Abstract & Commentary
Commentary by John J. Caronna, MD, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, and Associate Editor, Neurology Alert.
Synopsis: Clopidogrel and aspirin therapy is more effective than aspirin alone in reducing asymptotic MES in patients with recently symptomatic CS.
Source: Markus HS, et al. Dual Antiplatelet Therapy with Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated using Doppler Embolic Signal Detection. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial. Circulation. 2005; 111:2233-2240.
Clopidogrel is an ADP-receptor antagonist that has synergistic effects when given in addition to aspirin on platelet aggregation and thrombus formation in experimental animal models. In patients with unstable angina1 and after coronary stenting,2 combination therapy with clopidogrel and aspirin was more effective than aspirin alone. Evidence for the efficacy of dual antiplatelet therapy in stroke prevention is limited. In the clopidogrel vs aspirin in patients at risk of ischemic events (CAPRIE) trial,3 ischemic stroke patients receiving clopidogrel monotherapy showed a reduction in recurrent cardiovascular events compared with those on aspirin alone. Recent data from the MATCH trial,4 however, showed that combination antiplatelet therapy was no better than clopidogrel alone in long-term secondary prevention of ischemic stroke.
The CARESS trial evaluated the efficacy of dual antiplatelet therapy compared with aspirin alone on asymptomatic microembolic signals (MES) detected by transcranial Doppler ultrasound (TCD) in patients with recently symptomatic carotid stenosis (CS). Symptomatic CS patients are at high risk of early recurrent stroke. In this group, asymptomatic MES detected by TCD are markers of risks and can be found during a single hour’s TCD recording from the ipsilateral middle cerebral artery in up to 40% of symptomatic CS patients.
Patients were eligible for inclusion if they were over 18 years of age, had > 50% CS, and had experienced an ipsilateral carotid territory TIA, transient monocular blindness, or stroke within the last 3 months. Subjects were screened with TCD and, if MES were detected, they were randomized to dual antiplatelet therapy or aspirin monotherapy. MES were detected in 110 of 230 subjects at baseline, of whom 107 were randomized. TCD studies were repeated on days 2 and 7.
The qualifying event was TIA in 62% and stroke in 38%. Forty percent of patients experienced symptoms within the last week and 77% within the last month. Baseline rates of embolization were similar in the 2 groups, 9.5 ± 13.5 (mean ± SD) in the dual therapy group and 11.6 ± 17.8 in those receiving monotherapy. On day 2, there was no significant difference in MES-positive patients between the 2 groups. On day 7, however, 44% of dual-therapy patients were MES positive, compared with 73% of monotherapy patients. The relative risk reduction was 40%, P = 0.003. At days 2 and 7, MES frequency was significantly reduced by more than 60% in the dual therapy group. There were 4 recurrent strokes and 7 TIAs in the monotherapy group, and no strokes and 4 TIAs in the dual-therapy group. Markus and colleagues concluded that clopidogral and aspirin therapy is more effective than aspirin alone in reducing asymptotic MES in patients with recently symptomatic CS.
Commentary
Antiplatelet drugs alone, or in combination, are widely used for the secondary prevention of ischemic cardio- and cerebrovascular diseases. Cardiologists have favored the use of aspirin and clopidogrel in combination based on the results of trials in patients with unstable angina1 or coronary artery stents.2 Neurologists tend to use aspirin and dipyridamole together based on the positive results of the European Stroke Prevention Study 26, and have not used clopidogrel and aspirin in combination because of the negative results of the MATCH trial.4
The MATCH trial found no additional benefit of aspirin and clopidogrel over clopidogrel alone in the secondary prevention of stroke over an 18-month follow-up. All types of ischemic stroke were included, and an overrepresentation of patients with non-embolic, small-vessel disease, a group with a lower risk of early recurrent stroke, may have biased the results.
The CARESS results suggest that dual antiplatelet therapy is likely to be effective in patients with large-vessel atheroembolic stroke during the acute phase. Therefore, the combination of clopidogrel and aspirin warrants another look by means of a study of its efficacy for long-term stroke prevention. — John J. Caronna
References
1. Yusuf S, et al. N. Engl J Med. 2001;345:494-502.
2. Bertrand ME, et al. Circulation. 2000;102:624-629.
3. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
4. Diener HC, et al. Lancet. 2004;364:331-337.
Clopidogrel and aspirin therapy is more effective than aspirin alone in reducing asymptotic MES in patients with recently symptomatic CS.
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