Management of Ischemic Stroke in Geriatric Patients

Transcription

1 in Geriatric Patients Charles T. Taylor, PharmD, BCPS, Pamela Stamm, PharmD, Kelly H. Taylor, PharmD, and Kristi Kelley, PharmD INTRODUCTION Stroke is a major cause of death and disability among the elderly, typically defined as individuals over the age of 65. More than 750,000 Americans experience strokes annually, and 160,000 of these do not survive. Of the survivors, approximately one-third experience another stroke within five years. Evidence is emerging that the morbidity associated with stroke might be lower. Approximately 70% of strokes are associated with uncontrolled hypertension. Therefore, optimization of medication and formation of stroke teams might improve care and minimize disability. This article describes current evidence-based approaches for the treatment of acute ischemic stroke and secondary prevention in geriatric patients. 1,2 PATHOPHYSIOLOGY OF CEREBROVASCULAR DISEASE Charles T. Taylor, PharmD Strokes are typically classified as hemorrhagic or ischemic events, with ischemia accounting for approximately 85% of all strokes. 2 Transient ischemic attacks (TIAs), although referred to as mini-strokes, are not strokes but are considered cerebrovascular risk factors. Most ischemic strokes result from atherosclerotic plaque rupture, causing a thrombus or embolism. 3 Nearly 20% of strokes are associated with cardiogenic embolism resulting from atrial fibrillation. Other possible etiologic mechanisms include arterial dissection, profound anemia, blood hyperviscosity, venous occlusion, and temporal arteritis. Patients with a greater degree of carotid stenosis are more likely to experience ischemic symptoms. 2,4,5 Clots involved in ischemic strokes are of arterial origin and are composed mostly of fibrin. Typically, these clots are formed in response to tissue injury, resulting in the release of adenosine diphosphate (ADP), epinephrine, thrombin, and thromboxane A 2, promoting significant platelet aggregation. Platelets adhere to subendothelial matrix proteins (SEMs), activate the glycoprotein IIb/IIIa complex, and bind fibrinogen. 6 Fibrinogen binds additional platelets, producing an irreversible thrombus. Ischemia may develop as a result of enlargement of an existing thrombus or release of an embolus, thus compromising blood flow of smaller vessels. Dr. Charles T. Taylor is Associate Professor and Vice Chair in the Department of Pharmacy Practice, Harrison School of Pharmacy at Auburn University in Auburn, Alabama. Dr. Stamm is Assistant Professor, Dr. Kelly H. Taylor is Clinical Assistant Professor, and Dr. Kelley is Clinical Assistant Professor, all in the Department of Pharmacy Practice, Harrison School of Pharmacy at Auburn University. PATIENT RISK ASSESSMENT Age, sex, race, and family history are nonmodifiable risk factors for cerebrovascular events. Therefore, older patients (i.e., 65 years and above) are at higher risk for stroke-associated mortality and morbidity. Other factors associated with increased risk of stroke include hypertension, blood pressure differences in each arm, heart disease, carotid bruits, diabetes, dyslipidemia, elevated fibrinogen levels, migraine headaches, sickle cell disease, retinal emboli, and TIAs. The 10-year stroke risk relative to the average risk for a given age and sex can be assessed by means of Framingham data. This estimation of risk is limited to assessment based on sex, age, systolic blood pressure, antihypertensive treatment, cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy. Furthermore, it is unclear how accurately these predictors estimate the risk of cerebrovascular events in patients of advanced age. 7 9 CLINICAL PRESENTATION AND DIAGNOSIS Individuals may experience signs of cerebral ischemia as brief, intermittent events known as TIAs. There is a 4% to 8% risk of an ischemic stroke in each year following the initial TIA. 2 Stroke symptoms (Table 1), including aphasia, ataxia, blindness, confusion, and paralysis, vary according to the location of diminished cerebral blood flow. 2 Confirmative diagnosis requires imaging technology such as computed tomography (CT scan) to exclude