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STROKE: PREVENTION, DIAGNOSIS, AND MANAGEMENT

Galen V. Henderson

Stroke remains a major healthcare problem. It is estimated that there are >700,000 incident strokes in the United States each year, resulting in >160,000 deaths annually, with 4.8 million stroke survivors alive today. Although there was a 60% decline in stroke mortality over the 29-year period between 1968 and 1996, the rate of decline began to slow in the 1990s and has plateaued in several regions of the country. Despite an overall 3.4% fall in per capita stroke-related mortality between 1991 and 2001, the actual number of stroke deaths rose by 7.7%. Stroke ranks as the country’s third leading cause of death. Stroke incidence may be increasing. From 1988 to 1997, the age-adjusted stroke hospitalization rate grew 18.6% (from 560 to 664 per 100,000), while total stroke hospitalizations increased 38.6% (from 592,811 to 821,760 annually). In 2004, the cost of stroke was estimated at $53.6 billion (direct and indirect costs), with a mean lifetime cost estimated at $140,048.

    Stroke is also a leading cause of functional impairments, with 20% of survivors requiring institutional care after 3 months and 15–30% being permanently disabled. Stroke is a life-changing event that affects not only the person who may be disabled but the entire family and other caregivers as well. Utility analyses show that a major stroke is viewed by more than half of those at risk as being worse than death. Despite the advent of treatment of selected patients with acute ischemic stroke with intravenous tissue-type plasminogen activator and the promise of other acute therapies, effective prevention remains the best treatment for reducing the burden of stroke.

    Primary prevention is particularly important because >70% of strokes are first events. As discussed in the evidence-based guideline-supported sections that follow, high-risk or stroke-prone individuals can now be identified and targeted for specific interventions for primary prevention and some information regarding secondary prevention treatments and emergency management of ischemic stroke.

RECOMMENDATIONS FOR PRIMARY AND SECONDARY PREVENTION OF ISCHEMIC STROKE

GENETIC CAUSES OF STROKE

Referral for genetic counseling may be considered for patients with rare genetic causes of stroke. There remain insufficient data to recommend genetic screening for the prevention of a first stroke.

CARDIOVASCULAR DISEASE

Persons with evidence of noncerebrovascular atherosclerotic vascular disease (coronary heart disease, cardiac failure, or intermittent claudication) are at increased risk of a first stroke. Treatments used in the management of these other conditions (e.g., platelet antiaggregants) and as recommended in other sections of this guideline can reduce the risk of stroke.

HYPERTENSION

Regular screening for hypertension (at least every 2 years in adults and more frequently in minority populations and the elderly) and appropriate management, including dietary changes, lifestyle modification, and pharmacological therapy as summarized by the Joint National Committee 7 (JNC7), are recommended.

CIGARETTE SMOKING

Abstention from cigarette smoking and smoking cessation for current smokers are recommended. Data from cohort and epidemiological studies are consistent and overwhelming. Avoidance of environmental tobacco smoke for stroke prevention should also be considered. The use of counseling, nicotine products, and oral smoking-cessation medications has been found to be effective for smokers and should be considered.

DIABETES

It is recommended that hypertension be tightly controlled in patients with either type 1 or type 2 diabetes (the JNC7 recommendation of <130/80 mm Hg in diabetic patients is endorsed) as part of a comprehensive risk-reduction program. Treatment of adults with diabetes, especially those with additional risk factors, with a statin to lower the risk of a first stroke is recommended. Recommendations to consider treatment of diabetic patients with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are endorsed.

ATRIAL FIBRILLATION

Anticoagulation of patients with atrial fibrillation (AF) who have valvular heart disease (particularly those with mechanical heart valves) is recommended. Antithrombotic therapy (warfarin or aspirin) is recommended to prevent stroke in patients with nonvalvular AF based on assessment of their absolute stroke risk and estimated bleeding risk while considering patient preferences and access to high-quality anticoagulation monitoring. Warfarin (International Normalized Ratio [INR] 2.0 to 3.0) is recommended for high-risk (>4% annual risk of stroke) patients (and for most moderate-risk patients according to patient preferences) with AF who have no clinically significant contraindications to oral anticoagulants.

