Clopidogrel and its use in stroke patients.

Clopidogrel and Its Use in Stroke Patients To the Editor: Substantial clinical data support the use of antiplatelet therapy in reducing the incidence of secondary atherothrombotic events in individuals who have experienced a transient ischemic attack (TIA) or stroke.1 The consensus based on recent trials is that antiplatelet therapy can reduce the incidence of subsequent ischemic events in those patients for whom carotid endarterectomy is not indicated and for whom atrial fibrillation is not a contributing factor.2 Aspirin has been the antiplatelet drug most frequently evaluated, and numerous trials support its efficacy. Ticlopidine, a thienopyridine antiplatelet agent, is also effective in preventing recurrent ischemic events in the stroke patient,3 but the risk of bone marrow depression and questions about its superiority to aspirin in reducing ischemic vascular events other than subsequent stroke have been raised.4–6 Recently clopidogrel, an analog of ticlopidine that has not demonstrated bone marrow toxicity, was approved by the Food and Drug Administration for use in patients at risk of recurrent ischemic events, including stroke, myocardial infarction, and limb claudication. The clinical data supporting the use of clopidogrel, however, may provide no compelling justification for using clopidogrel in preference to aspirin in stroke patients. Although the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial7 found a statistically significant reduction in the combined incidence of stroke, myocardial infarction, and vascular death for clopidogrel compared to aspirin, the magnitude of the therapeutic advantage was small (an 8.7% relative risk reduction, or a decrease in the absolute event rate from 5.83%/y to 5.32%/y with clopidogrel). A difference of this magnitude would require switching 200 patients from aspirin to clopidogrel to see even 1 less atherothrombotic event per year. Furthermore, the therapeutic advantage attributable to clopidogrel was observed only when data from stroke patients were pooled with those enrolled in the study on the basis of a recent myocardial infarction or clinically active peripheral arterial disease. When stroke patients, a group totaling over 6400 individuals with over 12 000 patient-years of treatment, were evaluated in a post hoc analysis, no significant difference in efficacy was seen between clopidogrel and aspirin. The majority of the benefit of clopidogrel over aspirin in CAPRIE occurred in the group enrolled because of clinically active peripheral arterial disease. Also, it has been suggested that high-dose aspirin may be more effective than low-to-moderate-dose aspirin in the secondary prevention of stroke.8 Thus, the possibility exists that at higher doses aspirin may be more effective than clopidogrel in the prevention of recurrent stroke. Given these uncertainties surrounding the relative efficacy of clopidogrel compared with aspirin in stroke patients, it is difficult to justify switching patients to clopidogrel. No safety advantage for clopidogrel was evident in CAPRIE. Both agents produced similar side effect profiles (eg, upper gastrointestinal discomfort and general bleeding disorders were the most common adverse events for both drugs). Although upper gastrointestinal effects were somewhat more common in the aspirin-treated patients, it is possible that the incidence of these events would have been more comparable if a lower dose of aspirin or an enteric-coated formulation had been used in CAPRIE.9 If one considers the higher cost of clopidogrel over aspirin and the absence of a substantive safety advantage of clopidogrel over aspirin, there is little basis for switching stroke patients to clopidogrel. There is however, a place for clopidogrel in the treatment of stroke patients. The questionable status of clopidogrel utilization relative to aspirin should not detract from the conclusion that clopidogrel is an effective antiplatelet agent that would most likely demonstrate superiority to placebo if such a trial were ethically possible. There are, for example, a number of patients who are unable to tolerate or who have failed aspirin therapy, for whom clopidogrel may be indicated. Also, the CAPRIE trial suggests there may be a role for clopidogrel in the treatment of patients with peripheral vascular disease. However, at present, aspirin must still be considered the antiplatelet agent of choice for use in the prevention of recurrent ischemic events in stroke patients. Note: Dr Gorelick is on the Speakers Bureau for Janssen/ Excerpta Medica, Dupont, Roche Laboratories, and he has consultant agreements with NPS, Esaii, Searle/Lorex.