Five Keys to Reducing Secondary Stroke Risk

Emerg Med 36(4):18-26, 2004

The authors discuss the interventions with proven value against recurrent stroke and stroke subsequent to a transient ischemic attack, emphasizing lifestyle modifications, appropriate treatment of hypertension, indications for anticoagulant therapy, use of antiplatelet agents, and the importance of cholesterol monitoring.

By Chad M. Miller, MD, and Larry B. Goldstein, MD

Stroke is the third leading cause of death and a leading cause of adult disability in the United States. Each year, an estimated 700,000 Americans suffer a stroke. Approximately 5% of these patients will have another stroke within one month, and 16% of deaths in the month following a stroke can be attributed to such a recurrence. About 25% to 40% will have another stroke within five years.

In addition to treating other, unrelated conditions in patients with a history of stroke, both primary care and emergency physicians are called on to evaluate patients with a history of transient ischemic attack (TIA), a sudden focal neurologic deficit of presumed ischemic vascular etiology that resolves within 24 hours. Acute TIA requires an urgent evaluation for a remediable cause. As is the case with patients who have had a stroke, those with a history of TIA are at risk for further cerebrovascular events. A recent study found that approximately 11% of patients with TIA have a stroke within three months, with 50% of these strokes occurring within the first two days.

Prevention is the key to reducing the human, social, and economic burden of cerebrovascular disease, estimated in 1999 to be $50 billion annually in the United States. This article will address the major medical interventions that have been shown to reduce the risk of recurrent stroke: lifestyle modifications, treatment of hypertension, anticoagulant therapy, proper selection of antiplatelet agents, and lipid-lowering therapy. We will discuss key considerations in each of these areas, which are highlighted in the sidebar below. Although acute evaluation and management are not discussed, it should be understood that patients with nondisabling carotid artery distribution ischemic stroke or TIA need to be promptly evaluated for high-grade stenosis, to determine whether they might benefit from a specific intervention such as carotid endarterectomy.

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IMPACT OF LIFESTYLE MODIFICATIONS

Lifestyle modifications can have a significant impact on a patient's risk of recurrent stroke. Regular exercise has clear health benefits for persons with and without vascular disease. Individuals with an active lifestyle that includes regular exercise have a lower risk of stroke. Stroke patients who engage in an exercise program report improved quality of life, and those who are advised to exercise by their physicians are more likely to comply with the recommendation.

Initiating and maintaining a regular exercise program after a stroke may prove challenging for the patient with weakness, coordination difficulties, or significant sensory deficits. Physical and occupational therapy services are instrumental in evaluating the patient for appropriate rehabilitation and ensuring that a safe and reasonable exercise regimen is prescribed. Patients with stroke are at increased risk for coronary heart disease (CHD), and a careful cardiac assessment is advisable prior to initiation of an exercise program. Advice regarding exercise, based on the patient's overall cardiovascular condition, should be offered during every encounter.

A healthy diet can favorably affect blood pressure, lower cholesterol levels, and influence other risk factors for vascular disease. The metabolic syndrome (or insulin resistance syndrome, as some clinicians prefer to call it) is now recognized as an important risk factor for cardiovascular disease and stroke. Clinical hallmarks of the syndrome include a fasting blood glucose level above 110 mg/dl, waist circumference of more than 40 inches in men or more than 35 inches in women, fasting triglycerides above 150 mg/dl, high-density lipoprotein (HDL) below 40 mg/dl in men or below 50 mg/dl in women, and blood pressure above 130/85 mm Hg. (Having three or more of these findings confirms the diagnosis.) Exercise and a healthy diet can benefit persons with the metabolic syndrome.

A diet that includes five daily servings of fruits and vegetables has been shown to independently reduce the risk of stroke. As with exercise, nutritional advice from a physician is associated with improved adherence to dietary programs.

Although moderate alcohol consumption may have a favorable impact on cholesterol profiles and ischemic stroke risk, chronic excessive alcohol intake is associated with an increased risk of stroke. Men should be advised to restrict consumption to less than two drinks containing one ounce of alcohol per day. Women should restrict intake to less than one drink per day (and should not drink if they are pregnant or breastfeeding).

In addition to numerous other adverse health effects, cigarette smoking promotes platelet aggregation, increases hematocrit levels, worsens cholesterol profiles and hypertension, and increases the risk of both cardiovascular and cerebrovascular disease. Those exposed to second-hand smoke also have accelerated atherosclerotic disease and an increased risk of cardiovascular disease and stroke. As a result, smoking cessation should be emphasized to reduce the risk of recurrent events. Stroke risk returns to that of nonsmokers within three to five years after cessation.
 

