• 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.

1. Ralph L. Sacco, MD, MS, FAHA, FAAN, Chair; 
2. Robert Adams, MD, FAHA, Vice Chair; 
3. Greg Albers, MD; 
4. Mark J. Alberts, MD, FAHA;
5. Oscar Benavente, MD; 
6. Karen Furie, MD, MPH, FAHA; 
7. Larry B. Goldstein, MD, FAHA, FAAN; 
8. Philip Gorelick, MD, MPH, FAHA, FAAN;
9. Jonathan Halperin, MD, FAHA; 
10. Robert Harbaugh, MD, FACS, FAHA;
11. S. Claiborne Johnston, MD, PhD; 
12. Irene Katzan, MD, FAHA;
13. Margaret Kelly-Hayes, RN, EdD, FAHA; 
14. Edgar J. Kenton, MD, FAHA, FAAN; 
15. Michael Marks, MD; 
16. Lee H. Schwamm, MD, FAHA;
17. Thomas Tomsick, MD, FAHA

 

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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,⁴subarachnoid hemorrhage (SAH),⁵ and intracerebral hemorrhage (ICH).⁶Recommendations 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

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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.

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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.

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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 β-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 β-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.²¹Randomization 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.⁴⁷Both 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.⁶¹Several 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).