Clopidogrel
Clopidogrel inhibits platelet function by selectively blocking ADP-induced platelet aggregation and is metabolized by the liver to an active form. The action of clopidogrel appears to be permanent in that there is still antiplatelet activity for seven to ten days after the medication has been stopped. Platelet inhibition with clopidogrel is evident within two hours of an initial dose and the maximal effect with an initial dose has been noted to occur at 400 mg (40 % platelet inhibition). Maximal inhibition (60 % platelet inhibition) occurred within 4-7 days of continued dosing (50 to 100 mg/day) 1.The reported side effects of clopidogrel include severe rash (0.26 %), diarrhea (0.23 %), intracranial hemorrhage [0.33 % - less than that reported for aspirin (ASA)], and neutropenia [0.1%, similar to that reported for ASA 2.
Secondary Prevention. CAPRIE 2 was a large randomized trial with 19,185 patients comparing clopidogrel and ASA in secondary prevention for patients presenting with a cardiovascular event. The study accepted patients presenting with a myocardial infarction, ischemic stroke, or peripheral vascular disease and subsequently looked for subsequent cardiovascular events. A combined endpoint analysis revealed a small (5.8 vs. 5.3 % event rate) but significant benefit favoring the use of clopidogrel. When the subgroup of patients with any history of myocardial infarction were analyzed there was a lower incidence of subsequent fatal and non-fatal MIs in favor of clopidogrel. There was no mortality benefit associated with clopidogrel when compare to ASA. Of note, there were fewer gastrointestinal bleeding events (1.0 vs. 1.3 %) and fewer intracerebral hemorrhages (0.18 % vs. 0.25 %) in the clopidogrel vs. ASA groups.
Interventional Cardiology
To date there have been no published large trials regarding the efficacy of clopidogrel in percutaneous interventions, although a recent retrospective analysis revealed therapeutic equivalency in preventing stent thrombosis and major adverse cardiac events with a lower side effect profile than ticlopidine3. Theoretically, however, clopidogrel is more attractive than ticlopidine as it achieves platelet inhibition within a shorter period of time, has fewer severe adverse effects 4, requires only once per day dosing 5, and is cheaper than a twice per day regiment of ticlopidine. It also does not require subsequent follow-up CBCs. We have now established guidelines here at Stanford for the use of clopidogrel.
References
1. Fifth ACCP Consensus Conference on Antithrombotic Therapy (1998). Chest 114(5):626-8S.2. CAPRIE Steering Committee (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348 (9038):1329-39.
3. Moussa I, Oetgen M, Roubin G, Colombo A, Wang X, Iyer R, COllins M, Kreps E and JW Moses (1999). Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 99:2364-6.
4. Wang X, Oetgen M, Moussa I, Maida R, Kreps E, Iyer S, Collins M, Roubin G, Colombo A and J Moses (1998). The effectiveness of the combination of Plavix and aspirin versus Ticlid and aspirin after coronary stent implantation. Abstract TCT-48. Am J Card 82 (supp 7A):19S.
5. Jauahr R, Savino S, Deutsch E, Shaknovich A, Parikh M, Shannon T, McCrossan J, Undemir C, Sanborn T and G Bergman (1998). Aspirin and clopidogrel combination therapy in coronary stenting: a prospective registry. Abstract TCT-262. Am J Card 82 (supp 7A):96S.
Steven D. Filardo, M.D., M.P.H.