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Dual Antiplatelet Therapy After Acute Atherothrombotic Stroke
Study Questions:
Does aspirin plus clopidogrel, versus aspirin alone, reduce the risk of ischemic lesions on magnetic resonance imaging (MRI) within 30 days of acute ischemic stroke due to large artery atherosclerotic disease?
Methods:
COMPRESS was a multicenter, prospective, randomized, double-blind, placebo-controlled trial done at 20 Korean medical centers between January 2009 and April 2012. Patients with acute ischemic stroke due to large-vessel atherosclerotic disease within 48 hours were randomized to aspirin (300 mg loading dose followed by 100 mg daily) plus clopidogrel (75 mg daily) or aspirin monotherapy (300 mg loading dose followed by 100 mg daily) plus placebo for 30 days. All patients had a standard MRI prior to randomization and at 7 and 30 days to evaluate for ischemic lesions. The presence of large-vessel atherosclerotic disease intracranially was adjudicated by the treating physician and extracranial carotid stenosis needed to be >30% for enrollment. Patients with stroke due to nonlarge artery atherosclerotic disease as well as those with plans for surgical intervention (e.g., carotid endarterectomy) were excluded. The primary outcome was a new ischemic lesion (symptomatic or asymptomatic) on MRI within 30 days. Two investigators performed independent, blinded reviews of the MRIs. Safety outcomes were also monitored.
Results:
There were 358 patients randomized and 334 included in the primary analysis. Clinical and demographic factors were well balanced between the groups. The average National Institutes of Health stroke scale was 3, and most patients were randomized at about 32 hours after stroke onset. New ischemic lesions on MRI were seen in 36.5% of the dual antiplatelet group and 35.9% of the aspirin-only group (relative risk, 1.02; 95% confidence interval, 0.77-1.35). The majority of new ischemic lesions were asymptomatic (94.2%). There was no subgroup that seemed to benefit from dual antiplatelet therapy and there was no difference in post-stroke disability between the two groups. While not statistically significant, there were more bleeding events in the aspirin and clopidogrel group than the aspirin monotherapy group, including an increase in major or life-threatening bleeding (seven vs. two events).
Conclusions:
When compared with aspirin monotherapy, aspirin plus clopidogrel does not reduce the risk of developing new ischemic lesions on MRI in the 30 days after an ischemic stroke due to large artery atherosclerosis.
Perspective:
The combination of aspirin and clopidogrel for secondary prevention of ischemic events is frequently used in cardiac disease, but studies in stroke have shown an increase in bleeding risk without benefit in reducing ischemic events. The CHANCE study suggested that early, short-term use of dual antiplatelet treatment may be safe and reduce the risk of stroke recurrence. The generalizability of CHANCE has been questioned, so additional studies are needed to determine if dual antiplatelet therapy has a role in secondary stroke prevention.
The authors of this study evaluated patients with ischemic stroke due to large atherosclerosis, as these patients are at high risk of early stroke recurrence. Using MRI evidence of ischemic lesions as a surrogate endpoint for clinical stroke, they did not find a benefit for dual antiplatelet treatment when compared to aspirin alone. There were very few recurrent clinical ischemic strokes. While not statistically significant, the bleeding risk was increased in the dual antiplatelet therapy group.
This study differed from the CHANCE trial in that patients were enrolled later after their stroke onset (although still within 48 hours), and no loading dose of clopidogrel was administered. This may have led to less benefit in the dual antiplatelet group. The broad inclusion criteria surrounding large artery atherosclerotic disease makes the study more generalizable, but could have hampered the ability to find a difference between groups. Ongoing studies, such as the POINT trial, will help to define the role, if any, that aspirin plus clopidogrel has in secondary stroke prevention.
Keywords: Atherosclerosis, Aspirin, Platelet Aggregation Inhibitors, Carotid Stenosis, Endarterectomy, Carotid, Hemorrhage, Magnetic Resonance Imaging, Risk, Secondary Prevention, Stroke, Ticlopidine
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