OTHER CARDIAC CONDITIONS

Various practice guidelines recommend strategies to reduce the risk of stroke in patients with a variety of cardiac conditions. These include the management of patients with valvular heart disease, unstable angina, chronic stable angina, and acute myocardial infarction (MI). Strategies to prevent postoperative neurological injury and stroke in patients undergoing surgical revascularization for atherosclerotic heart disease are discussed in detail in the recently published coronary artery bypass graft surgery guidelines. It is reasonable to prescribe warfarin for post–ST-segment-elevation patients with MI and left ventricular (LV) dysfunction with extensive regional wall-motion abnormalities, and warfarin may be considered in patients with severe LV dysfunction with or without congestive heart failure.

DYSLIPIDEMIA

National Cholesterol Education Program III (NCEP III) guidelines for the management of patients who have not had a cerebrovascular event with elevated total cholesterol, or with elevated non–high-density lipoprotein (HDL) cholesterol in the presence of hypertriglyceridemia, are endorsed. It is recommended that patients with known coronary heart disease (CHD) and high-risk hypertensive patients even with normal low-density lipoprotein (LDL) cholesterol levels be treated with lifestyle measures and a statin. The use of lipid-lowering therapy in diabetic patients is specifically addressed in the diabetes section of this guideline. Suggested treatments for patients with known CHD and low HDL cholesterol include weight loss, increased physical activity, smoking cessation, and possibly niacin or gemfibrozil.

ASYMPTOMATIC CAROTID STENOSIS

It is recommended that patients with asymptomatic carotid artery stenosis be screened for other treatable causes of stroke and that intensive therapy of all identified stroke risk factors be pursued. The use of aspirin is recommended unless contraindicated, because aspirin was used in all of the cited trials as an antiplatelet drug except in the surgical arm of one study, in which there was a higher rate of MI in those who were not given aspirin. Prophylactic carotid endarterectomy is recommended in highly selected patients with high-grade asymptomatic carotid stenosis performed by surgeons with <3% morbidity/mortality rates. Patient selection should be guided by an assessment of comorbid conditions and life expectancy, as well as other individual factors, and be balanced by an understanding of the overall impact of the procedure if all-cause mortality is considered as one of the endpoints, and it should include a thorough discussion of the risks and benefits of the procedure with an understanding of patient preferences. Carotid angioplasty stenting might be a reasonable alternative to endarterectomy in asymptomatic patients at high risk for the surgical procedure. However, given the reported periprocedural and overall 1-year event rates, it remains uncertain whether this group of patients should have either procedure.

SICKLE CELL DISEASE

It is recommended that children with sickle cell disease (SCD) be screened with transcranial Doppler (TCD) ultrasound starting at 2 years of age. It is recommended that transfusion therapy be considered for those at elevated stroke risk. Although the optimal screening interval has not been established, it is reasonable that younger children and those with TCD velocities in the conditional range should be rescreened more frequently to detect development of high-risk TCD indications for intervention. Pending further studies, it is reasonable to continue transfusion even in those whose TCD velocities revert to normal. Magnetic resonance imaging (MRI) and MR angiography (MRA) criteria for selection of children for primary stroke prevention using transfusion have not been established, and these tests should not be substituted for TCD. Adults with SCD should be evaluated for known stroke risk factors and managed according to the general guidelines in this chapter.

POSTMENOPAUSAL HORMONE THERAPY

It is recommended that postmenopausal hormone therapy (estrogen with or without a progestin) not be used for primary prevention of stroke. The use of hormone replacement therapy for other indications should be informed by the risk estimate for vascular outcomes provided by the reviewed clinical trials. There are not sufficient data to provide recommendations about the use of other forms of therapy such as selective estrogen receptor modulators.

