Antiplatelet therapy to prevent recurrent stroke: Three good options
ABSTRACTDrugs that prevent platelets from sticking together—ie, aspirin, dipyridamole, and clopidogrel—are an important part of therapy to prevent recurrence of ischemic stroke of atherosclerotic origin. We discuss current indications for these drugs and review the evidence behind our current use of aspirin, dipyridamole, and clopidogrel.
KEY POINTS
- After a stroke, antiplatelet therapy lowers the rate of recurrent nonfatal stroke by about 25%.
- Aspirin is the most established, best tolerated, and least expensive of the three approved drugs.
- Adding dipyridamole to aspirin increases the efficacy, with a 22% reduction in relative risk, but only a 1% reduction in absolute risk.
- Clopidogrel is similar in efficacy to aspirin and to dipyridamole.
- All three agents are regarded as equal and appropriate for secondary prevention of stroke; the choice is based on individual patient characteristics.
- A small number of strokes result from atherosclerotic disease of the common carotid bifurcation, and patients with symptomatic carotid disease can be treated with the combination of surgery or stenting and drug therapy, or with drug therapy alone.
After a stroke, an important goal is to prevent another one.1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.
In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.
(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)
HOW WE REVIEWED THE LITERATURE
We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.
As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.
For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.
ASPIRIN: THE GOLD STANDARD
Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,5 are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.
Fields et al,6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.
The Danish Cooperative study8 (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.
AICLA.9 The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.
The Swedish Cooperative Study10 (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.
Later studies began to show a consistently favorable effect of aspirin.
Boysen et al11 in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.
UK-TIA.12 The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.
SALT.13 The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.
ESPS-2.14 The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” 14
Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.
ATT.15 The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.