hemorrhagic strokes. The evaluation of stroke in geriatric patients is challenging. For example, symptoms Table 1 Stroke Symptoms Sudden onset of any of the following: Confusion Dysphagia Difficulty understanding what others are saying Vision changes in one or both eyes Difficulty walking, dizziness, loss of balance or coordination Numbness, tingling, or weakness of the face, arm, or leg, particularly unilateral involvement Severe headache with no known cause or the worst headache the patient has ever experienced Decreased consciousness caused by fainting, confusion, convulsions, or coma Nausea with or without vomiting Brief loss of consciousness Fever Data from Welty TE. In Koda-Kimble MA et al, eds. Applied Therapeutics: The Clinical Use of Drugs, 7 th ed. Philadelphia, Lippincott Williams & Wilkins, 2001; 2 and Albers GW, et al. Chest 2001;119:300S 320S. 4 Vol. 27 No. 10 October 2002 P&T 495

2 Anticoagulation Therapy Immediately following an acute ischemic stroke, up to 5% of early deaths may be associated with deep venous thrombosis (DVT) or pulmonary embolism (PE). 4 In addition, the NINDS Stroke Data Bank estimated that 30% of neurological worsening of stroke patients during hospitalization occurs in those with atherosclerotic etiologic factors. Therefore, theoretical advantages for anticoagulation therapy have been proposed following ischemic strokes, but its general use should be initiated cautiously. Clinical trials evaluating anticoagulation for acute ischemic stroke did not result in significant improvement in primary outcomes, reduced mortality, or prevention of recurrent stroke and revealed a modest but significantly increased risk of hemorrhage. 15 Trials have assessed the adjunctive use of heparin and lowmolecular-weight heparin for 7 to 14 days following a stroke (Table 3) Safety and efficacy parameters consisted of stroke recurrence and rates of ICH between groups. The rates of recurrent stroke during emergent anticoagulation varied dramatically among studies. The rate of stroke recurrence was equal (1.1%) between treatment and control groups in the Trial of Org10172 in Acute Stroke Treatment (TOAST), although higher rates were observed in treated patients during the Heparin in Acute Embolic Stroke Trial (HAEST) (8.5% vs. 7.5%) and the Tinsuch as confusion may be difficult to evaluate in individuals with dementia or in patients who cannot communicate with health care providers. In addition, symptoms such as muscle weakness and gait changes may be attributed to advanced age instead of cerebrovascular ischemia. THERAPEUTIC CONSIDERATIONS The primary goal in patients during an acute stroke is immediate reperfusion of ischemic areas. Once patients are stabilized, long-range goals become the prevention of reocclusion and risk reduction of future cerebrovascular episodes. Individuals with multiple risk factors should be advised to consider lifestyle modifications and optimization of treatment for diabetes, hypertension, and dyslipidemia to reduce the risk of strokes. Thrombolytic Therapy For patients who experience symptoms consistent with a cerebrovascular event, time is of the essence. Thrombolytics have emerged as an option for acute treatment when they are administered within three to six hours of symptom onset. Their value beyond six hours is unknown. The goal is timely restoration of cerebral perfusion to limit irreversible brain injury. The agent most widely studied (Table 2) for acute treatment is recombinant tissue plasminogen activator (tpa); however, its routine use remains controversial. Optimal administration demands the implementation of institutional protocols and criteria for patient selection to foster appropriate use. Streptokinase has been studied in three trials but is not currently recommended for treatment because of an association with increased mortality and disability. 