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Combination antiplatelet therapy for stroke patients at high risk of recurrence

Susan C. Fagan, Pharm.D., BCPS, FCCP
May, 2005

Study: Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB. 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.

Antiplatelet therapy is recommended for all patients with a history of noncardioembolic ischemic stroke and TIA to reduce the risk of recurrence (1). One of three regimens are recommended as first line and they include: aspirin 50 - 325 mg daily, clopidogrel 75 mg daily or extended release dipyridamole 200 mg + aspirin 25 mg twice daily (1). Although the combination of aspirin and clopidogrel has been shown to be more effective than aspirin alone in patients with recent acute coronary syndromes (2), the combination was not superior to clopidogrel alone in stroke patients, and significantly increased the risk of major bleeding in the long term (3).

In the CARESS study, the investigators enrolled only patients with recent TIA or minor stroke associated with carotid stenosis with evidence of ongoing microemboli formation (MES) on transcranial Doppler ultrasound (TCD). One hundred and seven (107) patients (about half of those screened) were randomized to either clopidogrel and aspirin or aspirin monotherapy. The primary endpoint was the presence or absence of MES on day 7 of therapy. The combination treatment reduced the risk of MES by 40% (p=0.0046) compared to aspirin alone (43.8% vs. 72.7%) and there were more ischemic events in the monotherapy group (12 vs. 5; NS). Although not powered to detect differences in recurrence, the 17 patients experiencing recurrent events had a three fold higher increased MES frequency than those patients who did not (24 vs. 8 per hour; p=0.0003).

After the results of the MATCH study (3), in which the combination of clopidogrel and aspirin caused increased bleeding but no increased efficacy, we wondered whether there was a patient group that may still benefit from this approach. The results of CARESS suggest that, short-term combination therapy may be warranted in patients with symptomatic carotid stenosis since they are at high risk of early recurrence. Although MES may be a surrogate endpoint for such studies, only the results of randomized clinical trials will definitively determine which patients and for what duration this combination therapy should be used.


  1. Albers GW, Amerenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001; 119:300S - 320S.

  2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.

  3. Diener H-C, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht H-J, on behalf of the MATCH investigators. Aspirin and clopidogral 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.
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