This Article Free upon publication Abstract 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 Sacco, R. L. Articles by Tomsick, T. Search for Related Content PubMed PubMed Citation Articles by Sacco, R. L. Articles by Tomsick, T. Pubmed/NCBI databases Medline Plus Health Information Stroke Transient Ischemic Attack Related Collections Transient Ischemic Attacks Acute Stroke Syndromes Primary and Secondary Stroke Prevention Related Internet Resources

(Stroke. 2006;37:577.)
© 2006 American Heart Association, Inc.

AHA/ASA Guidelines

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.

Ralph L. Sacco, MD, MS, FAHA, FAAN, Chair; Robert Adams, MD, FAHA, Vice Chair; Greg Albers, MD; Mark J. Alberts, MD, FAHA; Oscar Benavente, MD; Karen Furie, MD, MPH, FAHA; Larry B. Goldstein, MD, FAHA, FAAN; Philip Gorelick, MD, MPH, FAHA, FAAN; Jonathan Halperin, MD, FAHA; Robert Harbaugh, MD, FACS, FAHA; S. Claiborne Johnston, MD, PhD; Irene Katzan, MD, FAHA; Margaret Kelly-Hayes, RN, EdD, FAHA; Edgar J. Kenton, MD, FAHA, FAAN; Michael Marks, MD; Lee H. Schwamm, MD, FAHA Thomas Tomsick, MD, FAHA
Abstract

The aim of this new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches for the implementation of guidelines and their use in high-risk populations. (Stroke. 2006;37:577-617.)

Key Words: AHA Scientific Statements • ischemia • ischemia attack, transient • stroke

Survivors of a transient ischemic attack (TIA) or stroke have an increased risk of another stroke, which is a major source of increased mortality and morbidity. Among the estimated 700 000 people with stroke in the United States each year, 200 000 of them are among persons with a recurrent stroke. The number of people with TIA, and therefore at risk for stroke, is estimated to be much greater. Epidemiological studies have helped to identify the risk and determinants of recurrent stroke, and clinical trials have provided the data to generate evidence-based recommendations to reduce this risk. Prior statements from the American Heart Association (AHA) have dealt with primary¹ and secondary stroke prevention.^2,3 Because most strokes are cerebral infarcts, these recommendations focus primarily on the prevention of stroke among the ischemic stroke or TIA group. Other statements from the AHA have dealt with acute ischemic stroke,⁴ subarachnoid hemorrhage (SAH),⁵ and intracerebral hemorrhage (ICH).⁶ Recommendations follow the AHA and the American College of Cardiology (ACC) methods of classifying the level of certainty of the treatment effect and the class of evidence (see Table 1).⁷

View this table: [in this window] [in a new window]   TABLE 1. Definition of Classes and Levels of Evidence Used in AHA Recommendations

The aim of this new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or TIA. A writing committee chair and vice chair were designated by the Stroke Council Manuscript Oversight Committee. A writing committee roster was developed and approved by the Stroke Council with representatives from neurology, cardiology, radiology, surgery, nursing, and health services research. The committee met in person and had a number of teleconferences to develop the outline and text of the recommendations. The writing group conducted a comprehensive review of the relevant literature. Although the complete list of keywords is beyond the scope of this section, the committee reviewed all compiled reports from computerized searches and conducted additional searching by hand. Searches were limited to English language sources and to human subjects. Literature citations were generally restricted to published manuscripts appearing in journals listed in Index Medicus and reflected literature published as of December 31, 2004. Because of the scope and importance of certain ongoing clinical trials and other emerging information, published abstracts were cited when they were the only published information available. The references selected for this document are exclusively for peer-reviewed papers that are representative but not all inclusive. All members of the committee had frequent opportunities to review drafts of the document, comment in writing or during teleconference discussions, and reach consensus with the final recommendations.

Although prevention of stroke is the primary outcome of interest, many of the grades for the recommendations were chosen to reflect the existing evidence on the reduction of all vascular outcomes after stroke, including stroke, myocardial infarction (MI), and vascular death. We have organized our recommendations in this statement to aid the clinician who has arrived at a potential explanation of the cause of the ischemic stroke in an individual patient and is embarking on therapy to reduce the risk of a recurrent event and other vascular outcomes. Our intention is to have these statements updated every 3 years, with additional interval updates as needed, to reflect the changing state of knowledge on the approaches to prevention of a recurrent stroke.

Definition of TIA and Ischemic Stroke Subtypes

The distinction between TIA and ischemic stroke has become less important in recent years because many of the preventive approaches are applicable to both groups. They share pathogenetic mechanisms; prognosis may vary, depending on their severity and cause; and definitions are dependent on the timing and degree of the diagnostic evaluation. By conventional clinical definitions, if the neurological symptoms continue for >24 hours, a person has been diagnosed with stroke; otherwise, a focal neurological deficit lasting <24 hours has been defined as a TIA. With the more widespread use of modern brain imaging, many patients with symptoms lasting <24 hours are found to have an infarction. The most recent definition of stroke for clinical trials has required either symptoms lasting >24 hours or imaging of an acute clinically relevant brain lesion in patients with rapidly vanishing symptoms. The proposed new definition of TIA is a "brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms typically lasting less than 1 hour, and without evidence of infarction."⁸ TIAs are an important determinant of stroke, with 90-day risks of stroke reported as high as 10.5% and the greatest stroke risk apparent in the first week.^9,10

Ischemic stroke is classified into various categories according to the presumed mechanism of the focal brain injury and the type and localization of the vascular lesion. The classic categories have been defined as large-artery atherosclerotic infarction, which may be extracranial or intracranial; embolism from a cardiac source; small-vessel disease; other determined cause such as dissection, hypercoagulable states, or sickle cell disease; and infarcts of undetermined cause.¹¹ The certainty of the classification of the ischemic stroke mechanism is far from ideal and reflects the inadequacy or timing of the diagnostic workup in some cases to visualize the occluded artery or to localize the source of the embolism. Recommendations for the timing and type of diagnostic workup for TIA and stroke patients are beyond the scope of this guideline statement.

I. Risk Factor Control for All Patients With TIA or Ischemic Stroke

A. Hypertension
It is estimated that 50 000 000 Americans have hypertension.¹² There is a continuous association between both systolic and diastolic blood pressures (BPs) and the risk of ischemic stroke.^13,14 Meta-analyses of randomized controlled trials confirm an approximate 30% to 40% stroke risk reduction with BP lowering.^14,15 Detailed evidence-based recommendations for the BP screening and treatment of persons with hypertension are summarized in the American Stroke Association Scientific Statement on the Primary Prevention of Ischemic Stroke¹ and the AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update¹⁶ and are detailed in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).¹⁷ JNC-7 stresses the importance of lifestyle modifications in the overall management of hypertension.¹⁷ Systolic BP reductions have been associated with weight loss; the consumption of a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption.¹⁷

Although a wealth of data from a variety of sources support the importance of treatment of hypertension for primary cardiovascular disease prevention in general and in stroke in particular, only limited data directly address the role of BP treatment in secondary prevention among persons with stroke or TIA.¹⁵ There is a general lack of definitive data to help guide the immediate management of elevated BP in the setting of acute ischemic stroke; a cautious approach has been recommended, and the optimal time to initiate therapy remains uncertain.¹⁸

A systematic review focused on the relationship between BP reduction and the secondary prevention of stroke and other vascular events.¹⁹ The analysis included 7 published, nonconfounded, randomized controlled trials with a combined sample size of 15 527 participants with ischemic stroke, TIA, or ICH randomized from 3 weeks to 14 months after the index event and followed up for 2 to 5 years. No relevant trials tested the effects of nonpharmacological interventions. Treatment with antihypertensive drugs has been associated with significant reductions in all recurrent strokes, nonfatal recurrent stroke, MI, and all vascular events with similar, albeit nonsignificant, trends toward a reduction in fatal stroke and vascular death. These results were seen in studies that recruited patients regardless of whether they had hypertension.