DIET AND NUTRITION

A reduced intake of sodium and increased intake of potassium is recommended to lower blood pressure in persons with hypertension (class I, level of evidence A), which may thereby reduce the risk of stroke. The recommended sodium intake is ≤2.3 g/day (100 mmol/day), and the recommended potassium intake is ≥4.7 g/day (120 mmol/day). The DASH diet, which emphasizes fruit, vegetables, and low-fat dairy products and is reduced in saturated and total fat, also lowers blood pressure and is recommended. A diet that is rich in fruits and vegetables may lower the risk of stroke and may be considered.

PHYSICAL INACTIVITY

Increased physical activity is recommended because it is associated with a reduction in the risk of stroke. Exercise guidelines as recommended by the Centers for Disease Control (CDC) and the National Institutes of Health (≥30 min of moderate-intensity activity daily) as part of a healthy lifestyle are reasonable.

OBESITY AND BODY FAT DISTRIBUTION

Epidemiological studies indicate that increased body weight and abdominal fat are directly associated with stroke risk. Weight reduction is recommended because it lowers blood pressure and may thereby reduce the risk of stroke.

METABOLIC SYNDROME

Management of individual components of the metabolic syndrome, including lifestyle measures and pharmacotherapy as recommended in the National Cholesterol Education Program ATP III and the JNC7 as reviewed in other sections of this guideline, are endorsed. Lifestyle management should include exercise, appropriate weight loss, and proper diet. Pharmacotherapy may include medications for blood pressure lowering, lipid lowering, glycemic control, treatment of microalbuminuria or proteinuria, and antiplatelet therapy (e.g., aspirin) according to the individual circumstance and risk. It is not known whether agents that ameliorate aspects of the insulin resistance syndrome are useful for reducing stroke risk.

ALCOHOL ABUSE

Reduction of alcohol consumption in heavy drinkers through established screening and counseling methods as outlined in the U.S. Preventive Services Task Force Update 2004 is endorsed. For those who consume alcohol, a recommendation of no more than two drinks per day for men and one drink per day for nonpregnant women best reflects the state of the science for alcohol and stroke risk.

DRUG ABUSE

Successful identification and management of drug abuse can be challenging. When a patient is identified as having a drug addiction problem, referral for appropriate counseling may be considered.

ORAL CONTRACEPTIVES

The incremental risk of stroke associated with use of low-dose oral contraceptives (OCs) in women without additional risk factors appears low, if it exists. It is suggested that OC be discouraged in women with additional risk factors (e.g., cigarette smoking or prior thromboembolic events. For those who elect to assume the increased risk, aggressive therapy of stroke risk factors may be useful.

SLEEP-DISORDERED BREATHING

Sleep-disordered breathing (SDB) is associated with stroke risk. Questioning bed partners and patients, particularly patients with abdominal obesity and hypertension, about symptoms of SDB and referral to a sleep specialist for further evaluation as appropriate may be useful, especially in the setting of drug-resistant hypertension.

MIGRAINE

There are insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in women with migraine, including migraine with aura.

Hyperhomocysteinemia

Recommendations to meet current guidelines for daily intake of folate (400 µg/day), vitamin B₆ (1.7 mg/day), and vitamin B₁₂ (2.4 µg/day) by consumption of vegetables, fruits, legumes, meats, fish, and fortified grains and cereals (for nonpregnant, nonlactating individuals) may be useful in reducing the risk of stroke. There are insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in patients with elevated homocysteine levels.

ELEVATED LIPOPROTEIN(A)

Although no definitive recommendations about lipoprotein (a) [Lp(a)] modification can be made because of an absence of outcome studies showing clinical benefit, treatment with niacin (extended-release or immediate-release formulation at a total daily dose of 2000 mg/day as tolerated) can be considered because it reduces Lp(a) levels by approximately 25%. Further recommendations must await the results of prospective trials utilizing niacin and statins in subjects stratified for Lp(a) concentration and apo(a) isoform subtypes.

ELEVATED LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A₂

No recommendations about Lp-PLA₂ modification can be made because of an absence of outcome studies showing clinical benefit with reduction in its blood levels.