4 The National Institute of Neurological Disorders and Stroke (NINDS) tpa Stroke Study was the first trial to demonstrate that patients given 0.9 mg/kg tpa within three hours of stroke onset had a 30% higher probability of recovery with few or no deficits at three months. Benefits observed were independent of age, stroke subtype, stroke severity, or previous aspirin use. Results indicated that for every 25 patients treated with tpa, one life would be saved at three months after a stroke. However, patients with severe initial neurological deficits or signs of brain edema were at higher risk for intracranial hemorrhage (ICH). Overall, 6.4% of patients in the tpa group developed ICH in contrast to 0.6% in the placebo group. Therefore, for every 17 patients Table 2 Use of Thrombolytic Agents in Acute Ischemic Stroke Significant Bleeding Mortality Rates Study tpa Placebo tpa Placebo NINDS 6.4% 0.6% 17.0% 20.6% ECASS 19.8% 6.5% 22.0% 15.6% ECASS II 8.8% 3.4% 10.5% 10.7% ATLANTIS-B 7.0% 1.1% 11.0% 6.9% ATLANTIS = Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; ECASS = European Cooperative Acute Stroke Study; NINDS = National Institute of Neurological Disorders and Stroke; tpa = tissue-plasminogen activator. Data from Ringleb PA, et al. Stroke 2002;33: treated with tpa, one patient would go on to experience a significant hemorrhage. 10 The European Cooperative Acute Stroke Study (ECASS) evaluated tpa at a higher dose (1.1 mg/kg) in patients whose stroke onset was within six hours. No statistical difference in efficacy was found between treatment and control groups; however, more patients in the tpa group developed parenchymal hemorrhages. In the ECASS II trial, patients with mild strokes presenting within six hours of symptoms received tpa 0.9 mg/kg. No statistical differences occurred in death rates or clinical improvement. The results illustrated that 500 patients would need to be treated with tpa to prevent one stroke-related death. Of these 500 patients, approximately 26 would develop significant hemorrhages. 11,12 Most recently, the Alteplase Thrombolytic for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS-B) study evaluated tpa 0.9 mg/kg in patients with stroke onset within three to five hours. However, the study was stopped early because patients who received tpa experienced increased hemorrhage and mortality rates compared with placebo-treated patients. 13 Meta-analyses indicated that tpa significantly reduced mortality rates from 71.6% to 57.7% in patients treated within three hours of symptom onset. This translated to one additional life saved for every seven patients treated with tpa. 4 When the treatment window was extended to six hours, the number needed to treat to prevent one death increased to 25 individuals. 14 Alternatively, the risk of death from ICH in the first 10 days following thrombolytic treatment increased dramatically. Rates of significant bleeding reported in clinical studies ranged from 6.5% to 19.8%. Therefore, strict adherence to treatment protocols and patient selection criteria are strongly recommended to achieve a favorable risk benefit profile. In addition, patients should not be excluded from treatment simply because of advanced age (i.e., 65 years and older). 4 These studies documented treatment advantages in patient populations whose average age ranged from 65 to 68 years. 496 P&T October 2002 Vol. 27 No. 4

3 zaparin in Acute Ischemic Stroke Trial (TAIST) (4.7% vs. 3.1%). In studies showing reduced stroke rates with anticoagulation therapy, between 36 and 166 patients needed to receive anticoagulation to prevent one stroke recurrence. Anticoagulants appear to reduce the risk of DVT and PE. In an analysis of 10 trials evaluating anticoagulation therapy in acute stroke, the incidence of DVT and PE was reduced by 80% and 58%, respectively. 19 In the five studies evaluating mortality rates, only one demonstrated mortality benefits over the control group. The FISS trial demonstrated that one life could be saved for every 45 individuals treated with emergent anticoagulation. 15 Besides the FISS trial, which noted no episodes of serious ICH, the remaining studies that evaluated anticoagulation showed rates of ICH ranging from 0.6% to 3.7% for low-dose administration. 