Data on the relative benefits of specific antihypertensive regimens for secondary stroke prevention are largely lacking. A meta-analysis showed a significant reduction in recurrent stroke with diuretics and diuretics and ACE inhibitors (ACEIs) combined but not with ß-blockers (BBs) or ACEIs used alone.¹⁹ Similar effects were found when all vascular events were considered as the outcome. The analysis included patients with ischemic stroke, TIA, or hemorrhagic stroke. The overall reductions in stroke and all vascular events were related to the degree of BP lowering achieved, and as pointed out in the meta-analysis, comparisons, "although internally consistent, are limited by the small numbers of trials, patients, and events for each drug class...especially for the ß-receptor antagonists for which the findings might be falsely neutral."¹⁹

Given these considerations, whether a particular class of antihypertensive drug or a particular drug within a given class offers a particular advantage for use in patients after ischemic stroke remains uncertain. Much discussion has focused on the role of ACEIs. The Heart Outcomes Prevention Evaluation (HOPE) Study compared the effects of the ACEI ramipril with placebo in high-risk persons and found a 24% risk reduction (95% CI, 5 to 40) for stroke, MI, or vascular death among the 1013 patients with a history of stroke or TIA.¹⁴ Although the BP-lowering effect as measured during the study was minimal (average, 3/2 mm Hg), it may have been related to the methodology used to measure BP. A substudy using ambulatory BP monitoring found a substantial 10/4 mm Hg reduction over 24 hours and a 17/8 mm Hg reduction during the nighttime.²⁰

The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was specifically designed to test the effects of a BP-lowering regimen, including an ACEI, in 6105 patients with stroke or TIA within the previous 5 years.²¹ Randomization was stratified by intention to use single (ACEI) or combination (ACEI plus the diuretic indapamide) therapy in both hypertensive (>160 mm Hg systolic or >90 mm Hg diastolic) and nonhypertensive patients. The combination (reducing BP by an average of 12/5 mm Hg) resulted in a 43% (95% CI, 30 to 54) reduction in the risk of recurrent stroke and a 40% (95% CI, 29 to 49) reduction in the risk of major vascular events (coronary heart disease [CHD]), with the effect present in both the hypertensive and normotensive groups. However, there was no significant benefit when the ACEI was given alone. Those given combination therapy were younger, were more likely to be men, were more likely to be hypertensive, had a higher mean BP at entry, were more likely to have CHD, and were recruited sooner after the event. The JNC-7 report concluded that "recurrent stroke rates are lowered by the combination of an ACEI and thiazide-type diuretic."¹⁷

A preliminary phase II study randomized 342 hypertensive patients with acute ischemic stroke to an angiotensin receptor blocker (ARB) or placebo over the first week.²² There were no significant differences in blood pressures between the active treatment and placebo patients, with both groups receiving the ARB after the first week. Although the number of vascular events among the ARB group was significantly reduced over the first week (OR, 0.475; 95% CI, 0.252 to 0.895), there were no differences in outcome at 3 months. At 12 months, a significant reduction in mortality was observed in the ARB group. The mechanisms by which an acute treatment led to this difference at 12 months, but no difference at 3 months, are uncertain; further studies are needed.

Recommendations

1. Antihypertensive treatment is recommended for both prevention of recurrent stroke and prevention of other vascular events in persons who have had an ischemic stroke or TIA and are beyond the hyperacute period (Class I, Level of Evidence A). Because this benefit extends to persons with and without a history of hypertension, this recommendation should be considered for all ischemic stroke and TIA patients (Class IIa, Level of Evidence B). An absolute target BP level and reduction are uncertain and should be individualized, but benefit has been associated with an average reduction of 10/5 mm Hg, and normal BP levels have been defined as <120/80 mm Hg by JNC-7 (Class IIa, Level of Evidence B).
   
2. Several lifestyle modifications have been associated with blood pressure reductions and should be included as part of a comprehensive antihypertensive therapy (Class IIb, Level of Evidence C). The optimal drug regimen remains uncertain; however, the available data support the use of diuretics and the combination of diuretics and an ACEI (Class I, Level of Evidence A). The choice of specific drugs and targets should be individualized on the basis of reviewed data and consideration of specific patient characteristics (eg, extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, and diabetes) (Class IIb, Level of Evidence C).
   

B. Diabetes
Diabetes is estimated to affect 8% of the adult population.²³ It is frequently encountered in stroke care, being present in 15%,²⁴ 21%,²⁵ and 33%²⁶ of patients with ischemic stroke. Diabetes is a clear risk factor for stroke.^27–31 The data supporting diabetes as a risk factor for recurrent stroke, however, are more sparse. Diabetes mellitus (DM) and age were the only significant independent predictors of recurrent stroke in a population-based study of stroke from Rochester, Minn.³² In another community-based stroke study, the Oxfordshire Stroke Project, diabetes was 1 of 2 factors independently associated with stroke recurrence (hazard ratio [HR] 1.85; 95% CI, 1.18 to 2.90; P<0.01), and investigators estimated that 9.1% (95% CI, 2.0 to 20.2) of the recurrent strokes were attributable to diabetes.³³ In the evaluation of 2-year stroke recurrence in the Stroke Data Bank, patients at the lowest risk had no history of diabetes.³⁴ Furthermore, diabetes has been shown to be a strong determinant for the presence of multiple lacunar infarcts in 2 different stroke cohorts.^35,36

Most of the available data on stroke prevention in patients with diabetes are on the primary rather than secondary prevention of stroke. Multifactorial approaches with intensive treatments to control hyperglycemia, hypertension, dyslipidemia, and microalbuminuria have demonstrated reductions in the risk of cardiovascular events.³⁷ These intensive approaches included behavioral measures and the use of a statin, ACEI, ARB, and antiplatelet drug as appropriate. Primary stroke prevention guidelines have emphasized the more rigorous control of BP among both type 1 and type 2 diabetics¹ with lower targets of 130/80 mm Hg.^16,17 Tight control of BP in diabetics has been shown to reduce the incidence of stroke significantly.^38–40 In the United Kingdom Prospective Diabetes Study (UKPDS), diabetic patients with controlled BP (mean BP, 144/82 mm Hg) had a 44% reduced relative risk (RR) of stroke compared with diabetics with poorer BP control (mean BP, 154/87 mm Hg; 95% CI, 11 to 65; P=0.013).³⁸ Intensive treatment of hypertension also significantly reduced the risk of the combined end point of MI, sudden death, stroke, and peripheral vascular disease by 34% (P=0.019). Additional clinical trials have corroborated the risk reduction in stroke and/or cardiovascular events with BP control in diabetics.^39,41–43 Although most of these studies did not reach the goal BP of 130/80 mm Hg, epidemiological analyses suggest a continual reduction in cardiovascular events to a BP of 120/80 mm Hg.^43–45

