leisure time physical activity and high cardiorespiratory fitness are associated with reduced plasma fibrinogen in eastern Finnish men. J Clin Epidemiol. 1993;46:1119–1127.[Medline] [Order article via Infotrieve]

179. Wang JS, Jen CJ, Chen HI. Effects of exercise training and deconditioning on platelet function in men. Arterioscler Thromb Vasc Biol. 1995;15:1668–1674.[Abstract/Free Full Text]

180. Rangemark C, Hedner JA, Carlson JT, et al. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep. 1995;18:188–194.[Medline] [Order article via Infotrieve]

181. Williams PT. High-density lipoprotein cholesterol and other risk factors for coronary heart disease in female runners. N Engl J Med. 1996;334:1298–1303.[Abstract/Free Full Text]

182. Physical activity and cardiovascular health: NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA. 1996;276:241–246.[Abstract/Free Full Text]

183. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA. 1995;273:402–407.[Abstract/Free Full Text]

184. Ascherio A, Rimm EB, Hernan MA, et al. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann Intern Med. 1999;130:963–970.[Abstract/Free Full Text]

185. Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282:1233–1239.[Abstract/Free Full Text]

186. Donahue RP, Abbott RD, Reed DM, et al. Alcohol and hemorrhagic stroke: the Honolulu Heart Program. JAMA. 1986;255:2311–2314.[Abstract/Free Full Text]

187. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med. 1988;319:267–273.[Abstract]

188. Tanaka H, Ueda Y, Hayashi M, et al. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke. 1982;13:62–73.[Abstract/Free Full Text]

189. Hillbom M, Kaste M. Does ethanol intoxication promote brain infarction in young adults? Lancet. 1978;2:1181–1183.[Medline] [Order article via Infotrieve]

190. Gorelick PB. The status of alcohol as a risk factor for stroke. Stroke. 1989;20:1607–1610.[Free Full Text]

191. Gorelick PB, Rodin MB, Langenberg P, et al. Is acute alcohol ingestion a risk factor for ischemic stroke? Results of a controlled study in middle-aged and elderly stroke patients at three urban medical centers. Stroke. 1987;18:359–364.[Abstract/Free Full Text]

192. Boysen G, Nyboe J, Appleyard M, et al. Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke. 1988;19:1345–1353.[Abstract/Free Full Text]

193. Gill JS, Shipley MJ, Tsementzis SA, et al. Alcohol consumption: a risk factor for hemorrhagic and non-hemorrhagic stroke. Am J Med. 1991;90:489–497.[Medline] [Order article via Infotrieve]

194. Klatsky AL, Armstrong MA, Friedman GD. Alcohol use and subsequent cerebrovascular disease hospitalizations. Stroke. 1989;20:741–746.[Abstract/Free Full Text]

195. Palomaki H, Kaste M. Regular light-to-moderate intake of alcohol and the risk of ischemic stroke: is there a beneficial effect? Stroke. 1993;24:1828–1832.[Abstract/Free Full Text]

196. Sacco RL, Elkind M, Boden-Albala B, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA. 1999;281:53–60.[Abstract/Free Full Text]

197. Rodgers H, Aitken PD, French JM, et al. Alcohol and stroke: a case-control study of drinking habits past and present. Stroke. 1993;24:1473–1477.[Abstract/Free Full Text]

198. Gill JS, Zezulka AV, Shipley MJ, et al. Stroke and alcohol consumption. N Engl J Med. 1986;315:1041–1046.[Abstract]

199. Eikelboom JW, Lonn E, Genest J Jr, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131:363–375.[Abstract/Free Full Text]

200. Frantzen F, Faaren AL, Alfheim I, et al. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem. 1998;44:311–316.[Abstract/Free Full Text]

201. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999;99:178–182.[Free Full Text]

202. Selhub J, Jacques PF, Wilson PWF, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693–2698.[Abstract/Free Full Text]

203. Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr. 1999;69:482–489.[Abstract/Free Full Text]

204. Selhub J, Jacques PF, Rosenberg IH, et al. Serum total homocysteine concentrations in the Third National Health and Nutrition Examination Survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med. 1999;131:331–339.[Abstract/Free Full Text]

205. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049–1057.[Abstract/Free Full Text]

206. Giles WH, Croft JB, Greenlund KJ, et al. Total homocyst(e)ine concentration and the likelihood of nonfatal stroke: results from the Third National Health and Nutrition Examination Survey, 1988–1994. Stroke. 1998;29:2473–2477.[Abstract/Free Full Text]

207. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med. 1999;131:352–355.[Abstract/Free Full Text]

208. Sacco RL, Roberts JK, Jacobs BS. Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. Neuroepidemiology. 1998;17:167–173.[Medline] [Order article via Infotrieve]

209. Perry IJ. Homocysteine, hypertension and stroke. J Hum Hypertens. 1999;13:289–293.[Medline] [Order article via Infotrieve]

210. Christen WG, Ajani UA, Glynn RJ, et al. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med. 2000;160:422–434.[Abstract/Free Full Text]

211. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998;316:894–898.[Abstract/Free Full Text]

212. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk. 1998;5:249–255.[Medline] [Order article via Infotrieve]

213. Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med. 1990;113:821–827.