15 These results indicate that for every 50 to 250 individuals receiving adjunctive anticoagulation therapy for acute stroke, approximately one individual would experience a significant ICH. These studies were conducted in patients with mean ages ranging from 63 to 80 years; however, age-specific differences were not identified. Oral anticoagulation with warfarin has not demonstrated benefit in large trials during acute management of ischemic stroke. Generally, warfarin is not a first-line treatment for secondary prevention because of the availability of safer alternative agents with similar efficacy profiles and fewer complications. The exception would be the patient with atrial fibrillation, the most common cause of cardiac embolism. Usually, oral anticoagulant therapy is the treatment of choice for secondary prevention of cardioembolic stroke and for patients with strokes of atherosclerotic origin but with contraindications to antiplatelet therapies. 4 However, clinicians may be hesitant to use warfarin in elderly patients with atrial fibrillation despite specific practice guidelines recommending use in patients older than 75 years of age. This reluctance is often related to the perceived risk of bleeding complications associated with falls or excessive anticoagulation. Also, warfarin should be initiated at anticipated maintenance doses instead of at loading doses in order to reduce the risk of significant bleeding complications. Most recently, the Warfarin-Aspirin Recurrent Stroke Study (WARSS) compared the effects of anticoagulation and aspirin in patients with a history of noncardioembolic stroke for secondary prevention. No statistical differences were noted in the prevention of recurrent stroke, death, or ICH; compared with warfarin, however, aspirin was associated with fewer side effects and a reduced risk of bleeding. 20 Antiplatelet Therapy Because most cerebral clots are composed of fibrin and platelet aggregates, antiplatelet therapy plays a vital role in the treatment and secondary prevention of stroke. Aspirin should be initiated within 48 hours of stroke symptoms in patients with acute ischemic stroke who are not candidates for thrombolytic or anticoagulation therapy. This recommendation is based partly on the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST), which collectively enrolled more than 40,000 geriatric patients and determined that nine deaths or recurrences of nonfatal stroke would be prevented for every 1,000 acute stroke patients treated with aspirin. 16,21 Currently, four antiplatelet choices have been evaluated for secondary prevention of noncardioembolic stroke and TIA: aspirin ticlopidine (Ticlid, Hoffman LaRoche, Inc.) clopidogrel (Plavix, Sanofi-Synthelabo, Inc.) dipyridamole plus aspirin (Aggrenox, Boehringer-Ingelheim) However, no studies have directly compared the safety and efficacy of all aspirin alternatives. Because the mechanisms of action are different among agents, one agent might offer benefit when the initial choice for therapy fails to prevent stroke. Aspirin is a first-line therapy based on its efficacy, safety, and cost. 4 Table 3 Use of Anticoagulants in Acute Ischemic Stroke Stroke Intracranial Study Medication Recurrence Hemorrhage Mortality FISS Nadroparin (Fraxiparine, 1.9% 0%* 16.8% Sanofi-Synthelabo SA France) IST Heparin sodium 1.6% 0.7% 22.0% TOAST Danaparoid (Orgaran, Organon) 1.1% 2.9% 6.6% HAEST Dalterparin (Fragmin, 8.5% 2.7% 17.9% Pharmacia & Upjohn) TOPAS Certoparin (not available in U.S.) 2.9% 2.0% nr** TAIST Tinzaparin (Innohep, DuPont Pharma) 4.7% 0.6% 11.8% * The follow-up FISS-bis study reported intracranial hemorrhage at a rate of 3.7%. ** nr = not reported. FISS = low-molecular-weight heparins; IST = International Stroke Trial; TOAST = Trial of Org10172 in Acute Stroke Treatment; HAEST = Heparin in Acute Embolic Stroke Trial; TOPAS = Therapy of Patients with Acute Stroke; TASIT = Tinzaparin in Acute Ischemic Stroke. Data from Adams HP. Stroke 2002;33: Aspirin Aspirin is the most widely used agent for the prevention of secondary stroke. The Antiplatelet Trialists studied the effect of antiplatelet agents in more than 73,000 elderly patients with stroke and TIAs, unstable angina, and myocardial infarction as well as patients at high risk for other events of atherosclerotic origin. 22 Antiplatelet agents, as a whole, reduced the odds of nonfatal stroke in high-risk patients by approximately 30%. Patients with a prior history of stroke and who received antiplatelet therapy experienced a 22% lower incidence of recurrent stroke or TIA. Specifically, aspirin reduced the combined risk of stroke, myocardial infarction, or vascular death by 25%. 22 Although the most effective dose of aspirin in preventing stroke remains controversial, dose comparison studies (the Dutch TIA Trial, the European Stroke and Prevention Study [ESPS II]) suggest that high doses (1,300 mg/day) do not provide additional benefit over Vol. 27 No. 10 October 2002 P&T 497