Thiazide diuretics, BBs, ACEIs, and ARBs are beneficial in reducing cardiovascular events and stroke incidence in patients with diabetes^43,46–50 and are therefore preferred for the initial treatment of hypertension. ACEIs have a favorable effect on stroke and other cardiovascular outcomes.^21,41,51 ACEI- and ARB-based treatments have been shown to favorably affect the progression of diabetic nephropathy and to reduce albuminuria, and ARBs have been shown to reduce the progression to macroalbuminuria.^{23,38,52–56} The American Diabetes Association (ADA) now recommends that all patients with diabetes and hypertension should be treated with a regimen that includes either an ACEI or an ARB.²³ Some studies have shown an excess of selected cardiac events in patients treated with calcium channel blockers (CCBs) compared with ACEIs.^57,58 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, which included >12 000 diabetic patients, demonstrated no difference between these 2 classes in the primary end point of coronary events regardless of diabetic status, although the diuretic chlorthalidone was found to be superior to both an ACEI (lisinopril) and a CCB (amlopidine) for selected secondary vascular end points.⁴⁷ Both diabetic and nondiabetic patients had similar vascular event rates treated with CCBs or ARBs in the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial.⁵⁹ In the Hypertension Optimal Treatment (HOT) study and the Systolic Hypertension in Europe (Syst-Eur) Trial, CCBs in combination with ACEIs, BBs, and diuretics did not appear to be associated with increased cardiovascular morbidity.^43,49 However, because of lingering concerns about a potential increase in cardiovascular events and in the ability to reduce progression of renal disease with CCBs, the ADA has suggested that this class of medications should be considered add-on agents in patients with diabetes.²³ It is important to note that polytherapy is usually needed to reach BP targets among diabetics and that the benefits of antihypertensive therapy depend more on BP achieved than the regimen used.²³

More rigorous control of lipids is now also recommended among diabetics with LDL cholesterol (LDL-C) targets as low as 70 mg/dL.⁶⁰ The Heart Protection Study (HPS) comparing simvastatin to placebo demonstrated the beneficial effect of lipid-lowering statin use in diabetic patients. In this randomized clinical trial (RCT), which included 5963 people with diabetes who were >40 years of age with a total cholesterol >135 mg/dL, simvastatin was associated with a 28% (95% CI, 8 to 44) reduction in ischemic strokes (3.4% simvastatin versus 4.7% placebo; P=0.01) and a 22% (95% CI, 13 to 30; P<0.0001) reduction in the first-event rate for vascular events, including major coronary artery events, strokes, and revascularizations. These results were independent of baseline LDL, preexisting vascular disease, type or duration of diabetes, or adequacy of glycemic control.⁶¹ Several other clinical trials of statin agents that have included smaller numbers of patients with diabetes have found similar reductions in both cardiovascular and cerebrovascular events.^62–64

Glycemic control, shown to reduce the occurrence of microvascular complications (nephropathy, retinopathy, and peripheral neuropathy) in several clinical trials,^62,65,66 is recommended in multiple guidelines of both primary and secondary prevention of stroke and cardiovascular disease.^{1,16,23,67–69} Data on the efficacy of glycemic control on macrovascular complications, including stroke, are more limited. RCTs of intensive glycemic control in patients with type 1 and type 2 diabetes have shown trends in reducing the risk of cardiovascular events, although they did not reach statistical significance.^30,70 Analysis of data from randomized trials suggests a continual reduction in vascular events with the progressive control of glucose to normal levels.⁷¹

Normal fasting glucose is defined as glucose <100 mg/dL (5.6 mmol/L), and impaired fasting glucose has been defined at levels between 100 and 126 mg/dL (5.6 and 6.9 mmol/L). A fasting plasma glucose level >126 mg/dL (7.0 mmol/L) or a casual plasma glucose >200 mg/dL (11.1 mmol/L) meets the threshold for the diagnosis of diabetes.²³ Hemoglobin A_1c level >7% is defined as inadequate control of hyperglycemia. Diet and exercise, oral hypoglycemic drugs, and insulin are recommended to obtain glycemic control.²³ Although the focus here is on the treatment of stroke patients with diabetes, there is growing recognition of the high prevalence of insulin resistance. Ongoing trials are addressing the use of rosiglitazone agents in secondary stroke prevention among those with insulin resistance.

Recommendations

1. More rigorous control of blood pressure and lipids should be considered in patients with diabetes (Class IIa, Level of Evidence B). Although all major classes of antihypertensives are suitable for BP control, most patients will require >1 agent. ACEIs and ARBs are more effective in reducing the progression of renal disease and are recommended as first-choice medications for patients with DM (Class I, Level of Evidence A).
   
2. Glucose control is recommended to near-normoglycemic levels among diabetics with ischemic stroke or TIA to reduce microvascular complications (Class I, Level of Evidence A) and possibly macrovascular complications (Class IIb, Level of Evidence B). The goal for hemoglobin A_1c should be 7% (Class IIa, Level of Evidence B).
   

C. Lipids
Hypercholesterolemia and hyperlipidemia are not as well established as risk factors for first or recurrent stroke in contrast to what is seen in cardiac disease.^72,73 Overall, prior observational cohort studies have shown only a weakly positive association for cholesterol level and risk of ischemic stroke or no clear relationship between plasma cholesterol and total stroke, and stroke risk reduction in statin trials may be primarily for nonfatal stroke.^72,74 Recent clinical trial data suggest, however, that stroke may be reduced by the administration of statin agents in persons with CHD.^75–77 The risk reductions with statins were beyond that expected solely through cholesterol reductions and have led to the consideration of other potential beneficial mechanisms. These findings led to approval of simvastatin and pravastatin for the prevention of stroke in those with CHD.⁷⁸

The Medical Research Council/British Heart Foundation HPS addressed the issue of stroke prevention with simvastatin administration in those with or without prior cerebrovascular disease.⁷⁹ In this study, 20 536 patients were identified who had coronary artery disease, occlusive vascular disease in other beds (including cerebrovascular disease), diabetes, or hypertension with other vascular risk factors. A patient was required to have a total cholesterol level of 135 mg/dL to qualify for the study. Patients were then assigned to either simvastatin 40 mg/d or placebo. Overall, there was a 25% RR reduction for the end point of stroke (P<0.0001). HPS showed that among those with preexisting cerebrovascular disease, the addition of statin therapy resulted in a significant reduction of coronary events and fewer revascularization procedures regardless of baseline cholesterol levels. However, among those with preexisting cerebrovascular disease, the incidence of stroke was not significantly reduced. Although many stroke patients with a history of CHD or DM may qualify for statin therapy, it remains uncertain whether those without CHD will benefit from statin therapy to reduce the risk of recurrent stroke according to HPS findings. This important question is being addressed in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study (SPARCL).⁸⁰

A review of recent prevention guidelines concerning cholesterol lowering by statin use in stroke prevention^16,68 suggests that the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (Adult Treatment Panel III)^81,82 is the most comprehensive guide for management of lipids in persons at risk for or who have cerebrovascular disease. NCEP emphasizes LDL-C lowering and 2 major modalities for LDL-C lowering: therapeutic lifestyle change and drug-specific therapy. Therapeutic lifestyle change stresses a reduction in saturated fats and cholesterol intake, weight reduction, and an increase in physical activity. LDL-C goals and cutpoints for initiation of therapeutic lifestyle change and drug therapy are based on 3 categories of risk: CHD and CHD risk equivalents (the latter category includes diabetes and symptomatic carotid artery disease), 2 cardiovascular risk factors stratified by 10-year risk of 10% to 20% for CHD and <10% for CHD according to the Framingham risk score, and 0 to 1 cardiovascular risk factor. When there is a history of CHD and CHD risk equivalents, the target LDL-C goal is <100 mg/dL.^81,82 Drug therapy options and management of metabolic syndrome and other dyslipidemias are addressed in the NCEP guideline. LDL-C lowering results in a reduction of total mortality, coronary mortality, major coronary events, coronary procedures, and stroke in persons with CHD.^81,82

Since the publication of ATP III, 5 major trials of statin therapy have been published that provide new insights for cholesterol lowering therapy in cardiovascular disease. On the basis of the results of these new studies, an addendum to the ATP III algorithm has been published.⁶⁰ The recommendation in very-high-risk persons is to aim for an LDL-C of <70 mg/dL.⁶⁰ Very-high-risk patients are those who have established cardiovascular disease plus (1) multiple major risk factors (especially diabetes), (2) severe and poorly controlled risk factors (especially continued cigarette smoking), (3) multiple risk factors of the metabolic syndrome (especially high triglycerides 200 mg/dL with low HDL cholesterol [<40 mg/dL]), and (4) patients with acute coronary syndromes.