214. Levine SR, Brust JC, Futrell N, et al. Cerebrovascular complications of the use of the "crack" form of alkaloidal cocaine. N Engl J Med. 1990;323:699–704.[Abstract]

215. Klonoff DC, Andrews BT, Obana WG. Stroke associated with cocaine use. Arch Neurol. 1989;46:989–993.[Abstract/Free Full Text]

216. Sloan MA, Kittner SJ, Rigamonti D, et al. Occurrence of stroke associated with use/abuse of drugs. Neurology. 1991;41:1358–1364.[Abstract/Free Full Text]

217. Qureshi AI, Akbar MS, Czander E, et al. Crack cocaine use and stroke in young patients. Neurology. 1997;48:341–345.[Abstract/Free Full Text]

218. Sloan MA, Kittner SJ, Feeser BR, et al. Illicit drug-associated ischemic stroke in the Baltimore-Washington Young Stroke Study. Neurology. 1998;50:1688–1693.[Abstract/Free Full Text]

219. Kittner SJ, Stern BJ, Wozniak M, et al. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology. 1998;50:890–894.[Abstract/Free Full Text]

220. Petitti DB, Sidney S, Quesenberry C, et al. Stroke and cocaine or amphetamine use. Epidemiology. 1998;9:596–600.[Medline] [Order article via Infotrieve]

221. Perez JA Jr, Arsura EL, Strategos S. Methamphetamine-related stroke: four cases. J Emerg Med. 1999;17:469–471.[Medline] [Order article via Infotrieve]

222. Siegel AJ, Sholar MB, Mendelson JH, et al. Cocaine-induced erythrocytosis and increase in von Willebrand factor: evidence for drug-related blood doping and prothrombotic effects. Arch Intern Med. 1999;159:1925–1929.[Abstract/Free Full Text]

223. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993–997.[Abstract/Free Full Text]

224. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med. 1992;117:303–308.

225. Bushnell CD, Goldstein LB. Ischemic stroke: recognizing risks unique to women. Womens Health Primary Care. 1999;2:788–804.

226. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. N Engl J Med. 1985;313:1038–1043.[Abstract]

227. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: a long-term cohort study. Am J Med. 1994;97:66–77.[Medline] [Order article via Infotrieve]

228. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–1775.[Abstract/Free Full Text]

229. Hunt K, Vessey M, McPherson K, et al. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynaecol. 1987;94:620–635.[Medline] [Order article via Infotrieve]

230. Rosenberg SH, Fausone V, Clark R. The role of estrogens as a risk factor for stroke in postmenopausal women. West J Med. 1980;133:292–296.[Medline] [Order article via Infotrieve]

231. Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users. Arch Intern Med. 1993;153:73–79.[Abstract/Free Full Text]

232. Falkeborn M, Persson I, Terent A, et al. Hormone replacement therapy and the risk of stroke: follow-up of a population-based cohort in Sweden. Arch Intern Med. 1993;153:1201–1209.[Abstract/Free Full Text]

233. Schairer C, Adami HO, Hoover R, et al. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology. 1997;8:59–65.[Medline] [Order article via Infotrieve]

234. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453–461.[Abstract/Free Full Text]

235. Petitti DB, Sidney S, Quesenberry CP Jr, et al. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke. 1998;29:23–28.[Abstract/Free Full Text]

236. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–78.[Abstract/Free Full Text]

237. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: a prospective study. BMJ. 1988;297:519–522.

238. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol. 1987;70:289–293.[Medline] [Order article via Infotrieve]

239. The American-Canadian Co-Operative Study Group. Persantine aspirin trial in cerebral ischemia, part III: risk factors for stroke. Stroke. 1986;17:12–18.[Abstract/Free Full Text]

240. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.

241. Collaborative Group for the Study of Stroke in Young Women. Oral contraceptives and stroke in young women: associated risk factors. JAMA. 1975;231:718–722.[Abstract/Free Full Text]

242. Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke: evidence from the Royal College of General Practitioners’ Oral Contraception Study. Stroke. 1994;25:935–942.[Abstract]

243. Lidegaard O. Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study. BMJ. 1993;306:956–963.

244. World Health Organization. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study: WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996;348:498–505.[Medline] [Order article via Infotrieve]

245. Schwartz SM, Siscovick DS, Longstreth WT Jr, et al. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med. 1997;127:596–603.

246. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335:8–15.[Abstract/Free Full Text]

247. Heinemann LA, Lewis MA, Thorogood M, et al. Case-control study of oral contraceptives and risk of thromboembolic stroke: results from International Study on Oral Contraceptives and Health of Young Women. BMJ. 1997;315:1502–1504.[Abstract/Free Full Text]

248. Poulter NR, Chang CL, Farley TMM, et al. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study: WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996;348:498–505.

249. Lidegaard O. Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease. Br J Obstet Gynaecol. 1995;102:153–159.[Medline] [Order article via Infotrieve]

250. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA. 2000;284:72–78.[Abstract/Free Full Text]

251. Iiyama K, Hajra L, Iiyama M, et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res. 1999;85:199–207.[Abstract/Free Full Text]

252. Chappell DC, Varner SE, Nerem RM, et al. Oscillatory shear stress stimulates adhesion molecule expression in cultured human endothelium. Circ Res. 1998;82:532–539.[Abstract/Free Full Text]

253. Tsuboi H, Ando J, Korenaga R, et al. Flow stimulates ICAM-1 expression time and shear stress dependently in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;206:988–996.[Medline] [Order article via Infotrieve]

254. Marui N, Offermann MK, Swerlick R, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993;92:1866–1874.

255. DeGraba TJ, Siren AL, Penix L, et al. Increased endothelial expression of intercellular adhesion molecule-1 in symptomatic versus asymptomatic human carotid atherosclerotic plaque. Stroke. 1998;29:1405–1410.[Abstract/Free Full Text]

256. Frostegard J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999;145:33–43.[Medline] [Order article via Infotrieve]

257. Jander S, Sitzer M, Schumann R, et al. Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization. Stroke. 1998;29:1625–1630.[Abstract/Free Full Text]