4 Table 4 Guidelines for Treatment of Acute Ischemic Stroke 3 Hours of Symptom Onset 3 to 6 Hours of Symptom Onset Thrombolytic Ineligibility Administer tpa 0.9 mg/kg; max Administer tpa only in selected patients Avoid full dose anticoagulation dose, 90 mg with 10% as initial bolus (occlusion of middle cerebral artery) in unselected patients then remainder over 1 hour Maintain blood pressure below tpa not generally recommended Aspirin mg within 180/105 mm Hg if time of symptom onset is unknown 48 hours of stroke onset or has been greater than 3 hours Avoid antithrombotic agents for Low-dose subcutaneous heparin 24 hours following thrombolytic or low-molecular-weight heparin administration for prophylaxis of deep vein thrombosis Data from Albers GW, et al. Chest 2001;119:300S 320S. tpa = tissue plasminogen activator. Early anticoagulation is warranted for patients with acute cardioembolic stroke lower doses (50 to 325 mg/day) for secondary prevention. At low doses, aspirin inhibits the formation of thromboxane A 2, consequently inhibiting platelet aggregation. The Food and Drug Administration (FDA) currently recommends aspirin (50 to 325 mg daily) for stroke prevention. 4 The most common adverse effects observed with aspirin are gastrointestinal ulcerations and bleeding. Patients with stroke events who are receiving aspirin therapy have no evidencebased antiplatelet alternative. Various approaches have been used in clinical practice, such as changing to an alternative antiplatelet agent, adding a different antiplatelet agent to an aspirin regimen, and switching to anticoagulation therapy. Ticlopidine Ticlopidine hydrochloride, a thienopyridine, was developed as an alternative antiplatelet in aspirin-intolerant patients experiencing TIAs or strokes. The Ticlopidine Aspirin Stroke Study (TASS), which compared ticlopidine (250 mg twice daily) to aspirin (650 mg twice daily), reported a significant risk reduction for stroke (21%) over aspirin-treated patients. 4,23 Even though ticlopidine was more effective than aspirin, it is less commonly used because of its severe hematological side effects, including neutropenia, thrombocytopenia, and thrombotic thrombocytopenia purpura (TTP). 4 Clopidogrel Ticlopidine has largely been replaced with the thienopyridine derivative clopidogrel. Clopidogrel inhibits platelet aggregation by modifying the platelet ADP receptor to prevent binding of the platelet to its receptor. As a result, the glycoprotein IIb/IIIa complex is inactivated. The CAPRIE Trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) compared clopidogrel (75 mg daily) and aspirin (325 mg daily) in reducing the risk of ischemic stroke, myocardial infarction, or vascular death in more than 19,000 patients (more than 6,000 with a stroke history). 24 Clopidogrel was more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death (annual risk, 5.3% and 5.8%, respectively). Clopidogrel is the agent of choice for patients who cannot tolerate aspirin or in whom it is contraindicated, and it may be more effective than aspirin in patients after coronary surgery. 25 The overall side effect profile is similar to that of aspirin. Dipyridamole Dipyridamole as a single agent is no more effective than aspirin (50 mg/day) for the prevention of ischemic stroke. In the ESPS II trial, however, aspirin (25 mg twice daily) was compared to placebo, extended-release dipyridamole (200 mg twice daily), and the combination of extended-release dipyridamole plus aspirin (200 mg/25 mg twice daily) in more than 6,600 patients with a history of stroke or TIA for a follow-up of 2 years. 