Other medications also used to treat dyslipidemia include niacin, fibrates, and cholesterol absorption inhibitors. These agents can be used in stroke or TIA patients who cannot tolerate statins, but data demonstrating their efficacy for prevention of stroke recurrence are scant. Niacin was associated with a reduction in cerebrovascular events in the Coronary Drug Project.⁸³ Gemfibrozil reduced the rate of unadjudicated total strokes among men with coronary artery disease and low levels of HDL-C (40 mg/dL) in the Veterans Administration HDL Intervention Trial (VA-HIT).⁸⁴ However, the results were not significant when only adjudicated events were analyzed.

Recommendations

1. Patients with ischemic stroke or TIA with elevated cholesterol, comorbid coronary artery disease, or evidence of an atherosclerotic origin should be managed according to NCEP III guidelines, which include lifestyle modification, dietary guidelines, and medication recommendations (Class I, Level of Evidence A) (Table 2). Statin agents are recommended, and the target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease is an LDL-C of <100 mg/dL and LDL-C of <70 mg/dL for very-high-risk persons with multiple risk factors (Class I, Level of Evidence A).
   
2. Patients with ischemic stroke or TIA presumed to be due to an atherosclerotic origin but with no preexisting indications for statins (normal cholesterol levels, no comorbid coronary artery disease, or no evidence of atherosclerosis) are reasonable candidates for treatment with a statin agent to reduce the risk of vascular events (Class IIa, Level of Evidence B).
   
3. Patients with ischemic stroke or TIA with low HDL cholesterol may be considered for treatment with niacin or gemfibrozil (Class IIb, Level of Evidence B) (Table 2).
   

View this table: [in this window] [in a new window]   TABLE 2. Recommendations for Treatable Vascular Risk Factors

D. Cigarette Smoking
There is strong and convincing evidence that cigarette smoking is a major independent risk factor for ischemic stroke.^85–89 The risk associated with smoking is present at all ages, in both sexes, and among different racial/ethnic groups.^88,90 In a meta-analysis, smoking has been shown to be associated with a doubling of risk among smokers compared with nonsmokers.⁸⁸ The pathological pathway contributing to increased risk includes changes in blood dynamics^91,92 and vascular stenosis.^86,93,94 Because ethical issues preclude conducting RCTs for smoking after stroke, RCTs of quitting after stroke are not available. However, from observational studies, we know that risk of stroke decreases after quitting and that the elevated risk disappears after 5 years.^85,89,90 In addition, smoking cessation has been associated with a reduction in stroke-related hospitalizations^95,96 and therefore supports secondary prevention efforts.

There is growing evidence that exposure to environmental tobacco smoke (or passive smoke) increases the risk of cardiovascular disease, including stroke.^97–99 Given the high prevalence of smoking, exposure to environmental smoke needs consideration in overall risk assessment.

Tobacco dependence is a chronic condition for which there are now effective behavioral and pharmacotherapy treatments.^100–103 A combination of nicotine replacement therapy, social support, and skills training has been proved to be the most effective approach for quitting.^100,104 Updated information on how to treat tobacco dependence is available in the 2004 report, The Health Consequences of Smoking: a Report of the Surgeon General.¹⁰⁵

Recommendation

All healthcare providers should strongly advise every patient with stroke or TIA who has smoked in the last year to quit (Class I, Level of Evidence C). Avoidance of environmental tobacco smoke is recommended (Class IIa, Level of Evidence C). Counseling, nicotine products, and oral smoking cessation medications have been found to be effective in helping smokers to quit (Class IIa, Level of Evidence B) (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Recommendations for Modifiable Behavioral Risk Factors

E. Alcohol Consumption
The effect of alcohol on stroke risk is controversial. There is strong evidence that chronic alcoholism and heavy drinking are risk factors for all stroke subtypes.^106–110 For ischemic stroke, studies have demonstrated an association between alcohol and stroke, ranging from a definite independent effect to no effect. Most studies have suggested a J-shaped association between alcohol and ischemic stroke, with a protective effect in light or moderate drinkers and an elevated stroke risk with heavy alcohol consumption.^{93,106,107,111–116} In a recent meta-analysis of 35 observational studies of the association between alcohol and stroke, alcohol consumption was categorized into 0, <1, 1 to 2, 2 to 5, >5 drinks per day; an average drink contained about 12 g, 15 mL, or 0.5 oz of alcohol, which was found in 1 bottle (12 oz) of beer, 1 small glass (4 oz) of wine, or 1 alcoholic (1.5 oz liquor) cocktail. Compared with nondrinkers, those who consumed >5 drinks per day had a 69% increased stroke risk (RR, 1.69).¹¹⁷ Consumption of <1 drink per day was associated with a reduced risk (RR, 0.80), and consumption of 1 to 2 drinks per day was associated with a reduced risk of 0.72. Although few studies have evaluated the association between alcohol consumption and recurrent stroke, stroke recurrence was significantly increased among those ischemic stroke patients with prior heavy alcohol use in the Northern Manhattan cohort.¹¹⁸ No studies have demonstrated that reduction of alcohol intake decreases stroke recurrence risk.

The mechanism for reduced risk of ischemic stroke with light to moderate alcohol consumption may be related to an increase in HDL,^119,120 decreases in platelet aggregation,^121,122 and lower plasma fibrinogen concentration.^123,124 The deleterious risk mechanisms for those who are heavy alcohol consumers include alcohol-induced hypertension, hypercoagulable state, reduced cerebral blood flow, and atrial fibrillation (AF).^106,115,125 In addition, the brain that has been subjected to heavy alcohol consumption is more vulnerable because of an increase in the presence of brain atrophy.^126,127

It has been well established that alcohol can induce dependence and that alcoholism is a major public health problem. When advising a patient about behaviors to reduce recurrent stroke risk, clinicians need to take into consideration the interrelationship between other risk factors and alcohol consumption. A primary goal for secondary stroke prevention is to eliminate or reduce alcohol consumption in heavy drinkers through established screening and counseling methods as outlined in the US Preventive Services Task Force Update 2004.¹²⁸

Recommendation

Patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their consumption of alcohol (Class I, Level of Evidence A). Light to moderate levels of no more than 2 drinks per day for men and 1 drink per day for nonpregnant women may be considered (Class IIb, Level of Evidence C) (Table 3).