258. Rohde LE, Lee RT, Rivero J, et al. Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 1998;18:1765–1770.[Abstract/Free Full Text]

259. Hwang SJ, Ballantyne CM, Sharrett AR, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1997;96:4219–4225.[Abstract/Free Full Text]

260. De Caterina R, Basta G, Lazzerini G, et al. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17:2646–2654.[Abstract/Free Full Text]

261. Esposito G, Blasi F, Allegra L, et al. Demonstration of viable Chlamydia pneumoniae in atherosclerotic plaques of carotid arteries by reverse transcriptase polymerase chain reaction. Ann Vasc Surg. 1999;13:421–425.[Medline] [Order article via Infotrieve]

262. Chiu B. Multiple infections in carotid atherosclerotic plaques. Am Heart J. 1999;138:S534–S536.[Medline] [Order article via Infotrieve]

263. Maass M, Krause E, Engel PM, et al. Endovascular presence of Chlamydia pneumoniae in patients with hemodynamically effective carotid artery stenosis. Angiology. 1997;48:699–706.

264. Yamashita K, Ouchi K, Shirai M, et al. Distribution of Chlamydia pneumoniae infection in the atherosclerotic carotid artery. Stroke. 1998;29:773–778.[Abstract/Free Full Text]

265. Grayston JT, Kuo CC, Coulson AS, et al. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation. 1995;92:3397–3400.[Abstract/Free Full Text]

266. Markus HS, Sitzer M, Carrington D, et al. Chlamydia pneumoniae infection and early asymptomatic carotid atherosclerosis. Circulation. 1999;100:832–837.[Abstract/Free Full Text]

267. Fagerberg B, Gnarpe J, Gnarpe H, et al. Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension. Stroke. 1999;30:299–305.[Abstract/Free Full Text]

268. Melnick SL, Shahar E, Folsom AR, et al. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis: Atherosclerosis Risk in Communities (ARIC) Study Investigators. Am J Med. 1993;95:499–504.[Medline] [Order article via Infotrieve]

269. Cook PJ, Honeybourne D, Lip GY, et al. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke. 1998;29:404–410.[Abstract/Free Full Text]

270. Wimmer ML, Sandmann-Strupp R, Saikku P, et al. Association of chlamydial infection with cerebrovascular disease. Stroke. 1996;27:2207–2210.[Abstract/Free Full Text]

271. Melissano G, Blasi F, Esposito G, et al. Chlamydia pneumoniae eradication from carotid plaques: results of an open, randomised treatment study. Eur J Vasc Endovasc Surg. 1999;18:355–359.[Medline] [Order article via Infotrieve]

272. Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke. Circulation. 1998;98:2796–2799.[Abstract/Free Full Text]

273. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.[Abstract/Free Full Text]

274. Rohde LE, Hennekens CH, Ridker PM. Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol. 1999;84:1018–1022.[Medline] [Order article via Infotrieve]

275. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among healthy women. Circulation. 1998;98:731–733.[Abstract/Free Full Text]

276. Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100:793–798.[Abstract/Free Full Text]

277. Feng D, Tracy RP, Lipinska I, et al. Effect of short-term aspirin use on C-reactive protein. J Thromb Thrombolysis. 2000;9:37–41.[Medline] [Order article via Infotrieve]

278. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol And Recurrent Events (CARE) Investigators. Circulation. 1998;98:839–844.[Abstract/Free Full Text]

279. Hallenbeck JM, Dutka AJ, Kochanek PM, et al. Stroke risk factors prepare rat brainstem tissues for modified local Shwartzman reaction. Stroke. 1988;19:863–869.[Abstract/Free Full Text]

280. Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;25:1901–1914.[Medline] [Order article via Infotrieve]

281. Whisnant JP. Effectiveness versus efficacy of treatment of hypertension for stroke prevention. Neurology. 1996;46:301–307.[Free Full Text]

282. Yin D, Carpenter JP. Cost-effectiveness of screening for asymptomatic carotid stenosis. J Vasc Surg. 1998;27:245–255.[Medline] [Order article via Infotrieve]

283. Colgan MP, Strode GR, Sommer JD, et al. Prevalence of asymptomatic carotid disease: results of duplex scanning in 348 unselected volunteers. J Vasc Surg. 1988;8:674–678.[Medline] [Order article via Infotrieve]

284. The Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from 3 randomized trials. Arch Intern Med. 1997;157:1237–1240.[Abstract/Free Full Text]

285. Prati P, Vanuzzo D, Casaroli M, et al. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke. 1992;23:1705–1711.[Abstract/Free Full Text]

286. Pujia A, Rubba P, Spencer MP. Prevalence of extracranial carotid artery disease detectable by echo-Doppler in an elderly population. Stroke. 1992;23:818–822.[Abstract/Free Full Text]

287. Ramsey DE, Miles RD, Lambeth A, et al. Prevalence of extracranial carotid artery disease: a survey of an asymptomatic population with noninvasive techniques. J Vasc Surg. 1987;5:584–588.[Medline] [Order article via Infotrieve]

288. Wilterdink JL, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol. 1992;49:857–863.[Abstract/Free Full Text]

289. Ahmed A, Adams RJ. Sickle cell disorders and cerebrovascular disease. In: Gillum RF, Gorelick PB, Cooper ES, eds. Stroke in Blacks: A Guide to Management and Prevention. Basel, Switzerland: S. Karger AG; 1999:62–69.