TREATMENT FOR HYPERTENSION

Elevated systolic and diastolic blood pressure are independent risk factors for ischemic stroke. The importance of lowering blood pressure for primary stroke prevention has been recognized for many years, but its impact on reducing recurrent events has only recently been established. In a post-hoc subgroup analysis, data from the Heart Outcomes Prevention and Evaluation (HOPE) study was used to compare the addition of ramipril, an angiotensin-converting enzyme (ACE) inhibitor, to the current medical regimen in more than 1000 patients with prior TIA or stroke. Treatment was associated with a 24% reduction in the risk of the composite endpoints of stroke, myocardial infarction (MI), and vascular death over a four-year follow-up period. It is not clear whether the overall benefit of the ACE inhibitor was independent of the blood-pressure-lowering effect of the drug.

The Perindopril Protection Against Recurrent Stroke (PROGRESS) study was designed to investigate the impact of an ACE inhibitor with and without the diuretic indapamide in secondary stroke prevention. The study design was somewhat complicated, but a significant benefit was associated with the combined treatment. No benefit was seen with either drug given alone. The benefit of the combined treatment could be ascribed to the blood-pressure-lowering effect, but it was found in both hypertensive and nonhypertensive patients.

The benefits of certain classes of antihypertensive medications, beyond those attributable to blood pressure lowering, continue to be debated. Therefore, the choice of an antihypertensive agent remains a complex issue, but it should include consideration of age, race, concomitant medical illnesses, and medication tolerability. The Joint National Committee on the Prevention and Treatment of High Blood Pressure (JNC-7) designates diuretics as first-line therapy for control of hypertension. Blood pressures should be checked at every patient encounter, and patients with prior cerebrovascular events should be counseled about their risk and the need for treatment.

The timing of the initiation of antihypertensive therapy after stroke is another uncertain issue. In the acute setting, the long-term benefits of blood pressure reduction must be carefully balanced with the need for adequate perfusion, particularly among patients with high-grade vascular lesions. Patients recovering from an acute stroke often have impaired cerebral autoregulation. Aggressive blood pressure control during this phase may prove to be deleterious; ample time should be allowed to pass before initiating antihypertensive therapy. The ideal time to begin therapy is not known, and expert recommendations vary. Infarct size and stroke etiology are important factors in the decision. Conservative management would allow at least one week to elapse before starting therapy to gradually lower blood pressure toward target levels.

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INDICATIONS FOR ANTICOAGULATION THERAPY

Long-term treatment with warfarin (with a target INR of 2.0 to 3.0) is indicated for secondary stroke prophylaxis in patients with stroke or TIA associated with atrial fibrillation and no contraindication to anticoagulation. The European Atrial Fibrillation Trial (EAFT) demonstrated a 68% reduction in the risk of recurrent stroke in patients who received warfarin versus placebo. The results were consistent with several previous studies that demonstrated benefit in primary prevention of stroke in high-risk patients with atrial fibrillation.

Although the INR goal for the EAFT was 2.5 to 4.0, the risk of intracranial hemorrhage was increased with higher INR values. A target INR of 2.0 to 3.0 balances the benefits and risks of anticoagulation for patients with atrial fibrillation and is recommended in current guidelines. It should be noted that stroke risk is independent of whether atrial fibrillation is chronic or paroxysmal. Therefore, all patients with prior stroke or TIA and atrial fibrillation should receive warfarin unless contraindications exist. Those patients with contraindications to warfarin should be treated with aspirin (325 mg daily). Oral direct thrombin inhibitors may soon become available as an alternative to anticoagulation with warfarin.

Warfarin has no proven benefit compared to antiplatelet therapy in preventing recurrent stroke in patients with prior noncardioembolic stroke. The Warfarin Aspirin Recurrent Stroke Study (WARSS) randomized more than 2200 patients with a recent stroke of noncardiac origin to aspirin or warfarin and followed the cohorts for two years. No subgroup of patients with noncardioembolic stroke significantly benefited from warfarin therapy.

However, the study did not specifically address patients with large-vessel, symptomatic, intracranial disease. The retrospective Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study suggested that warfarin was superior to aspirin in patients with this condition. This has recently been investigated in a prospective, randomized trial of the same name. As reported at the 29th International Stroke Conference in 2004, there was no benefit with warfarin as compared to aspirin (1300 mg daily) in this group of patients. Warfarin, in fact, was associated with a higher rate of bleeding complications.

Patent foramen ovale (PFO) is a common congenital cardiac defect, affecting approximately 20% of adults. There are no findings on physical examination to suggest the presence of PFO, which is commonly diagnosed by echocardiography or transcranial Doppler ultrasonography performed with agitated saline contrast. Its presence, combined with a right-to-left cardiac shunt, can lead to paradoxical embolization (for example, cerebral embolism associated with a venous thrombus). The actual risk of recurrent stroke associated with PFO remains uncertain, and literature regarding anticoagulation of patients with PFO has been conflicting. A subgroup analysis of data from WARSS found no benefit with warfarin compared to aspirin in preventing recurrent stroke in patients with PFO. Studies are in progress assessing the effects of endovascular PFO closure with a mechanical device.