26 Combination therapy demonstrated an additive risk reduction for stroke recurrence over the individual antiplatelet agents (18%, 16%, and 37%, respectively). 4,25 In the ESPS II trial, there was a 23% reduction for combination therapy, compared with aspirin alone, for fatal and nonfatal stroke. 26 Treatment Guidelines Table 4 summarizes the recommendations of the Sixth American College of Chest Physicians Conference on Antithrombotic Therapy for the treatment of ischemic stroke. The emphasis of treatment depends on the time frame in which patients present to health care providers with symptoms. The guidelines recommend strict adherence to inclusion and exclusion criteria as well as supervision by a physician with expertise in stroke management and in CT scan interpretation. Table 5 summarizes recommendations for preventing stroke. In addition, several other well-documented, modifiable risk factors should be considered as ways to lower the risk for recurrent stroke. Interventions should be taken to control hypertension, encourage smoking cessation, ensure tight glycemic control in diabetes, achieve target low-density-lipoprotein concentrations, and provide warfarin for patients with atrial fibrillation. Patients should be encouraged to eat nutritious diets consisting of at least five servings of fruits and vegetables daily, to consume alcohol in moderation (no more than two drinks per day in men and one drink per day in nonpregnant women), and to incorporate approximately 30 minutes of moderate-intensity exercise three to four times weekly. 23,27, P&T October 2002 Vol. 27 No. 4

5 Table 5 Recommendations for Prevention of Ischemic Stroke Antiplatelet/Anticoagulation Initial preventive treatment for noncardioembolic strokes - Aspirin mg daily - Aspirin + extended-release dipyridamole 25/200 mg b.i.d. - Clopidogrel 75 mg daily Initial preventive treatment for cardioembolic strokes - Warfarin (goal INR ) in patients with atrial fibrillation Optimize Disease State Management Hypertension Diabetes Hyperlipidemia Sickle cell disease Lifestyle Modifications Smoking cessation Weight reduction in overweight patients Regular exercise Healthy diet Alcohol moderation Recommended daily amounts of folic acid and vitamins B 6 and B 12 Adapted from Weinberger J. Curr Cardiol Rep 2002;4: ; 23 Pearson TA, et al. Circulation 2002;106: ; 27 and Goldstein LB, et al. Circulation 2001;103: INR = International Normalized Ratio. CONCLUSION Geriatric patients are at increased risk of cerebrovascular disease and should be closely evaluated for interventions to lower their relative risk for future events. Immediate treatment of stroke is essential to limiting disability; lifestyle modifications and disease management should be included in the secondary prevention of cerebrovascular events. REFERENCES 1. National Stroke Association Home Page. National Stroke Association. August 1, Available at: 2. Welty TE. Cerebrovascular disorders. In: Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ, eds. Applied Therapeutics: The Clinical Use of Drugs, 7 th ed. Philadelphia: Lippincott Williams & Wilkins, 2001: Gorelick PB. Stroke prevention therapy beyond antithrombotics: Unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: An invited review. Stroke 2002;33: Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. 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Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308: Weinberger J. Prevention of ischemic stroke. Curr Cardiol Rep 2002;4: CAPRIE Steering Committee. A randomized, blinded, trial of Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CA- PRIE). Lancet 1996; 348: European Stroke Initiative recommendations for stroke management. European Stroke Council, European Neurological Society and European Federation of Neurological Societies. Cerebrovasc Dis 2000;10: Diener HC, Cunha L, Forbes C, et al. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke: European Stroke Prevention Study 2: J Neurol Sci 1996;143: Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 Update. Circulation 2002;106: Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001;103: Vol. 27 No. 10 October 2002 P&T 499