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Platelet response to aspirin and clopidogrel in healthy men

Esben Hjort Madsen

Summary

Aspirin and clopidogrel are platelet inhibitors used in the treatment and prevention of myocardial infarction and stroke. Aspirin inhibits platelet activation dependent on the COX-1 enzyme, and clopidogrel inhibits the ADP-dependent activation. Use of a combination of the two drugs is important in high risk patients, e.g., patients with coronary heart disease undergoing invasive treatment (PCI). Therefore it is of concern that several studies report high residual platelet reactivity in some patients despite aspirin and clopidogrel therapy. These patients seem to face a worse prognosis than patients with low platelet reactivity. Such low-response to aspirin or clopidogrel is, however, not precisely defined and a standard laboratory method is needed to identify patients who may benefit from intensified platelet inhibition. The aims of this project were: 1) To estimate reference ranges and variation for the Platelet Function Analyzer 100 (PFA) and Light Transmission Aggregometry (LTA) during aspirin and clopidogrel therapy 2) To test the hypothesis that the response to clopidogrel would decrease during long-term therapy with a combination of aspirin and clopidogrel. 3) To compare laboratory methods for assessing long-term aspirin and clopidogrel effects on platelet inhibition. 4) To describe platelet response to aspirin and clopidogrel in a large population of patients with peripheral artery disease (PAD). 

To address 1) we studied 20 healthy men taking aspirin and clopidogrel separately for two 11-day periods, using PFA and LTA. In a study designed to answer 2) and 3) we repeatedly tested 26 patients undergoing PCI and taking aspirin and clopidogrel for 1 year using VerifyNow, thrombelastograpy and LTA. To address 4) we measured platelet function twice, 3 months apart, in 267 aspirin treated patients with PAD. In a 72 subgroup of 43 patients, the platelet inhibiting effects of clopidogrel were also assessed. Platelet function was measured with PFA, LTA and the Multiplate instrument (whole blood impedance aggregometry). 

The main findings were that low-response to aspirin defined as lack of COX-1 inhibition seemed to be very rare, whereas low-response to clopidogrel seemed to be a more frequent finding. The variation of the PFA was substantial, and a higher number of low-responders to aspirin was found by this method. The platelet inhibiting effect of clopidogrel remained unchanged during long-term treatment. In general the agreement of the various platelet tests for low-response to clopidogrel was rather poor and it was not possible to recommend a specific test for this purpose. Large clinical trials are needed to elucidate the significance of high residual platelet reactivity during antiplatelet treatment. Furthermore, research on alternative antiplatelet treatment strategies for the high-risk patients is needed.