290. Gorelick PB. Stroke prevention: windows of opportunity and failed expectations? A discussion of modifiable cardiovascular risk factors and a prevention proposal. Neuroepidemiology. 1997;16:163–173.[Medline] [Order article via Infotrieve]

291. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991–1998. JAMA. 1999;282:1519–1522.[Abstract/Free Full Text]

292. Schmidt R, Auer-Grumbach P, Fazekas F, et al. Anticardiolipin antibodies in normal subjects: neuropsychological correlates and MRI findings. Stroke. 1995;26:749–754.[Abstract/Free Full Text]

293. Lockwood CJ, Romero R, Feinberg RF, et al. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol. 1989;161:369–373.[Medline] [Order article via Infotrieve]

294. Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome: a prospective study. Ann Intern Med. 1994;120:470–475.[Abstract/Free Full Text]

295. Pattison NS, Chamley LW, McKay EJ, et al. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol. 1993;100:909–913.[Medline] [Order article via Infotrieve]

296. Ridker PM, Miletich JP, Hennekens CH, et al. Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. JAMA. 1997;277:1305–1307.[Abstract/Free Full Text]

297. Awidi A, Shannak M, Bseiso A, et al. High prevalence of factor V Leiden in healthy Jordanian Arabs. Thromb Haemost. 1999;81:582–584.[Medline] [Order article via Infotrieve]

298. Lowe GD, Rumley A, Woodward M, et al. Activated protein C resistance and the FV:R506Q mutation in a random population sample: associations with cardiovascular risk factors and coagulation variables. Thromb Haemost. 1999;81:918–924.[Medline] [Order article via Infotrieve]

299. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995;346:1133–1134.[Medline] [Order article via Infotrieve]

300. Antoniadi T, Hatzis T, Kroupis C, et al. Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in a Greek population of blood donors. Am J Hematol. 1999;61:265–267.[Medline] [Order article via Infotrieve]

301. Zoller B, Garcia de Frutos P, Hillarp A, et al. Thrombophilia as a multigenic disease. Haematologica. 1999;84:59–70.[Medline] [Order article via Infotrieve]

302. Hessner MJ, Luhm RA, Pearson SL, et al. Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR. Thromb Haemost. 1999;81:733–738.[Medline] [Order article via Infotrieve]

303. Cooper DN, Krawczak M. Venous Thrombosis: From Genes to Clinical Medicine. Oxford, UK: BIOS Scientific Publishers Ltd; 1997.

304. Pepe G, Rickards O, Vanegas OC, et al. Prevalence of factor V Leiden mutation in non-European populations. Thromb Haemost. 1997;77:329–331.[Medline] [Order article via Infotrieve]

305. Horner J, Massey EW, Riski JE, et al. Aspiration following stroke: clinical correlates and outcome. Neurology. 1988;38:1359–1362.[Abstract/Free Full Text]

306. Dombovy ML, Sandok BA, Basford JR. Rehabilitation for stroke: a review. Stroke. 1986;17:363–369.[Abstract/Free Full Text]

307. Franco RF, Santos SE, Elion J, et al. Prevalence of the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene in different human populations. Acta Haematol. 1998;100:9–12.[Medline] [Order article via Infotrieve]

308. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79:706–708.[Medline] [Order article via Infotrieve]

309. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73:87–93.[Medline] [Order article via Infotrieve]

310. Tait RC, Walker ID, Perry DJ, et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol. 1994;87:106–112.[Medline] [Order article via Infotrieve]

311. The Antiphospholipid Antibodies in Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology. 1993;43:2069–2073.[Abstract/Free Full Text]

312. Camerlingo M, Casto L, Censori B, et al. Anticardiolipin antibodies in acute non-hemorrhagic stroke seen within six hours after onset. Acta Neurol Scand. 1995;92:69–71.[Medline] [Order article via Infotrieve]

313. Metz LM, Edworthy S, Mydlarski R, et al. The frequency of phospholipid antibodies in an unselected stroke population. Can J Neurol Sci. 1998;25:64–69.[Medline] [Order article via Infotrieve]

314. Tuhrim S, Rand JH, Wu XX, et al. Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke. 1999;30:1561–1565.[Abstract/Free Full Text]

315. Nagaraja D, Christopher R, Manjari T. Anticardiolipin antibodies in ischemic stroke in the young: Indian experience. J Neurol Sci. 1997;150:137–142.[Medline] [Order article via Infotrieve]

316. Brey RL, Abbott RD, Sharp DS, et al. Beta-2-glycoprotein 1-dependent (B2GP1-dep) anticardiolipin antibodies (aCL) are an independent risk factor for ischemic stroke in the Honolulu Heart Cohort. Stroke. 1999;30:252. Abstract.

317. Martinelli I, Franchi F, Akwan S, et al. The transition G to A at position 20210 in the 3'-untranslated region of the prothrombin gene is not associated with cerebral ischemia. Blood. 1997;90:3806–3811.[Free Full Text]

318. Lalouschek W, Aull S, Serles W, et al. C677T MTHFR mutation and factor V Leiden mutation in patients with TIA/minor stroke: a case-control study. Thromb Res. 1999;93:61–69.[Medline] [Order article via Infotrieve]

319. Margaglione M, D’Andrea G, Giulani N, et al. Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol. 1999;19:1751–1756.[Abstract/Free Full Text]

320. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995;332:912–917.[Abstract/Free Full Text]

321. Tosetto A, Ruggeri M, Castaman G, et al. Inherited abnormalities of blood coagulation in juvenile stroke. Blood Coagul Fibrinolysis. 1997;8:397–402.[Medline] [Order article via Infotrieve]

322. Lalouschek W, Aull S, Series W, et al. The prothrombin G20210A mutation and factor V Leiden mutation in patients with cerebrovascular disease. Blood. 1998;92:704–705.[Free Full Text]

323. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999;99:999–1004.[Abstract/Free Full Text]

324. Corral J, Gonzalez-Conejero R, Lozano ML, et al. The venous thrombosis risk factor 20210A allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease. Br J Haematol. 1997;99:304–307.[Medline] [Order article via Infotrieve]

325. De Stefano V, Chiusolo P, Paciaroni K, et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood. 1998;91:3562–3565.[Abstract/Free Full Text]

326. Folsom AR, Rosamond WD, Shahar E, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation. 1999;100:736–742.[Abstract/Free Full Text]

327. Lidegaard O, Kreiner S. Cerebral thrombosis and oral contraceptives: a case-control study. Contraception. 1998;57:303–314.[Medline] [Order article via Infotrieve]

328. Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Stroke. 1998;29:554–562.[Free Full Text]

329. Perry JR, Szalai JP, Norris JW. Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis: Canadian Stroke Consortium. Arch Neurol. 1997;54:25–28.[Abstract/Free Full Text]

330. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023.[Abstract/Free Full Text]

This article has been cited by other articles:

				N. Fassiadis, K. Adams, H. Zayed, D. Goss, C. Deane, P. MacCarthy, and H. Rashid Occult carotid artery disease in patients who have undergone coronary angioplasty Interactive CardioVascular and Thoracic Surgery, October 1, 2008; 7(5): 855 - 857. [Abstract] [Full Text] [PDF]

				R. Mikulik, L. Bunt, D. Hrdlicka, L. Dusek, D. Vaclavik, and J. Kryza Calling 911 in Response to Stroke: A Nationwide Study Assessing Definitive Individual Behavior Stroke, June 1, 2008; 39(6): 1844 - 1849. [Abstract] [Full Text] [PDF]

				A. Coca, F. H. Messerli, A. Benetos, Q. Zhou, A. Champion, R. M. Cooper-DeHoff, and C. J. Pepine Predicting Stroke Risk in Hypertensive Patients With Coronary Artery Disease: A Report From the INVEST Stroke, February 1, 2008; 39(2): 343 - 348. [Abstract] [Full Text] [PDF]

				S. Clauser, S. Peyrard, P. Gaussem, M. Crespin, J. Emmerich, M. Aiach, and D. Borgel Development of a Novel Immunoassay for the Assessment of Plasma Gas6 Concentrations and Their Variation with Hormonal Status Clin. Chem., October 1, 2007; 53(10): 1808 - 1813. [Abstract] [Full Text] [PDF]

				N. E. Mayo, L. Nadeau, S. S. Daskalopoulou, and R. Cote The evolution of stroke in Quebec: A 15-year perspective Neurology, April 3, 2007; 68(14): 1122 - 1127. [Abstract] [Full Text] [PDF]

				R. Wilcox, M.-G. Bousser, D. J. Betteridge, G. Schernthaner, V. Pirags, S. Kupfer, J. Dormandy, and for the PROactive Investigators Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke: Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04) Stroke, March 1, 2007; 38(3): 865 - 873. [Abstract] [Full Text] [PDF]

				J. P. Casas, G. L. Cavalleri, L. E. Bautista, L. Smeeth, S. E. Humphries, and A. D. Hingorani Endothelial Nitric Oxide Synthase Gene Polymorphisms and Cardiovascular Disease: A HuGE Review Am. J. Epidemiol., November 15, 2006; 164(10): 921 - 935. [Abstract] [Full Text] [PDF]

				N. Koren-Morag, U. Goldbourt, and D. Tanne Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease. Neurology, July 25, 2006; 67(2): 224 - 228. [Abstract] [Full Text] [PDF]

				S. E. Vermeer, W. Sandee, A. Algra, P. J. Koudstaal, L. J. Kappelle, D. W.J. Dippel, and on behalf of the Dutch TIA Trial Study Group Impaired Glucose Tolerance Increases Stroke Risk in Nondiabetic Patients With Transient Ischemic Attack or Minor Ischemic Stroke Stroke, June 1, 2006; 37(6): 1413 - 1417. [Abstract] [Full Text] [PDF]

				P. L. Faries, R. A. Chaer, S. Patel, S. C. Lin, B. DeRubertis, and K. C. Kent Current Management of Extracranial Carotid Artery Disease Vascular and Endovascular Surgery, May 1, 2006; 40(3): 165 - 175. [Abstract] [PDF]

				G. S. Roubin, S. Iyer, A. Halkin, J. Vitek, and C. Brennan Realizing the Potential of Carotid Artery Stenting: Proposed Paradigms for Patient Selection and Procedural Technique Circulation, April 25, 2006; 113(16): 2021 - 2030. [Abstract] [Full Text] [PDF]

				K. Matz, K. Keresztes, C. Tatschl, M. Nowotny, A. Dachenhausen, M. Brainin, and J. Tuomilehto Disorders of Glucose Metabolism in Acute Stroke Patients: An underrecognized problem Diabetes Care, April 1, 2006; 29(4): 792 - 797. [Abstract] [Full Text] [PDF]

				K. L. Kaplan and L. B. Goldstein What does cerebral platelet activation mean in the setting of carotid stenosis? Neurology, March 28, 2006; 66(6): 792 - 793. [Full Text] [PDF]

				R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Circulation, March 14, 2006; 113(10): e409 - e449. [Abstract] [Full Text] [PDF]

				R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Stroke, February 1, 2006; 37(2): 577 - 617. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind, R. Sciacca, B. Boden-Albala, T. Rundek, M. C. Paik, and R. L. Sacco Moderate Alcohol Consumption Reduces Risk of Ischemic Stroke: The Northern Manhattan Study Stroke, January 1, 2006; 37(1): 13 - 19. [Abstract] [Full Text] [PDF]

