Preventing recurrent ischemic stroke: A 3-step plan
To prevent recurrent stroke, address the patient’s risk factors, clear stenosis, and thin the blood
TABLE 2
Factors determining management of symptomatic carotid stenosis
| FAVORING MEDICAL THERAPY ALONE | FAVORING CEA |
|---|---|
| Stenosis <50% | Stenosis 70%–99%* |
| Stenosis 50%–69%, with qualification† | Age ≥75 years |
| String sign‡ | Hemispheric stroke |
| Last symptoms >3 years earlier | Last symptoms ≤2 weeks earlier |
| TMB only symptom | Contralateral occlusion |
| *Consider angioplasty with or without stenting in patients with symptomatic stenosis 70% to 99% who have failed medical management and are not candidates for CEA. | |
| † Arrange for serial imaging every 6 to 12 months, and consider CEA if stenosis increases to >70% | |
| ‡ String sign is an angiographic finding of severe carotid stenosis associated with distal collapse of the internal carotid artery in the neck. | |
| CEA, carotid endarterectomy; TMB, transient monocular blindness. | |
| Adapted from JL Saver with permission. January 14, 2004. | |
Intracranial stenosis
Patients found to have ischemic stroke secondary to intracranial large artery stenosis or occlusion present a difficult therapeutic problem. An attempt to bypass the blocked artery was studied in a large prospective randomized trial of extracranial to intracranial bypass surgery. While the study remains controversial to this day, it failed to show any benefit for surgery compared with best medical management.37 A study is now underway to examine whether patients selected for the procedure based on results of positron emission tomography will benefit.
Attempts to open stenotic and even occluded intracranial arteries have been reported in anecdotal series. However, the safety, efficacy, and durability of these procedures in this setting are speculative and should only be considered in exceptional circumstances.
Medical management of intracranial stenosis is also controversial. A retrospective study suggested that these patients may do better with anticoagulation compared with aspirin. However, a prospective randomized trial found that warfarin was no more effective than aspirin and increased risk.38
Applying the evidence. At this time, patients who have ischemic stroke due to large artery intracranial stenosis should be treated with best medical management including risk reduction and antithrombotic agents (see below). Bypass or angioplasty should be considered only if medical management fails.
Step 3: Thin the blood Anticoagulation
Warfarin is appropriate for primary stroke prevention in many patients with AF and for secondary prevention in most AF patients with a history of embolic events.10 For secondary prevention, warfarin is 68% better than placebo and significantly better than aspirin.7 Appropriate timing of warfarin therapy following ischemic stroke or TIA is controversial. Some trials indicate that the risk without acute anticoagulation is fairly low in the first 2 weeks following an initial stroke, and that the risk of recurrent stroke does not diminish with anticoagulation.
Anticoagulation for secondary stroke prevention in patients with noncardioembolic stroke is an issue still unsettled. The Stroke Prevention In Reversible Ischemia Trial (SPIRIT) compared anticoagulants—phenprocoumon, acenocoumarol, or warfarin—(international normalized ratio [INR]=3.0–4.5) with aspirin (30 mg daily) in the prevention of death from all vascular causes, nonfatal stroke, nonfatal MI, or nonfatal major bleeding complication.39 A high rate of major bleeding complications in the anticoagulation arm led to early termination of this study.39 The hazard ratio associated with the use of anticoagulants was 2.3 (95% confidence interval [CI], 1.6–3.5). Intracranial hemorrhage was the most frequently encountered bleeding complication.
The Warfarin-Aspirin Recurrent Stroke Study (WARSS) was conducted with 2206 patients who had suffered recent noncardioembolic ischemic strokes. 40 Dose-adjusted warfarin (INR=1.4–2.8) was compared with aspirin 325 mg daily.40 The primary end point of death or recurrent ischemic stroke occurred in 16.9% of patients.40 No significant differences in efficacy were found between warfarin and aspirin. Safety profiles were similar as well, although patients taking warfarin had significantly more minor hemorrhages than did those in the aspirin group.40 The Warfarin-Aspirin in Symptomatic Intracranial Disease trial compared dose-adjusted warfarin (INR=2–3) with aspirin 1300 mg/d in 569 patients with symptomatic intracranial stenosis. They recently reported a recurrent stroke rate of 11% to 12% for each treatment arm, with a somewhat higher rate of hemorrhage in the patients receiving warfarin.41
Applying the evidence. Given the absence of data favoring warfarin for secondary stroke prevention in most ischemic stroke settings apart from cardioembolic stroke, using antiplatelet agents as a first line therapy is reasonable. Based on subset analysis of data from the WARSS trial, prescribing warfarin for patients who have failed aspirin is not a reasonable choice for most patients.
Antiplatelet agents
Aspirin. Aspirin both inhibits and promotes thrombogenesis. In its antithrombotic activity, aspirin inactivates platelet cyclooxygenase irreversibly—which, in turn, inhibits formation of thromboxane A2, a potent stimulator of platelet activation and vasoconstriction. This irreversible inhibition lasts for the lifespan of the platelet (about 7 to 10 days). Aspirin’s prothrombotic action comes from blocking production of endothelial prostacyclin, a prostaglandin that causes vasodilation and deaggregation.