HYPERCOAGULABILITY

There are insufficient data to support specific recommendations for primary stroke prevention in patients with a hereditary or acquired thrombophilia.

INFLAMMATION

Currently, no evidence supports the use of high-sensitivity C-reactive protein (hs-CRP) screening of the entire adult population as a marker of general vascular risk. Aggressive risk factor modification is recommended for patients at high risk for stroke given exposure to traditional risk factors regardless of hs-CRP level. In agreement with AHA/CDC guidelines, hs-CRP can be useful in considering the intensity of risk factor modification in those at moderate general cardiovascular risk on the basis of traditional risk factors (class IIa, level of evidence B).

INFECTION

Data are insufficient to recommend antibiotic therapy for stroke prevention on the basis of seropositivity for one or a combination of putative pathogenic organisms. Future studies on stroke risk reduction based on treatment of infectious diseases will require careful stratification and identification of patients at risk for organism exposure.

ASPIRIN

Aspirin is not recommended for the prevention of a first stroke in men. The use of aspirin is recommended for cardiovascular (including but not specific to stroke) prophylaxis among persons whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment (a 10-year risk of cardiovascular events of 6–10%). Aspirin can be useful for prevention of a first stroke among women whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment.

RECOMMENDATION FOR ANTIPLATELETS IN SECONDARY PREVENTION OF STROKE

1.  For patients with noncardioembolic ischemic stroke or transient ischemic attack (TIA),, antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events

2. Aspirin (50–325 mg/day) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy

3. The combination of aspirin and extended-release dipyridamole is recommended over aspirin alone

4. Clopidogrel may be considered over aspirin alone on the basis of direct-comparison trials and if patient is allergic to aspirin, clopidogrel is reasonable.

5. The addition of aspirin to clopidogrel increases the risk of hemorrhage. Combination therapy of aspirin and clopidogrel is not routinely recommended for ischemic stroke or TIA patients unless they have a specific indication for this therapy (i.e., coronary stent or acute coronary syndrome).

6. For patients who have an ischemic cerebrovascular event while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered for noncardioembolic patients, no single agent or combination has been well studied in patients who have had an event while receiving aspirin.

Recommendations for Statins in Secondary Prevention of Stroke

1. Ischemic stroke or TIA patients 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.

2. Statin agents are recommended, and the target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease is an LDL-C level of <100 mg/dL. An LDL-C <70 mg/dL is recommended for very high-risk persons with multiple risk factors.

3. On the basis of the Stroke Prevention by Reduction of Cholesterol Levels (SPARCL) trial, administration of statin therapy with intensive lipid- lowering effects is recommended for patients with atherosclerotic ischemic stroke or TIA and without known CHD to reduce the risk of stroke and cardiovascular events.

4. Ischemic stroke or TIA patients with low HDL cholesterol may be considered for treatment with niacin or gemfibrozil.

RECOMMENDATIONS FOR ORAL ANTITHROMBOTIC AGENTS FOR THE PREVENTION OF STROKE IN NONVALVULAR AF

It is important to acknowledge several issues related to the clinical use of dabigatran, rivaroxaban, and apixaban. There are no published data directly comparing dabigatran, rivaroxaban, and apixaban to one another—only comparisons to warfarin. The duration of follow-up in the clinical trials was limited. Factors relevant to long-term, real-world adherence are not known, especially if these new drugs are used outside of a care structure designed to assess adherence, such as an anticoagulation clinic. Because of their short half-lives, patients who are noncompliant and miss medication doses might be at risk for thromboembolism. Treatment decisions should account for differences in costs to patients, which could also affect compliance. Drug activity of the newer agents presently cannot be assessed in routine clinical practice, which poses a potential risk of undertreating or overtreating individuals. The transition from warfarin must be managed carefully and may constitute a period of increased risk. There are no antidotes to emergently reverse dabigatran, apixaban, or rivaroxaban in the setting of hemorrhage.

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