Several other scenarios are challenging for the physician contemplating anticoagulation. Patients with low cardiac ejection fractions after MI probably benefit from a short course of anticoagulation. The outcomes of this treatment will be reported by the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) and Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trials. Anticoagulants are also often used when ischemic stroke is associated with a coagulopathy (for example, antiphospholipid antibody syndrome, factor V Leiden mutation, prothrombin gene mutation, and protein C deficiency).
 

USE OF ANTIPLATELET AGENTS

The use of an antiplatelet agent is an essential part of secondary stroke prevention for patients who are not being treated with an anticoagulant. Aspirin, ticlopidine, clopidogrel, and a formulation of aspirin combined with extended-release dipyridamole are among the most commonly used antiplatelet medications.

The benefit of aspirin in secondary stroke prevention is well established, with an overall approximate risk reduction of 18%. There is no clear evidence of a dose effect in combined analyses of placebo-controlled studies with doses ranging from 50 to 1300 mg daily. However, the frequency of gastrointestinal side effects (particularly gastrointestinal hemorrhage) increases with higher aspirin doses. The Food and Drug Administration has recommended daily doses between 50 and 325 mg for prevention of recurrent ischemic stroke.

The Ticlopidine Aspirin Stroke Study found that ticlopidine was superior to aspirin for prevention of recurrent stroke in patients enrolled within three months of a minor stroke or TIA. Patients given ticlopidine had a 21% reduction in fatal or nonfatal strokes over three years compared to an aspirin cohort. However, ticlopidine use was associated with increased rates of diarrhea, gastrointestinal discomfort, potentially life-threatening neutropenia, and, rarely, thrombotic thrombocytopenic purpura. The drug's side effect profile, the need for complete blood counts every two weeks for the first three months of therapy, and the introduction of better-tolerated alternatives have made this medication a less popular choice for stroke prevention. In addition, a recently reported clinical trial found no benefit with ticlopidine compared to aspirin among African-Americans (African-American Antiplatelet Stroke Prevention Study).

Clopidogrel is pharmacologically similar to ticlopidine, but its use has not been associated with neutropenia. Thrombotic thrombocytopenic purpura seems infrequent; in the cases in which it has been reported, it may have been due to other causes. As a result, monitoring of blood counts is not required. The Clopidogrel versus Aspirin for the Prevention of Recurrent Ischemic Events (CAPRIE) trial compared the effects of clopidogrel and aspirin on MI, stroke, or vascular death in patients with CHD, stroke, or symptomatic peripheral arterial disease. Although there was an overall benefit with clopidogrel compared to aspirin, there was only an insignificant trend toward reduced risk in patients with prior stroke. (However, the study was not powered to detect subgroup differences.) Aspirin is often given in addition to clopidogrel, but the long-term safety and efficacy of this combination is not known. The Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent TIA or Ischemic Stroke (MATCH) trial will attempt to address these clinical questions.

A formulation of aspirin combined with extended-release dipyridamole is also available for use in secondary stroke prevention. The European Stroke Prevention Study (ESPS)-2 trial studied this formulation in patients with recent stroke. Given twice a day, the combination of 25 mg aspirin with 200 mg extended-release dipyridamole reduced recurrent stroke by 37% over two years versus placebo. The combination was associated with an absolute annual risk reduction of 1.3% compared with aspirin alone. The main side effects are headache and gastrointestinal upset. The headache often subsides within days of beginning therapy, or it may be reduced by initiating treatment with a half-dose nightly schedule. The addition of aspirin at doses greater than 81 mg may compromise the antiplatelet effects of the combination.

Changes are often made in a treatment regimen after a TIA or stroke that occurs while a patient is taking aspirin. However, there are no data showing a benefit in changing to a different antiplatelet regimen. Aside from aspirin, there have been no direct comparisons of the various antiplatelet agents. Until these trials are performed, the choice of antiplatelet medications for secondary stroke prevention should be made with consideration of costs, patient compliance, tolerability, and concomitant medical illnesses.
 

LIPID-LOWERING THERAPY

Treatment of patients with CHD or high CHD risk with an HMG-CoA reductase inhibitor (or statin) reduces the risk of stroke. Data on the impact of statins in patients with stroke or TIA but no known CHD are less certain. The Heart Protection Study (HPS) suggests a benefit in this group, but because of the study design, the finding is not definitive. The Stroke Prevention with Aggressive Reduction in Cholesterol Levels (SPARCL) trial will specifically test the effect of a statin in prevention of recurrent stroke.

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