Recommendations for Prevention of Recurrent Stroke Reviewed

[Gatekeeper]

Recommendations for Prevention of Recurrent Stroke Reviewed

January 27, 2009 — Recommendations for prevention of recurrent stroke are reviewed in the January issue of Mayo Clinic Proceedings. In addition to control of modifiable risk factors, virtually all patients who have had ischemic stroke should be prescribed antiplatelet agents.

"Stroke is the leading cause of death and disability in the United States," writes Harold Adams Jr, MD, from the University of Iowa in Iowa City. "The economic consequences of stroke, including health care costs and lost economic productivity, are substantial. These are the reasons that stroke prevention, including treatment of underlying causes, are clearly of critical importance."

The leading cause of ischemic stroke is atherosclerotic vascular disease, which gives rise to occlusion or severe stenosis of major intracranial or extracranial arteries, as well as narrowing of small penetrating arteries of the brain.

Coronary artery disease, or atherosclerosis of the coronary arteries, may result in myocardial infarction, which in turn is an indirect cause of cardioembolic stroke. Atrial fibrillation and cardioembolic stroke may also complicate ischemic heart disease.

"Some risk factors associated with increased likelihood of advanced atherosclerosis and ischemic disease are not modifiable," Dr. Adams writes. "These risk factors include age, sex, ethnicity, family history and premature vascular disease. However, several conditions that augment the course of atherosclerosis can be effectively addressed across the continuum of care."

For patients with symptomatic ischemic cerebrovascular disease, a crucial aspect of treatment is prevention of recurrent stroke, myocardial infarction, and other ischemic events. This requires optimal control of modifiable risk factors that accelerate development of atherosclerosis, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking.

Management of hypertension should aim to achieve a normal blood pressure for the patient, realizing that no single, specific antihypertensive regimen is ideal for all patients. When prescribing a blood pressure–lowering treatment plan, clinicians should consider a patient's history, while awaiting the results of ongoing and future studies.

Some evidence suggests that aggressive lowering of cholesterol levels may modestly increase the risk for hemorrhagic stroke. However, the benefits of statins to decrease the risk for recurrent ischemic stroke and other ischemic vascular events are thought to outweigh the risk of bleeding. In patients with diabetes mellitus, management should include aggressive control of blood pressure and lipid levels as well as of blood glucose levels.

More aggressive interventions may be required, such as carotid endarterectomy and endovascular treatment. In selected patients, carotid endarterectomy should be considered as complementary to use of antiplatelet agents and other medications. For other patients with atherosclerotic cerebrovascular disease, extracranial-intracranial bypass surgery and carotid artery stenting may be considered, pending the results of ongoing clinical trials.

The keystone of management to prevent recurrent stroke and other cardiovascular events in patients at risk continues to be administration of antiplatelet agents, which should be prescribed for virtually all patients who have had ischemic stroke. Therapeutic options include aspirin, aspirin plus extended-release dipyridamole, or clopidogrel. Specific choice among these should be guided by the patient's previous treatment and history of ischemic events as well as allergies or other potential contraindications.

Specific recommendations of the American Heart Association/American Stroke Association for antithrombotic therapy in patients with ischemic stroke of noncardioembolic origin (secondary prevention), and their accompanying levels of evidence, are as follows:

Antiplatelet agents are recommended vs oral anticoagulants (level of evidence, I, A).
Preferred options for initial treatment are aspirin (50 - 325 mg/day), a combination of aspirin and extended-release dipyridamole, or clopidogrel (level of evidence, I, A).
The combination of aspirin and extended-release dipyridamole may be preferred vs aspirin alone (level of evidence, I, B).
Instead of aspirin alone, clopidogrel may be considered (level of evidence, IIb, B).
Clopidogrel is a reasonable option for patients who are hypersensitive to aspirin (level of evidence, IIa, B).
Addition of aspirin to clopidogrel increases the risk for hemorrhage (level of evidence, III, A).
"Use of an integrated treatment approach involving risk-factor management, antiplatelet therapy and surgical procedure when indicated presents the opportunity to lower the risk of recurrent stroke and other ischemic events in patients with recent ischemic stroke," Dr. Adams concludes. "Future research may provide support for using new medications, clarify the role of currently available medications, and better define the appropriate role of surgery, particularly endovascular treatments."

In an accompanying editorial, James F. Meschia, MD, from the Mayo Clinic in Jacksonville, Florida, confirms that "after the immediate post-thrombolytic period, care needs to focus on secondary prevention."