F. Obesity
Obesity, defined as a body mass index (BMI) of >30 kg/m², has been established as an independent risk factor for CHD and premature mortality.^129–131 The prevalence of obesity in the United States has increased dramatically over the past several decades, with current estimates of 63% of men and 55% of women considered overweight and 30% considered obese.^132,133 For individuals with disabling conditions with associated physical disabilities, obesity is even more prevalent.¹³⁴

The relationship of obesity and weight gain in adult years to stroke is complex. Obesity is strongly related to several major risk factors, including hypertension, diabetes, and dyslipidemia.^135,136 Studies documenting the specific impact of obesity to stroke have varied.^136–142 In men, findings from the Physicians’ Health Study have shown that an increasing BMI is associated with a steady increase in ischemic stroke, independently of the effects of hypertension, diabetes, and cholesterol.¹⁴³ Among women, data are inconsistent, with some positive¹³⁸ and others with no association.^140–142

Several studies have suggested that abdominal obesity, rather than general obesity, is more related to stroke risk.^144,145 Clinically, abdominal obesity is defined by a waist circumference >102 cm (40 in) in men and 88 cm (35 in) in women. Temporal trends in waist circumference among adults in the United States show a rapid increase in obesity, especially abdominal obesity.¹⁴⁶ For stroke, a significant and independent association between abdominal obesity and ischemic stroke was found in all racial/ethnic groups in the Northern Manhattan Study.¹⁴⁴ Comparing the first quartile of waist-to-hip ratio with the third and fourth quartiles gave ORs of 2.4 (95% CI, 1.5 to 3.9) and 3.0 (95% CI, 1.8 to 4.8), respectively, after adjustment for other risk factors and BMI.

No study has demonstrated that weight reduction will reduce stroke recurrence. Losing weight, however, significantly improves BP, fasting glucose values, serum lipids, and physical endurance.¹⁴⁷ Because obesity is a contributing factor to other risk factors associated with recurrent stroke, promoting weight loss and the maintenance of a healthy weight is a high priority. Diets rich in fruits and vegetables, such as the Mediterranean diet, can help with weight control and have been shown to reduce the risk of stroke, MI, and death.^148,149

Dietary guidelines are more adequately addressed in other AHA statements, including the primary prevention guideline (Primary Prevention of Ischemic Stroke), which is currently being updated.^1,150

Recommendation

Weight reduction may be considered for all overweight ischemic stroke and TIA patients to maintain the goal of a BMI of between 18.5 and 24.9 kg/m² and a waist circumference of <35 in for women and <40 in for men (Class IIb, Level of Evidence C). Clinicians should encourage weight management through an appropriate balance of calorie intake, physical activity, and behavioral counseling (Table 3).

G. Physical Activity
Substantial evidence exists that physical activity exerts a beneficial effect on multiple cardiovascular disease risk factors, including those for stroke.^16,151–155 In a recent review of existing studies on physical activity and stroke, overall moderately or highly active individuals had a lower risk of stroke incidence or mortality than did low-activity individuals.¹⁵⁴ Moderately active men and women had a 20% lower risk, and those who were highly active had a 27% lower risk. A plausible explanation for these observed reductions is that physical activity tends to lower BP and weight,^151,156 enhance vasodilation,¹⁵⁷ improve glucose tolerance,^158,159 and promote cardiovascular health.¹³⁰ Through lifestyle modification, exercise can minimize the need for more intensive medical and pharmacological interventions or enhance treatment end points.

Despite the established benefits of an active lifestyle, sedentary behaviors continue to be the national trends.^160,161 For those at risk for recurrent stroke and TIA, these sedentary behaviors complicate the recovery process and affect recurrent risk status. Because disability after stroke is substantial¹² and because neurological deficits predispose to activity intolerance and physical deconditioning,¹⁶² the challenge for clinicians is to establish a safe therapeutic exercise regimen that allows the patient to regain prestroke levels of activity and then to attain sufficient physical activity and exercise to reduce stroke recurrence. Several studies support the implementation of aerobic exercise and strength training to improve cardiovascular fitness after stroke.^162–165 Structured programs of therapeutic exercise have been shown to improve mobility, balance, and endurance.¹⁶³ Beneficial effects have been demonstrated in different ethnic groups and in both older and younger groups.¹⁶⁶ Encouragement of physical activity and exercise can optimize physical performance and functional capacity, thus reducing the risk for recurrent stroke. Recommendations on the benefits of physical activity for stroke survivors are reviewed more extensively in other AHA Scientific Statements.¹⁵⁷

Recommendation

For patients with ischemic stroke or TIA who are capable of engaging in physical activity, at least 30 minutes of moderate-intensity physical exercise most days may be considered to reduce the risk factors and comorbid conditions that increase the likelihood of recurrence of stroke (Class IIb, Level of Evidence C). For those individuals with disability after ischemic stroke, a supervised therapeutic exercise regimen is recommended (Table 3).

II. Interventional Approaches for the Patient With Large-Artery Atherosclerosis

A. Extracranial Carotid Disease
Among patients with TIA or stroke and documented carotid stenosis, a number of randomized trials have compared endarterectomy plus medical therapy with medical therapy alone. For patients with symptomatic atherosclerotic carotid stenosis >70%, as defined using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, the value of carotid endarterectomy (CEA) has been clearly established from the results of 3 major prospective randomized trials: the NASCET, the European Carotid Surgery Trial (ECST), and the Veterans Affairs Cooperative Study Program.^167–169 Among symptomatic patients with TIAs or minor strokes and high-grade carotid stenosis, each trial showed impressive relative and absolute risk reductions for those randomized to surgery.

For patients with carotid stenosis <50%, these trials showed that there was no significant benefit of surgery. In ECST, no benefit of surgery was demonstrated among those with <50% ipsilateral carotid stenosis.¹⁶⁸ Among those patients with <50% stenosis in NASCET, there was no significant reduction in the ipsilateral stroke risk among those treated with endarterectomy compared with those treated medically.¹⁷⁰ Although not specifically addressed by these trials, patients with nonstenosing ulcerative plaque generally would have been included in the groups with carotid stenosis <50% and would not have been found to benefit from endarterectomy.

For those with symptomatic carotid stenosis in the moderate category (50% to 69% stenosis), there is some uncertainty. The results from NASCET and ECST demonstrated less impressive benefits for CEA in this moderate group compared with medical therapy.^170,171 In NASCET, the 5-year risk of fatal or nonfatal ipsilateral stroke over the 5-year period was 22.2% in the medically treated group and 15.7% in patients treated surgically (P=0.045).¹⁷⁰ The relative and absolute risk reductions for surgery were less impressive than those observed for more severe degrees of stenosis.

Various comorbid features altered the benefit-to-risk ratio for CEA for moderate carotid stenosis. Benefits were greatest among those with more severe stenosis, those 75 years of age, men, patients with recent stroke (rather than TIA), and patients with hemispheric symptoms rather than transient monocular blindness.^170,172 Other radiographic factors found to predict better outcomes after CEA included the presence of intracranial stenosis, the absence of leukoaraiosis, and the presence of collaterals.^170,173,174 Gender and age differences, as well as comorbidity, must be considered when treatment options are evaluated in patients with stenosis between 50% and 69%, because the absolute benefit of surgery is less than that for more severe degrees of stenosis. Pooled analyses from endarterectomy trials have shown that early surgery is associated with increased benefits compared with delayed surgery. Benefit from surgery was greatest in men, patients 75 years of age, and those randomized within 2 weeks after their last ischemic event and fell rapidly with increasing delay.¹⁷⁵

Studies documenting the benefit of endarterectomy were conducted before the widespread use of medical treatments that have been demonstrated to reduce stroke risk in patients with vascular disease such as clopidogrel, extended-release dipyridamole and aspirin, statins, and more aggressive BP control. In NASCET, aspirin was the recommended antithrombotic agent, and only 14.5% of patients were on lipid-lowering therapy at the beginning of the study. During the NASCET study, although BP was monitored at regular office visits, there was not a recommended BP treatment algorithm across centers, and there was not consistent involvement by hypertension or vascular medicine specialists at each center. Whether the use of more aggressive medical therapy will alter the benefit of CEA plus best medical care over best medical care alone remains to be determined; however, it would be expected to reduce the stroke rates in both groups, leading to lower absolute risk reductions. Therefore, stroke or TIA patients who undergo interventional procedures also need to be treated with maximal medical therapies, as reviewed in the other recommendations in this document.