				B. J. Witt, R. D. Brown Jr., S. J. Jacobsen, S. A. Weston, B. P. Yawn, and V. L. Roger A Community-Based Study of Stroke Incidence after Myocardial Infarction Ann Intern Med, December 6, 2005; 143(11): 785 - 792. [Abstract] [Full Text] [PDF]

				F. Vancheri, M. Curcio, A. Burgio, S. Salvaggio, G. Gruttadauria, M.C. Lunetta, R. Dovico, and M. Alletto Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus QJM, December 1, 2005; 98(12): 871 - 878. [Abstract] [Full Text] [PDF]

				H. S. Kirshner, J. Biller, and A. S. Callahan III Long-Term Therapy to Prevent Stroke J Am Board Fam Med, November 1, 2005; 18(6): 528 - 540. [Abstract] [Full Text] [PDF]

				B. Bates, J. Y. Choi, P. W. Duncan, J. J. Glasberg, G. D. Graham, R. C. Katz, K. Lamberty, D. Reker, and R. Zorowitz Veterans Affairs/Department of Defense Clinical Practice Guideline for the Management of Adult Stroke Rehabilitation Care: Executive Summary Stroke, September 1, 2005; 36(9): 2049 - 2056. [Abstract] [Full Text] [PDF]

				K. Kario, J. Ishikawa, S. Hoshide, Y. Matsui, M. Morinari, K. Eguchi, S. Ishikawa, and K. Shimada Diabetic Brain Damage in Hypertension: Role of Renin-Angiotensin System Hypertension, May 1, 2005; 45(5): 887 - 893. [Abstract] [Full Text] [PDF]

				Task Force Members, L. H. Schwamm, A. Pancioli, J. E. Acker III, L. B. Goldstein, R. D. Zorowitz, T. J. Shephard, P. Moyer, M. Gorman, S. C. Johnston, et al. Recommendations for the Establishment of Stroke Systems of Care: Recommendations From the American Stroke Association's Task Force on the Development of Stroke Systems Stroke, March 1, 2005; 36(3): 690 - 703. [Full Text] [PDF]

				L. H. Schwamm, A. Pancioli, J. E. Acker III, L. B. Goldstein, R. D. Zorowitz, T. J. Shephard, P. Moyer, M. Gorman, S. C. Johnston, P. W. Duncan, et al. Recommendations for the Establishment of Stroke Systems of Care: Recommendations From the American Stroke Association's Task Force on the Development of Stroke Systems Circulation, March 1, 2005; 111(8): 1078 - 1091. [Full Text] [PDF]

				J. E. Sousa, M. A. Costa, E. M. Tuzcu, J. S. Yadav, and S. Ellis New Frontiers in Interventional Cardiology Circulation, February 8, 2005; 111(5): 671 - 681. [Full Text] [PDF]

				L. B. Goldstein and P. Amarenco Prevention and Health Services Delivery Stroke, February 1, 2005; 36(2): 222 - 224. [Full Text] [PDF]

				K. J. Mukamal, A. Ascherio, M. A. Mittleman, K. M. Conigrave, C. A. Camargo Jr, I. Kawachi, M. J. Stampfer, W. C. Willett, and E. B. Rimm Alcohol and Risk for Ischemic Stroke in Men: The Role of Drinking Patterns and Usual Beverage Ann Intern Med, January 4, 2005; 142(1): 11 - 19. [Abstract] [Full Text] [PDF]

				J. P. Casas, A. D. Hingorani, L. E. Bautista, and P. Sharma Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls Arch Neurol, November 1, 2004; 61(11): 1652 - 1661. [Abstract] [Full Text] [PDF]

				D. Tanne, N. Koren-Morag, and U. Goldbourt Fasting Plasma Glucose and Risk of Incident Ischemic Stroke or Transient Ischemic Attacks: A Prospective Cohort Study Stroke, October 1, 2004; 35(10): 2351 - 2355. [Abstract] [Full Text] [PDF]

				P.M. Rothwell and L.B. Goldstein Carotid Endarterectomy for Asymptomatic Carotid Stenosis: Asymptomatic Carotid Surgery Trial Stroke, October 1, 2004; 35(10): 2425 - 2427. [Full Text] [PDF]

				J. R. Sowers Treatment of Hypertension in Patients With Diabetes Arch Intern Med, September 27, 2004; 164(17): 1850 - 1857. [Abstract] [Full Text] [PDF]

				M. Churchill, S. Grimm, and M. Reding Risks of Diuretic Usage following Stroke Neurorehabil Neural Repair, September 1, 2004; 18(3): 161 - 165. [Abstract] [PDF]

				Task Force Members, J. Lopez-Sendo, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on {beta}-adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society of Cardiology Eur. Heart J., August 1, 2004; 25(15): 1341 - 1362. [Full Text] [PDF]

				H. Eyre, R. Kahn, R. M. Robertson, and and the ACS/ADA/AHA Collaborative Writing Committe Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association Stroke, August 1, 2004; 35(8): 1999 - 2010. [Abstract] [Full Text] [PDF]

				H. Eyre, R. Kahn, R. M. Robertson, and the ACS/ADA/AHA Collaborative Writing Committe, N. G. Clark, C. Doyle, T. Gansler, T. Glynn, Y. Hong, R. A. Smith, et al. Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association CA Cancer J Clin, July 1, 2004; 54(4): 190 - 207. [Abstract] [Full Text] [PDF]