"Patients with acute ischemic stroke are at high risk of recurrent stroke," Dr. Meschia writes. "If successful reperfusion therapy is like dodging a bullet, successful secondary prevention is like being caught in the line of fire again. [Dr. Adams'] review will be welcomed by clinicians seeking guidance beyond evidence-based guidelines."

The Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership funded editorial support for Dr. Adams' review. Dr. Adams has disclosed no relevant financial relationships. Dr. Meschia has received support from the Siblings with Ischemic Stroke Study and the Carotid Revascularization Endarterectomy vs Stenting Trial.

Mayo Clin Proc. 2009;84:3-4, 43-51.


Clinical Context
Stroke is a leading cause of death and disability in the United States. Atherosclerosis is the leading causal factor, especially in patients 50 years or older, with patients at risk for ischemic stroke also at risk for peripheral arterial disease and myocardial infarction. Although many stoke risk factors are not modifiable, such as age, sex, ethnicity, and family history, current guidelines delineate 3 recommended approaches to prevent recurrent stroke. These approaches are risk factor management, antiplatelet therapy, and surgical interventions.

This is a review of the evidence for strategies to prevent recurrent ischemic stroke in patients with evidence of atherosclerosis.
Study Highlights

Arterial hypertension, defined as systolic blood pressure of more than 140 mm Hg or diastolic blood pressure of more than 90 mm Hg, is the most important modifiable risk factor for stroke.
A 30% to 40% reduction in the risk for recurrent stroke can be achieved by reducing blood pressure.
Guidelines for the prevention of recurrent stroke suggest that a diuretic or combination of diuretic and angiotensin-converting enzyme inhibitor may be the most appropriate choice for initial antihypertensive therapy.
However, the optimal medical management strategy for hypertension after stroke has not been established.
Although hyperlipidemia is associated with an increased risk for primary stroke, its link to recurrent stroke is less clear.
Because hyperlipidemia is a strong predictor of myocardial infarction, a fasting lipid profile should be taken after ischemic stroke.
A target range of less than 70 to 100 mg/dL for low-density lipoprotein cholesterol levels and more than 50 mg/dL for high-density lipoprotein cholesterol levels is recommended to prevent recurrent stroke.
Lifestyle modifications and medications should be initiated in the hospital and maintained long term for patients with hyperlipidemia.
Atorvastatin has been shown to reduce the relative risk for recurrent stroke by 16% at 5 years of follow-up.
Updated American Heart Association and American Stoke Association guidelines recommend the use of statins for all patients after ischemic stroke or transient ischemic attack to prevent recurrence.
Statin therapy should not be withheld from patients with ischemic stroke.
In addition, for patients with low high-density lipoprotein cholesterol levels, ezetimibe, niacin, or gemfibrozil should be considered.
25% of patients with stroke also have diabetes mellitus, which increases the likelihood of recurrent stroke.
Patients with metabolic syndrome also have an increased risk for stroke.
The best choices for antihypertensive agents are angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with diabetes and recent ischemic stroke because of renal protection.
The recommended target low-density lipoprotein cholesterol level in patients with diabetes is less than 70 mg/dL.
Smoking cessation is an important strategy to prevent recurrent stroke.
The risk for stroke decreases to that found in a nonsmoker 5 years after smoking cessation.
Other risk factors to address include increasing fruit and vegetable intake, increasing potassium intake and reducing sodium intake, weight loss, regular exercise, and avoidance of heavy alcohol consumption.
Women should avoid postmenopausal hormone therapy, which is associated with an increased risk for ischemic stroke.
Current evidence supports the use of antiplatelet agents (not oral anticoagulants) in noncardioembolic stroke.
Aspirin monotherapy, aspirin plus extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy.
Aspirin in doses from 30 to 1300 mg/day has been shown to protect patients from secondary ischemic events and is commonly used because of its availability and known safety profile.
Carotid endarterectomy remains the preferred surgical intervention for symptomatic patients with severe stenosis of more than 50% at the origin of the internal carotid artery.
The decision for surgery is affected by neurologic status, concomitant disease, surgeon's skill, and arterial condition.
In general, the greatest benefit of surgery is seen in patients with 70% to 99% stenosis.
In summary, the authors recommend an integrated approach to prevention of recurrent stroke after ischemic stroke.

Pearls for Practice
Management of risk factors and the use of antiplatelet agents are recommended to prevent recurrent stroke after ischemic stroke.
Carotid endarterectomy is used to complement medical treatment and is most effective in patients with severe occlusion of the internal carotid artery