Extracranial-intracranial (EC/IC) bypass surgery was not found to provide any benefit for patients with carotid occlusion or those with carotid artery narrowing distal to the carotid bifurcation.¹⁷⁶ New efforts using more sensitive imaging to select patients with the greatest hemodynamic compromise for RCTs using EC/IC bypass surgery are ongoing.^177,178

Data on carotid artery balloon angioplasty and stenting (CAS) for symptomatic patients with internal carotid artery stenosis in stroke prevention consist primarily of a number of individual published case series but few controlled randomized multicenter comparisons of CEA and CAS.^179–181 The Wallstent Trial randomized 219 symptomatic patients with 60% to 90% stenosis to CEA or CAS. CAS was performed without distal protection and currently accepted antiplatelet prophylaxis. Study design allowed operators with limited experience to participate. The risk of perioperative stroke or death was 4.5% for CEA and 12.1% for CAS, and the risk of major stroke or death at 1 year was 0.9% for CEA and 3.7% for CAS. The trial was halted because of poor results from CAS.¹⁸²

The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) trial randomly compared angioplasty with surgical therapy among 504 symptomatic carotid patients, in whom only 26% received stents.¹⁸³ Major outcome events within 30 days did not differ between endovascular treatment and surgery groups, with a 30-day risk of stroke or death of 10.0% and 9.9%, respectively. Despite the increased risk of severe ipsilateral carotid stenosis in the endovascular group at 1 year, no substantial difference in the rate of ipsilateral stroke was noted up to 3 years after randomization.

The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial randomized 334 patients to endarterectomy or stenting with the use of an emboli-protection device, testing the hypothesis that stenting was not inferior to endarterectomy. Only 30% of the study population was symptomatic. Qualified CAS operators had a periprocedural stroke, death or MI complication rate of 4%. The primary end point of the study (the cumulative incidence of death, stroke, or MI within 30 days after the intervention, or death or ipsilateral stroke between 31 days and 1 year) occurred in 20 stent patients and 32 endarterectomy patients (30-day risk, 5.8% versus 12.6%; P=0.004 for noninferiority).¹⁸⁴ Most of the benefit was detected in the lower risk of MI for the stent compared with the high-surgical risk endarterectomy cases.

The National Institute of Neurological Diseases and Stroke (NINDS)–funded Carotid Revascularization With Endarterectomy or Stent Trial (CREST) is currently comparing CEA and CAS in patients with symptomatic severe stenosis (70% by ultrasonography or 50% by NASCET angiography criteria). The primary objective is to compare the efficacy of CAS versus CEA in preventing stroke over a follow-up period of up to 4 years. Other randomized trials are ongoing in Europe and Australia.

At present, CAS has been used in selected patients in whom stenosis is difficult to access surgically, medical conditions that greatly increase the risk for surgery are present, or other specific circumstances exist such as radiation-induced stenosis or restenosis after CEA. CAS has also been used in selected cases after arterial dissection, fibromuscular hyperplasia, or Takayasu’s arteritis. More definitive evidence is needed before we can advocate the widespread use of angioplasty plus stent as routine care for patients with extracranial carotid stenosis.

Recommendations

1. For patients with recent TIA or ischemic stroke within the last 6 months and ipsilateral severe (70% to 99%) carotid artery stenosis, CEA by a surgeon with a perioperative morbidity and mortality of <6% (Class I, Level of Evidence A) is recommended. For patients with recent TIA or ischemic stroke and ipsilateral moderate (50% to 69%) carotid stenosis, CEA is recommended, depending on patient-specific factors such as age, gender, comorbidities, and severity of initial symptoms (Class I, Level of Evidence A). When the degree of stenosis is <50%, there is no indication for CEA (Class III, Level of Evidence A) (Table 4).
   
2. When CEA is indicated for patients with TIA or stroke, surgery within 2 weeks is suggested rather than delaying surgery (Class IIa, Level of Evidence B).
   
3. Among patients with symptomatic severe stenosis (>70%) in whom the stenosis is difficult to access surgically, medical conditions are present that greatly increase the risk for surgery, or other specific circumstances exist such as radiation-induced stenosis or restenosis after CEA, CAS is not inferior to endarterectomy and may be considered (Class IIb, Level of Evidence B). CAS is reasonable when performed by operators with established periprocedural morbidity and mortality rates of 4% to 6%, similar to that observed in trials of CEA and CAS (Class IIa, Level of Evidence B).
   
4. Among patients with symptomatic carotid occlusion, EC/IC bypass surgery is not routinely recommended (Class III, Level of Evidence A).
   

View this table: [in this window] [in a new window]   TABLE 4. Recommendations for Interventional Approaches to Patients With Stroke Caused by Large-Artery Atherosclerotic Disease

B. Extracranial Vertebrobasilar Disease
Revascularization procedures can be performed on patients with extracranial vertebral artery stenosis who are having repeated vertebrobasilar TIAs or strokes despite medical therapy. Atherosclerotic plaques of both the vertebral and carotid arteries that are concentric, smooth, fibrous lesions without ulceration are amenable to endovascular therapy, which has generally moved from simple angioplasty to stenting to prevent recoil and restenosis.^185,186 Retrospective case series have shown that the procedure can be performed with a high degree of technical success.^187–190 Long-term follow-up data are limited, and further randomized studies are needed to more clearly define evidence-based recommendations in this setting.

Recommendation

Endovascular treatment of patients with symptomatic extracranial vertebral stenosis may be considered when patients are having symptoms despite medical therapies (antithrombotics, statins, and other treatments for risk factors) (Class IIb, Level of Evidence C) (Table 4).

C. Intracranial Atherosclerosis
Data from prospective studies show that patients with symptomatic intracranial atherosclerosis have a relatively high risk of recurrent stroke. The EC/IC bypass study randomized 352 patients with atherosclerotic disease of the middle cerebral artery to bypass surgery or medical treatment with aspirin.¹⁹¹ The medically treated patients were followed up for a mean of 42 months and had an overall stroke rate of 9.5% and an ipsilateral stroke rate of 7.8%. The Warfarin Aspirin Symptomatic Intracranial Disease (WASID) study evaluated 569 patients with symptomatic intracranial stenoses who were prospectively randomized to aspirin or warfarin.¹⁹² This study, which was stopped for safety reasons, showed no significant difference between groups in terms of the primary end point (ischemic stroke, brain hemorrhage, and nonstroke vascular death). In addition, retrospective data indicate that patients with symptomatic intracranial stenosis who fail antithrombotic therapy may have even greater rates of recurrent stroke.¹⁹³

Intracranial angioplasty and/or stenting provide an opportunity to rapidly improve cerebral blood flow. Results from single-center experiences suggest that the procedure can be performed with a high degree of technical success.^194–198 These studies have generally been performed among patients who have hemodynamically significant intracranial stenoses and symptoms despite medical therapy. More long-term follow-up has been lacking, but available data raise the possibility that angioplasty may improve the natural history compared with medical therapy.¹⁹⁴

It is not clear that stenting confers any improvement in the long-term clinical or angiographic outcome compared with angioplasty alone in this setting. One prospective trial has evaluated stenting in a mixed group of patients with intracranial and/or extracranial disease. The Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) Trial, a corporate-sponsored multicenter, nonrandomized, prospective feasibility study, evaluated 1 stent for treatment of vertebral or intracranial artery stenosis.¹⁹⁹ Forty-three intracranial arteries (70.5%) and 18 extracranial vertebral arteries (29.5%) were treated. Successful stent placement was achieved in 58 of 61 cases (95%). Thirty-day stroke incidence was 6.6%, with no deaths. Four of 55 patients (7.3%) had strokes later than 30 days, 1 of which was in the only patient not stented. Recurrent stenosis >50% within 6 months occurred in 12 of 37 intracranial arteries (32.4%) and 6 of 14 extracranial vertebral arteries (42.9%). Seven recurrent stenoses (39%) were symptomatic. Although a few different stents have been approved by the Food and Drug Administration (FDA) for use in patients with arterial stenoses, further studies are necessary to determine whether these interventional procedures have short-term and long-term efficacy.