				H. Eyre, R. Kahn, and R. M. Robertson Preventing Cancer, Cardiovascular Disease, and Diabetes: A common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association Diabetes Care, July 1, 2004; 27(7): 1812 - 1824. [Abstract] [Full Text] [PDF]

				K.M.A. Welch Statins for the prevention of cerebrovascular disease: the rationale for robust intervention Eur. Heart J. Suppl., July 1, 2004; 6(suppl_C): C34 - C42. [Abstract] [Full Text] [PDF]

				D. W. Dodick, I. Meissner, F. B. Meyer, and H. J. Cloft Evaluation and Management of Asymptomatic Carotid Artery Stenosis Mayo Clin. Proc., July 1, 2004; 79(7): 937 - 944. [Abstract] [PDF]

				L. Pedelty and P. B. Gorelick Chronic Management of Blood Pressure After Stroke Hypertension, July 1, 2004; 44(1): 1 - 5. [Full Text] [PDF]

				H. Eyre, R. Kahn, R. M. Robertson, the ACS/ADA/AHA Collaborative Writing Committee, ACS/ADA/AHA Collaborative Writing Committee Member, N. G. Clark, C. Doyle, Y. Hong, T. Gansler, T. Glynn, et al. Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association Circulation, June 29, 2004; 109(25): 3244 - 3255. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind and R. L. Sacco Direct Thrombin Inhibition: A Novel Approach to Stroke Prevention in Patients With Atrial Fibrillation Stroke, June 1, 2004; 35(6): 1519 - 1522. [Full Text] [PDF]

				A. J. Greenspon, R. G. Hart, D. Dawson, A. S. Hellkamp, M. Silver, G. C. Flaker, E. Schron, L. Goldman, K. L. Lee, G. A. Lamas, et al. Predictors of stroke in patients paced for sick sinus syndrome J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1617 - 1622. [Abstract] [Full Text] [PDF]

				N. F. Gordon, M. Gulanick, F. Costa, G. Fletcher, B. A. Franklin, E. J. Roth, and T. Shephard Physical Activity and Exercise Recommendations for Stroke Survivors: An American Heart Association Scientific Statement From the Council on Clinical Cardiology, Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention; the Council on Cardiovascular Nursing; the Council on Nutrition, Physical Activity, and Metabolism; and the Stroke Council Stroke, May 1, 2004; 35(5): 1230 - 1240. [Full Text] [PDF]

				N. F. Gordon, M. Gulanick, F. Costa, G. Fletcher, B. A. Franklin, E. J. Roth, and T. Shephard Physical Activity and Exercise Recommendations for Stroke Survivors: An American Heart Association Scientific Statement From the Council on Clinical Cardiology, Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention; the Council on Cardiovascular Nursing; the Council on Nutrition, Physical Activity, and Metabolism; and the Stroke Council Circulation, April 27, 2004; 109(16): 2031 - 2041. [Full Text] [PDF]

				S. Dukkipati, W. W. O'Neill, K. J. Harjai, W. P. Sanders, D. Deo, J. A. Boura, B. A. Bartholomew, M. W. Yerkey, H. M. Sadeghi, and J. K. Kahn Characteristics of cerebrovascular accidents after percutaneous coronary interventions J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1161 - 1167. [Abstract] [Full Text] [PDF]

				C. Bode Recent trials in atrial fibrillation: lessons learned beyond rate and rhythm Eur. Heart J. Suppl., April 1, 2004; 6(suppl_B): B15 - B19. [Abstract] [Full Text] [PDF]

				S. C. Horton and T. J. Bunch Patent Foramen Ovale and Stroke Mayo Clin. Proc., January 1, 2004; 79(1): 79 - 88. [Abstract] [PDF]

				J. E. Ho, F. Paultre, and L. Mosca Is Diabetes Mellitus a Cardiovascular Disease Risk Equivalent for Fatal Stroke in Women?: Data From the Women's Pooling Project Stroke, December 1, 2003; 34(12): 2812 - 2816. [Abstract] [Full Text] [PDF]

				A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension, December 1, 2003; 42(6): 1206 - 1252. [Abstract] [Full Text] [PDF]

				K. Eguchi, K. Kario, and K. Shimada Greater Impact of Coexistence of Hypertension and Diabetes on Silent Cerebral Infarcts Stroke, October 1, 2003; 34(10): 2471 - 2474. [Abstract] [Full Text] [PDF]

				G.Q. Villani, M. Piepoli, P.E. Villani, and A. Capucci Anticoagulation in atrial fibrillation: what is certain and what is to come Eur. Heart J. Suppl., September 1, 2003; 5(suppl_H): H45 - H50. [Abstract] [PDF]

				C. P. Derdeyn, J. D. Barr, A. Berenstein, John. J. Connors, J. E. Dion, G. R. Duckwiler, R. T. Higashida, C. M. Strother, T. A. Tomsick, and P. Turski The International Subarachnoid Aneurysm Trial (ISAT): A Position Statement from the Executive Committee of the American Society of Interventional and Therapeutic Neuroradiology and the American Society of Neuroradiology AJNR Am. J. Neuroradiol., August 1, 2003; 24(7): 1404 - 1408. [Full Text] [PDF]

				G. J. Hankey and J. W. Eikelboom Editorial Comment--Routine Thrombophilia Testing in Stroke Patients Is Unjustified Stroke, August 1, 2003; 34(8): 1826 - 1827. [Full Text] [PDF]

				L. B. Goldstein Editorial Comment--Advertising Strategies to Increase the Public Knowledge of the Warning Signs of Stroke Stroke, August 1, 2003; 34(8): 1968 - 1969. [Full Text] [PDF]

