Therapeutic Interventions for Prevention of Recurrent Ischemic Stroke

Volume 14: S212-S226 June 2008 Number 7 Suppl

Therapeutic Interventions for Prevention of Recurrent Ischemic Stroke

Howard S. Kirshner, MD

Patients who suffer ischemic stroke or transient ischemic attack (TIA) are at increased risk for subsequent cerebrovascular events. Secondary prevention is essential to reduce risks of recurrence and should include lifestyle modification to improve cardiovascular health, along with strict control of blood pressure, glucose, and lipids. Recurrent stroke in ischemic stroke patients is likely to be the same subtype as the initial stroke, and treatment should be unique to the stroke subtype and patient risk factors.

This article presents an overview of the recommendations for the secondary prevention of ischemic stroke or TIA and a review of the evidence supporting the role of antiplatelet therapy in managing the risk of recurrent noncardioembolic stroke. Although anticoagulants are recommended preventive treatment for cardioembolic stroke, they can increase the patient’s risk of bleeding complications and are not recommended for all subtypes of ischemic stroke. The American Heart Association/ American Stroke Association guidelines recommend 3 antiplatelet regimens for the secondary prevention of noncardioembolic ischemic stroke: aspirin (ASA), clopidogrel, and combined ASA + extended-release (ER) dipyridamole (DP). ASA + ER-DP is recommended over ASA alone.

Several studies have established the effectiveness of these 3 antiplatelet regimens as first-line options in the secondary prevention of noncardioembolic ischemic stroke. Clopidogrel monotherapy is a reasonable alternative for patients who cannot tolerate ASA. ASA + ER-DP has been shown to be more effective than ASA alone and does not increase the risk of bleeding. Effective secondary prevention must also address modifiable risk factors, such as obesity, smoking, and excessive alcohol consumption.

(Am J Manag Care. 2008;14:S212-S226)

Introduction

Secondary Prevention of Noncardioembolic Ischemic Stroke

Ischemic Stroke: Acute Management and Secondary Prevention

Participating Faculty

Overview of Platelet Glycoprotein IIb/IIIa Receptor Antagonist Treatment in the Management of Coronary Interventions and Acute Ischemic Coronary Syndromes

Patients who experience a stroke or transient ischemic attack (TIA) face an increased risk of having another stroke1-3 or other vascular event.^3,4 Approximately one quarter of the 780,000 strokes that occur in the United States each year are recurrent.^2,5 Therefore, a principal goal in managing stroke or TIA patients is to prevent another cerebrovascular event. Recommended management for the secondary prevention of stroke includes addressing modifiable risk factors, initiating long-term antithrombotic therapy, and intervening surgically, when indicated.¹

Considerations for Secondary Prevention of Vascular Events
General Considerations
When considering the secondary prevention of vascular events, it is critical to recognize that ischemic events tend to recur in the same vascular beds; 75% to 79% of vascular events after a stroke are strokes,^5,6 and 76% to 84% of events after myocardial infarction (MI) are MI.⁵ Thus, primary poststroke prevention efforts should be geared toward preventing a recurrent stroke.⁵ Antithrombotic therapies should be selected according to their demonstrated efficacy in secondary stroke prevention, rather than myocardial protection.⁵

Stroke and TIA patients also bear an increased risk of suffering ischemic events in other vascular beds (eg, MI, ischemic limb),^3,4 and their risk of cardiovascular events should not be discounted. In poststroke years 1 through 10, the most common cause of death for stroke patients is cardiovascular disease (CVD).^3,7-10In a recent study on secondary prevention of stroke in patients without known coronary heart disease (CHD), major coronary events exceeded recurrent strokes.¹¹ This suggests that many stroke patients have unrecognized CHD.¹²Although the primary concern when treating stroke patients should be preventing recurrent stroke, treatment plans should also consider the prevention of coronary events, especially for stroke patients who have a history of MI or peripheral arterial disease (PAD).

Cerebral vasculature appears to differ from that in other vascular beds, and stroke pathogenesis likely differs from the pathogenesis of CHD or PAD.⁵For example, the association between stroke and dyslipidemia is not as well established as dyslipidemia’s association with CHD.^1,13Stroke patients constitute a unique vascular disease population⁵; they may therefore require different preventive treatments than CHD or PAD patients. For example, certain antithrombotic agents are more likely to cause bleeding in stroke patients than in MI or PAD patients.⁵The administration of warfarin at an anticoagulation intensity well tolerated by patients with CHD has been known to cause severe bleeding in stroke patients.⁵ The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction) trial found that patients with a history of stroke or TIA were more prone to episodes of major bleeding.¹⁴ The choice of an antithrombotic therapy, therefore, should consider any adverse event risks specific to stroke patients.

Additional Considerations Unique to Ischemic Stroke Patients
If a patient’s initial stroke is ischemic, another level of complexity is added to treatment decisions. Ischemic stroke comprises several pathogenic subtypes. The main etiologic subtypes are large vessel disease (LVD), small vessel disease (SVD, also called lacunar), cardioembolic, other known cause (eg, hypercoagulable state, arterial dissection), and cryptogenic (unknown cause).¹ Some risk factors vary according to ischemic stroke subtype. Risk factors more commonly associated with SVD are smoking,^15-17diabetes,^15,18an elevated white blood cell count,¹⁵ and possibly hypertension (evidence of this is not conclusive).¹⁹ Strong risk factors for LVD include smoking,^16,17,20,21 abdominal obesity,^15,22dyslipidemia,^20,21,23,24infection/inflammation,^25,26 and hyperhomocysteinemia.²⁷ Infection/inflammation^25,26and von Willebrand factor¹⁵ are strong risk factors for cardioembolic stroke.^25,26Effective secondary prevention depends heavily on addressing modifiable risk factors.

Ischemic stroke subtypes differ in severity and cause varying degrees of impairment; for example, SVD is associated with a lower 5-year mortality rate and better functional outcomes,²⁸ whereas cardioembolic stroke has the highest 5-year mortality rate (>80%).²⁸ The risk of stroke recurrence also varies according to ischemic stroke subtype. SVD is associated with a lower 30-day risk of recurrence, and LVD stroke conveys the highest 30-day risk of recurrence. ²⁸ Approximately 60% to 70% of first recurrent strokes are the same subtype as the initial stroke.^28,29

The stroke-patient population is heterogeneous, and treatment strategies may need to be uniquely tailored not only to the ischemic stroke subtype but also to the patient. Some LVD stroke patients with severe carotid artery stenosis, extracranial vertebral artery stenosis, or hemodynamically significant intracranial stenosis will benefit from surgical or endovascular interventions.¹Anticoagulant agents are recommended for cardioembolic stroke patients with a high-risk source of embolism, whereas antiplatelet agents are preferred for other stroke subtypes.¹ Treatment decisions should always consider the subtype of the initial ischemic stroke, and they should be individualized with regard to the patient’s modifiable risk factors.

AHA/American Stroke Association Guidelines for Secondary Prevention of Stroke
Together, the American Heart Association (AHA) and American Stroke Association have established evidence-based guidelines for preventing stroke in patients who have a history of ischemic stroke or TIA.^1,12 A brief summary of these guidelines follows.

Recommendations Regarding Modifiable Risk Factors
Smoking.¹ Clinicians should urge ischemic stroke/TIA patients not to smoke and to avoid environmental smoke; counseling, nicotine products, and medications can help facilitate cessation.

Alcohol.¹ Light to moderate levels (≤2 alcoholic drinks/day for men and 1 drink/day for women) may be permitted, but heavier drinking should be discouraged.

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