Recommendation

For patients with hemodynamically significant intracranial stenosis who have symptoms despite medical therapies (antithrombotics, statins, and other treatments for risk factors), the usefulness of endovascular therapy (angioplasty and/or stent placement) is uncertain and is considered investigational (Class IIb, Level of Evidence C) (Table 4).

III. Medical Treatments for the Patient With Cardiogenic Embolism

Cardiogenic cerebral embolism derived from a diversity of cardiac disorders is responsible for 20% of ischemic strokes. There is a history of nonvalvular AF in about one half the cases, of valvular heart disease in one fourth, and of left ventricular (LV) mural thrombus in almost one third.²⁰⁰ Sixty percent of emboli of LV origin have been associated with acute MI.²⁰⁰ Intracavitary thrombus occurs in about one third of patients in the first 2 weeks after anterior MI and in an even greater proportion of those with large infarcts involving the LV apex.²⁰¹ Ventricular thrombi also occur in patients with chronic ventricular dysfunction resulting from coronary disease, hypertension, or other forms of dilated cardiomyopathy. Congestive heart failure affects >4 000 000 Americans and increases stroke risk by a factor of 2 to 3, accounting for 10% of ischemic stroke events.²⁰²

In general, patients with cardiac disease and cerebral infarction face a high risk of recurrent stroke. Because it is often difficult to determine the precise mechanism, the choice of a platelet inhibitor or anticoagulant drug may be difficult. Patients who have suffered an ischemic stroke who have a high-risk source of cardiogenic embolism should generally be treated with anticoagulant drugs to prevent recurrence.

The reader should review other AHA statements on the recommendations for the management of cardiac disease when planning treatments for patients with stroke or TIA who have other cardiac conditions.^203–208

A. Atrial Fibrillation
Both persistent AF and paroxysmal AF are potent predictors of first and recurrent stroke. More than 75 000 cases of stroke per year are attributed to AF. It has been estimated that AF affects >2 000 000 Americans and becomes more frequent with age, ranking as the leading cardiac arrhythmia in the elderly. Data from the AF clinical trials show that age, recent congestive heart failure, hypertension, diabetes, and prior thromboembolism have been found to identify high-risk groups for arterial thromboembolism among patients with AF. LV dysfunction, left atrial size, mitral annular calcification (MAC), spontaneous echo contrast, and left atrial thrombus by echocardiography have also been shown to predict increased thromboembolic risk. Overall, patients with prior stroke or TIA carry the highest stroke risk (RR, 2.5).

Multiple clinical trials have demonstrated the superior therapeutic effect of warfarin compared with placebo in the prevention of thromboembolic events among patients with nonvalvular AF. Pooled data from 5 primary prevention trials of warfarin versus control have been reported.²⁰⁹ The efficacy of warfarin has been shown to be consistent across studies, with an overall RR reduction of 68% (95% CI, 50 to 79) and an absolute reduction in annual stroke rate from 4.5% for the control patients to 1.4% in patients assigned to adjusted-dose warfarin. This absolute risk reduction indicates that 31 ischemic strokes will be prevented each year for every 1000 patients treated. Overall, warfarin use has been shown to be relatively safe, with an annual rate of major bleeding of 1.3% for patients on warfarin compared with 1% for patients on placebo or aspirin.

The optimal intensity of oral anticoagulation for stroke prevention in patients with AF appears to be 2.0 to 3.0. Results from a large case-control study²¹⁰ and two RCTs^211,212 suggest that the efficacy of oral anticoagulation declines significantly below an international normalized ratio (INR) of 2.0. Unfortunately, a high percentage of AF patients have subtherapeutic levels of anticoagulation and therefore are inadequately protected from stroke.

Evidence supporting the efficacy of aspirin is substantially weaker than that for warfarin. A pooled analysis of data from 3 trials resulted in an estimated RR reduction of 21% compared with placebo (95% CI, 0 to 38). At present, data are sparse with regard to the efficacy of alternative antiplatelet agents for stroke prevention in AF patients who are allergic to aspirin.²¹³ An ongoing study, Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE), is evaluating the safety and efficacy of the combination of clopidogrel and aspirin in AF patients.

The superior efficacy of anticoagulation over aspirin for stroke prevention in patients with AF and a recent TIA or minor stroke was demonstrated in the European Atrial Fibrillation Trial.²¹⁴ Therefore, unless a clear contraindication exists, AF patients with a recent stroke or TIA should receive long-term anticoagulation rather than antiplatelet therapy. There is no evidence that combining anticoagulation with an antiplatelet agent reduces the risk of stroke compared with anticoagulant therapy alone.

The narrow therapeutic margin of warfarin in conjunction with numerous associated food and drug interactions requires frequent INR testing and dose adjustments. These liabilities of warfarin contribute to significant underutilization, even in high-risk patients. Therefore, alternative therapies that are easier to use are needed.

Ximelagatran is a direct thrombin inhibitor that is orally administered, has stable pharmacokinetics independent of the hepatic P₄₅₀ enzyme system, and has a low potential for food or drug interactions. Two large studies, Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Atrial Fibrillation (SPORTIF) -III and -V,²¹⁵ compared ximelagatran with dose-adjusted warfarin (INR, 2 to 3) in high-risk patients with AF. A total of 7329 patients were included in these trials. Ximelagatran was administered at a fixed dose of 36 mg twice daily without coagulation monitoring. SPORTIF-III was an open-label study, involving 3407 patients randomized in 23 countries in Europe, Asia, and Australasia. SPORTIF-V was a double-blind trial otherwise identical in design that randomized 3922 patients in North America. About 25% of the patients in these trials had a history of stroke or TIA. In both trials, ximelagatran was noninferior to warfarin and was associated with fewer bleeding complications. In a pooled analysis of SPORTIF-III and -V, the rate of primary events (combined ischemic stroke, hemorrhagic stroke, and systemic embolic event) was 1.62% per year with ximelagatran and 1.65% per year with warfarin (difference, –0.03; 95% CI, –0.50 to 0.44; P=0.94) over 11 346 patient-years (mean, 18.5 months). The primary outcome event rate in patients with prior stroke was 2.83% per year in the ximelagatran group (n=786) and 3.27% per year in the warfarin group (n=753; P=0.63). There were no significant differences between treatments in rates of hemorrhagic stroke, fatal bleeding, or other major bleeding, but combined rates of minor and major bleeding were significantly lower with ximelagatran (31.7% versus 38.7% per year; P<0.0001). Serum alanine-aminotransferase levels rose transiently >3 times above normal in 6% of patients with ximelagatran, usually within 6 months.