				J. M McKenney Potential Nontraditional Applications of Statins Ann. Pharmacother., July 1, 2003; 37(7): 1063 - 1071. [Abstract] [Full Text] [PDF]

				I. L. Katzan, R. D. Cebul, S. H. Husak, N. V. Dawson, and D. W. Baker The effect of pneumonia on mortality among patients hospitalized for acute stroke Neurology, February 25, 2003; 60(4): 620 - 625. [Abstract] [Full Text] [PDF]

				T. A. Pearson, T. L. Bazzarre, S. R. Daniels, J. M. Fair, S. P. Fortmann, B. A. Franklin, L. B. Goldstein, Y. Hong, G. A. Mensah, J. F. Sallis Jr, et al. American Heart Association Guide for Improving Cardiovascular Health at the Community Level: A Statement for Public Health Practitioners, Healthcare Providers, and Health Policy Makers From the American Heart Association Expert Panel on Population and Prevention Science Circulation, February 4, 2003; 107(4): 645 - 651. [Full Text] [PDF]

				S. I. McFarlane and J. R. Sowers Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 516 - 523. [Full Text] [PDF]

				L. B. Goldstein Prevention and Health Services Delivery Stroke, February 1, 2003; 34(2): 367 - 369. [Full Text] [PDF]

				J. R. Sowers and S. Haffner Treatment of Cardiovascular and Renal Risk Factors in the Diabetic Hypertensive Hypertension, December 1, 2002; 40(6): 781 - 788. [Full Text] [PDF]

				M. J. Reeves, J. G. Hogan, and A. P. Rafferty Knowledge of stroke risk factors and warning signs among Michigan adults Neurology, November 26, 2002; 59(10): 1547 - 1552. [Abstract] [Full Text] [PDF]

				L. Tauchmanova, R. Rossi, B. Biondi, M. Pulcrano, V. Nuzzo, E.-A. Palmieri, S. Fazio, and G. Lombardi Patients with Subclinical Cushing's Syndrome due to Adrenal Adenoma Have Increased Cardiovascular Risk J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4872 - 4878. [Abstract] [Full Text] [PDF]

				S. E. Straus, S. R. Majumdar, and F. A. McAlister New Evidence for Stroke Prevention: Scientific Review JAMA, September 18, 2002; 288(11): 1388 - 1395. [Abstract] [Full Text] [PDF]

				T. A. Pearson, S. N. Blair, S. R. Daniels, R. H. Eckel, J. M. Fair, S. P. Fortmann, B. A. Franklin, L. B. Goldstein, P. Greenland, S. M. Grundy, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases Circulation, July 16, 2002; 106(3): 388 - 391. [Full Text] [PDF]

				F. W. Booth, M. V. Chakravarthy, S. E. Gordon, and E. E. Spangenburg Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy J Appl Physiol, July 1, 2002; 93(1): 3 - 30. [Abstract] [Full Text] [PDF]

				V. Kothari, R. J. Stevens, A. I. Adler, I. M. Stratton, S. E. Manley, H. A. Neil, and R. R. Holman UKPDS 60: Risk of Stroke in Type 2 Diabetes Estimated by the UK Prospective Diabetes Study Risk Engine Stroke, July 1, 2002; 33(7): 1776 - 1781. [Abstract] [Full Text] [PDF]

				R. B. Horenstein, D. E. Smith, and L. Mosca Cholesterol Predicts Stroke Mortality in the Women's Pooling Project Stroke, July 1, 2002; 33(7): 1863 - 1868. [Abstract] [Full Text] [PDF]

				P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]

				M L Bots THE EUROSTROKE PROJECT J Epidemiol Community Health, February 1, 2002; 56(90001): i1 - 1. [Full Text] [PDF]

				K. J. Greenlund, W. H. Giles, N. L. Keenan, J. B. Croft, G. A. Mensah, and S. L. Huston Physician Advice, Patient Actions, and Health-Related Quality of Life in Secondary Prevention of Stroke Through Diet and Exercise * The Physician's Role in Helping Patients to Increase Physical Activity and Improve Eating Habits Stroke, February 1, 2002; 33(2): 565 - 571. [Abstract] [Full Text] [PDF]

				P. A. Tunick and I. Kronzon Primary Prevention of Ischemic Stroke Circulation, September 11, 2001; 104 (11): e59 - e59. [Full Text] [PDF]

				L. Mosca, P. Collins, D. M. Herrington, M. E. Mendelsohn, R. C. Pasternak, R. M. Robertson, K. Schenck-Gustafsson, S. C. Smith Jr, K. A. Taubert, and N. K. Wenger Hormone Replacement Therapy and Cardiovascular Disease: A Statement for Healthcare Professionals From the American Heart Association Circulation, July 24, 2001; 104(4): 499 - 503. [Full Text] [PDF]

				L. K. Massey Dairy Food Consumption, Blood Pressure and Stroke J. Nutr., July 1, 2001; 131(7): 1875 - 1878. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind Implications of stroke prevention trials: Treatment of global risk Neurology, July 12, 2005; 65(1): 17 - 21. [Abstract] [Full Text] [PDF]

This Article Free upon publication Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldstein, L. B. Articles by Members Search for Related Content PubMed PubMed Citation Articles by Goldstein, L. B. Articles by Members, Pubmed/NCBI databases Medline Plus Health Information Stroke Related Collections Lipids Cerebrovascular disease/stroke Thrombosis risk factors Other diabetes AHA Statements and Guidelines Carotid Stenosis Primary and Secondary Stroke Prevention Risk Factors for Stroke Anticoagulants Antiplatelets Other Stroke Treatment - Medical Carotid endarterectomy Transient Ischemic Attacks