Stroke Prevention

Principal Developer: R. Côté

Secondary Developers: M. David, G. Deveber, P. Massicotte, A. Roussin                                        

Background

Stroke constitutes a major medical problem representing one of the most common causes of mortality and disability.  Although strokes can be of an hemorrhagic nature, ischemic strokes are by far the most common ones accounting for approximately 85% of all strokes.

Epidemiology

Prevention of Ischemic Stroke

* If symptomatic carotid stenosis (≥70%) endarterectomy is indicated. Endarterectomy can also be considered in selected patient with ≥50% symptomatic carotid stenosis.

As mentioned previously carotid endarterectomy is beneficial in some patients,however angioplasty/stenting of the cervical/intracranial arteries is still considered investigational. Recent reviews (see references 1 and 2) have covered several aspects of stroke prevention in a more comprehensive fashion.The following focuses on the antithrombotic aspects.

• Acetylsalicylic Acid (ASA):  Drug most commonly used for stroke prevention, recommended dosage is between 50-325 mg/day. Side effects are mostly GI related including peptic ulcer disease.

• Clopidogrel:  Analog of ticlopidine but with better safety profile.  Comparable antiplatelet effect showing a modest advantage over ASA for prevention of ischemic events and no increased incidence of neutropenia compared to ASA.  The dosage is 75 mg once a day.  Clopidogrel is the drug of choice in cases where ASA is not tolerated or an allergy to ASA exists.

• Dipyridamole:  Dipyridamole in combination with low dose ASA has been shown to be effective for stroke prevention.  The combination of ASA 50mg/day and dipyridamole slow release 400mg/day has been shown to reduce the risk of stroke by approximately 16-23% compared to ASA. The most common side effect of dipyridamole is headache which leads a substantial number of patients to discontinue the drug.

• Ticlopidine:  Slightly superior to ASA for preventing stroke but less well tolerated. Dosage of ticlopidine,is 250  mg b.i.d.  Common side effects include diarrhea and rash.  Hematological complications include severe neutropenia in 0.8% of cases.  Close monitoring of neutrophil count is suggested every 2 weeks for first 3 months.  Increased incidence of thrombotic thrombocytopenic purpura has also been reported.

Comparison of antiplatelet agents

        The following is a semi-quantitative evaluation of antiplatelets for the prevention of stroke and other vascular events based on selected criteria and available evidence.

All of the above antiplatelet agents except for Ticlopidine,because of adverse reactions, are acceptable for initial therapy but because of its efficacy, safety and low cost, ASA is the one used in most circumstances for ischemic stroke prevention. However,recent evidence seems to confirm an advantage of the ASA/Dipyridamole combination over ASA .The combination of ASA and Clopidogrel cannot be recommended for long term stroke prevention both because of a lack of efficacy and increased risk of intracranial hemorrhage.

• Warfarin:   Oral anticoagulants have been shown to provide more benefit in certain conditions where the mechanism of ischemic stroke is presumed to be cardioembolic (atrial fibrillation, post MI) [See guidelines for these specific conditions] or in the case of cerebral sinovenous thrombosis.Recent evidence does not support it’s use over ASA for the prevention of recurrent stroke after a first noncardioemblic ischemic stroke or for patients presenting a symptomatic intracranial arterial stenosis.

Childhood stroke

The incidence of pediatric ischemic stroke is 3.3/1,000,000 children/year.  The ratio of arterial ischemic stroke to sinovenous thrombosis is approximately 4:1.  Neonates make up 25-30% of pediatric ischemic stroke patients and there is a slight male predominance.Residual neurological deficits are present in 20% of sinus thrombosis and 50% of arterial ischemic stroke survivors.

• Aspirin: For prevention of ischemic stroke, the recommended dosage is 3-5mg/kg/day.  Grouping the doses into every other day scheduling is feasible because of the prolonged effect of the medication on platelet function.  Reye’s syndrome has not been reported at this low dose.

• Warfarin: Arterial Ischemic Stroke:  Major uses of warfarin treatment in children with arterial ischemic stroke include congenital or acquired heart disease, severe hypercoagulable states, arterial dissection and recurrent stroke or transient ischemic attack while on aspirin.  Target International Normalized Ratio (INR) is 2.0-3.0.                                                                                                                   

• Sinovenous Thrombosis: Following acute anticoagulation, children with sinovenous thrombosis can be treated as is the practice in adults, a minimum of 3-6 months of warfarin.

References

1. Straus SE,Majumdar SR,McAlister FA New evidence for stroke prevention. JAMA 2002;288:1388-1395.
2. Hankey GJ Secondary prevention of recurrent stroke Stroke 2005;36:218-221.
3. Barnett HJM, w:st="on">Taylor DW, Eliasziw M, et al.  Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.  N Engl J Med 1998;339:1415-1425.
4. Atrial Fibrillation Investigators:  Atrial Fibrillation, Aspirin, Anticoagulation Study; Boston area Anticoagulation Trial for Atrial Fibrillation Study; Canadian Atrial Fibrillation Anticoagulation Study; Stroke Prevention in Atrial Fibrillation Study; Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Study.  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.  Arch Intern Med 1994;154:1449-1457.
5. Diener H,Bogousslavsky J,Brass LM et al. Aspirin and Clopidogrel compared with Clopidogrel alone after recent ischaemic stroke or transient ischemic attack in high risk patients (MATCH):randomized,double-blind,placebo-controlled trial. Lancet 2004;364:331-337.
6. Diener H, Cunha L, Forbes C, et al.  European stroke prevention study 2.  Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.  J Neuro Sci 1996; 143:1-13.
7. Antithrombotic Trialists’ Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for  prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ 2002;324:71-86.
8. CAPRIE Steering Committee.  A randomised, blind, trial of Clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).  Lancet 1996;348:1329-1339.
9. deVeber G.  Cerebrovascular Diseases.  Chapter in “Principles and Practice”.  3^rd ed. Editors:  K.F. Swaiman and S. Ashwal.  C V Mosby, Philadelphia PA.  1999.
10. Albers GW,Amarenco P,Easton JD et al.Antithrombotic and Thrombolytic Therapy  for Ischemic Stroke.Chest 2004 (Suppl);126:483S-512S.
11. Mohr JP,Thompson RM,Lazar B et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444-1451.
12. Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic Therapy in Children: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 645S-687S.  
13. The ESPRIT study group.Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial.Lancet 2006;367:1665-73.
14. Chimowitz M,Lynn MJ,Howlett-Smith H et al. Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis. N Engl J Med 2005;352:1305-16.