The results of SPORTIF-III and -V provide evidence that ximelagatran 36 mg twice daily is essentially equivalent to well-controlled, dose-adjusted warfarin at INRs of 2.0 to 3.0. Because ximelagatran does not need anticoagulation monitoring or dose adjustment, it was developed to be an easier drug to administer than adjusted-dose warfarin; however, the need for monitoring hepatic enzymes may lessen its advantage in ease of use. At the time these guidelines were written, the FDA and certain European regulatory authorities have not approved ximelagatran; therefore, it will not be included in the recommendations.

Available data do not show greater efficacy of the acute administration of anticoagulants over antiplatelet agents in the setting of cardioembolic stroke.¹⁸ More studies are required to clarify whether certain subgroups of patients who are perceived to be at high risk of recurrent embolism may benefit from urgent anticoagulation.

No data are available to address the question of when to initiate oral anticoagulation in a patient with AF after a stroke or TIA. In the European Atrial Fibrillation Trial (EAFT),²¹⁴ oral anticoagulation was initiated within 14 days of symptom onset in about one half of the patients. Patients in this trial had minor strokes or TIAs and AF. In general, we recommend initiation of oral anticoagulation within 2 weeks of an ischemic stroke or TIA; however, for patients with large infarcts or uncontrolled hypertension, further delays may be appropriate.

For patients with AF who suffer an ischemic stroke or TIA despite therapeutic anticoagulation, no data indicate that either increasing the intensity of anticoagulation or adding an antiplatelet agent provides additional protection against future ischemic events. In addition, both strategies are associated with an increase in bleeding risk.

About one third of patients who present with AF and an ischemic stroke will be found to have other potential causes for the stroke such as carotid stenosis. For these patients, treatment decisions should focus on the presumed most likely stroke origin. In many cases, it will be appropriate to initiate anticoagulation, because of the AF, and additional therapy (such as CEA).

Recommendations

1. For patients with ischemic stroke or TIA with persistent or paroxysmal (intermittent) AF, anticoagulation with adjusted-dose warfarin (target INR, 2.5; range, 2.0 to 3.0) is recommended (Class I, Level of Evidence A) (Table 5).
   
2. For patients unable to take oral anticoagulants, aspirin 325 mg/d is recommended (Class I, Level of Evidence A).
   

View this table: [in this window] [in a new window]   TABLE 5. Recommendations for Patients With Cardioembolic Stroke Types

B. Acute MI and Left Ventricular Thrombus
Stroke or systemic embolism is less common among uncomplicated MI patients but can occur in up to 12% of patients with acute MI complicated by a LV thrombus. The rate is higher in those with anterior than inferior infarcts and may reach 20% of those with the large anteroapical infarcts.²¹⁶ The incidence of embolism is highest during the period of active thrombus formation in the first 1 to 3 months, yet the embolic risk remains substantial even beyond the acute phase in patients with persistent myocardial dysfunction, congestive heart failure, or AF. Although thrombus remains echocardiographically apparent for 1 year after MI in more than one third of patients in whom the diagnosis is initially made and evidence of thrombus persists for 2 years in about one fourth of cases, relatively few of these persistent thrombi are associated with late embolic events. The concurrent use of aspirin with oral anticoagulation is based on ACC/AHA guidelines for patients with ST-segment elevation MI.²⁰⁶

Recommendations

1. For patients with an ischemic stroke or TIA caused by an acute MI in whom LV mural thrombus is identified by echocardiography or another form of cardiac imaging, oral anticoagulation is reasonable, aiming for an INR of 2.0 to 3.0 for at least 3 months and up to 1 year (Class IIa, Level of Evidence B).
   
2. Aspirin should be used concurrently for ischemic coronary artery disease during oral anticoagulant therapy in doses up to 162 mg/d (Class IIa, Level of Evidence A).
   

C. Cardiomyopathy
When LV systolic function is impaired, the reduced stroke volume creates a condition of relative stasis within the left ventricle that may activate coagulation processes and increase the risk of thromboembolic events. The cause of cardiomyopathy may be ischemia or infarction based on coronary artery disease or nonischemic as a result of genetic or acquired defects of myocardial cell structure or metabolism. Although stroke rate was not found to be related to the severity of heart failure, 2 large studies did find the incidence of stroke to be inversely proportional to ejection fraction (EF).^217,218 In the Survival and Ventricular Enlargement (SAVE) study,^217,218 patients with an EF of 29% to 35% (mean, 32%) had a stroke rate of 0.8% per year; the rate in patients with EF 28% (mean, 23%) was 1.7% per year. There was an 18% increment in the risk of stroke for every 5% decline in EF. These findings apply mainly to men, who represented >80% of trial participants. A retrospective analysis of data from the Studies of Left Ventricular Dysfunction (SOLVD) trial,⁵¹ which excluded patients with AF, found a 58% increase in risk of thromboembolic events for every 10% decrease in EF among women (P=0.01). There was no significant increase in stroke risk among men.

In patients with nonischemic dilated cardiomyopathy, the rate of stroke appears similar to that associated with cardiomyopathy resulting from ischemic heart disease. An estimated 72 000 initial stroke events per year have been associated with LV systolic dysfunction, and the 5-year recurrent stroke rate in patients with cardiac failure has been reported to be as high as 45%.¹¹⁸ Warfarin is sometimes prescribed to prevent cardioembolic events in patients with cardiomyopathy; however, no randomized clinical studies have demonstrated the efficacy of anticoagulation, and considerable controversy surrounds the use of warfarin in patients with cardiac failure or reduced LV EF.^219,220 Several trials have been initiated to address this issue.^221–223 The primary objective of the Warfarin/Aspirin Study in Heart Failure (WASH) was to demonstrate feasibility and aid in the design of a larger outcome study.²¹⁷ The study showed no significant differences in the primary outcome (death, nonfatal MI, or nonfatal stroke) between the groups, with 26%, 32%, and 26% of patients randomized to no antithrombotic treatment, aspirin, and warfarin, respectively. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure Trial (WATCH) was designed to evaluate the efficacy of antithrombotic strategies among symptomatic heart failure patients in sinus rhythm with EFs 35%.²¹⁸ Patients were randomized to open-label warfarin (target INR, 2.5 to 3.0) or double-blind antiplatelet therapy with aspirin 162 mg or clopidogrel 75 mg. The trial was terminated early for poor recruitment after 1587 patients among the 4500 planned were enrolled, with a resulting reduction of its power to achieve its original objective.

Two studies of patients with MI, involving a total of 4618 patients,^224,225 found that warfarin (INR, 2.8 to 4.8) reduced the risk of stroke compared with placebo by 55%²²⁴ and 40%²²⁵ over 37 months. In the SAVE study, both warfarin and aspirin (given separately) were associated with a lower risk for stroke than no antithrombotic therapy.²¹⁸ Warfarin appears to exert a similar effect on the reduction of stroke both in patients with nonischemic cardiomyopathy and in those with ischemic heart disease.²²⁶ Aspirin reduces the stroke rate by 20%.²²⁷ Potential antiplatelet therapies used to prevent recurrent stroke include aspirin (50 to 325 mg/d), the combination of aspirin (25 mg twice daily) and extended-release dipyridamole (200 mg twice daily), and clopidogrel (75 mg daily).

In the ongoing Warfarin Versus Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) study, the primary end point includes both stroke and death, and patients with and without prior stroke are enrolled. This trial is not statistically powerful enough to determine whether warfarin has an effect on stroke risk reduction; however, by pooling results with those of other trials, we may be able to draw some conclusions about thi