Aspirin in coronary artery disease: an appraisal of functions and limitations

Aspirin (acetylsalicylic acid) is an antiplatelet drug used to treat and prevent coronary artery disease. Aspirin is used more frequently than any other drug in the world, however it does not inhibit platelet function equally well in all patients. The risk of platelet-dependent cardiovascular events is increased in patients, in whom aspirin inhibits platelet function suboptimally. Platelet inhibition with aspirin can be evaluated by use of modern whole blood platelet function tests. The overall aim of this dissertation was to identify and describe functions and limitations of aspirin. We used whole blood platelet aggregometry (Multiplate® Analyzer and VerifyNow® Aspirin) as the primary measure of platelet function. To identify biological mechanisms explaining our findings we also measured a number of biological markers, including markers of cyclooxygenase-1 activity, platelet activation, and platelet turnover. All participants (except healthy individuals in study 1) were treated with non-enteric coated aspirin 75 mg once daily during study participation and received no other drugs affecting platelet function. We used serum TXB2 measurements to verify that all patients were adherent to aspirin. In study 1, we investigated the association between platelet aggregometry results and platelet count, red blood cell count, and white blood cell count. The study population consisted of 417 aspirin-treated patients with stable coronary artery disease and 21 drug-naïve healthy individuals. We found consistent associations between aggregation and platelet count, red blood cell count, and white blood cell count. In particular, platelet count was an independent predictor of platelet aggregation, although generally associations were rather weak. In study 2, we focused on patients previously suffering definite stent thrombosis because these patients may be at a prothrombotic state. We compared levels of platelet aggregation and platelet turnover in 39 patients with previous definite stent thrombosis with levels in 78 patients with stable coronary artery disease. We found that patients with previous definite stent thrombosis displayed increased platelet aggregation and had a tendency towards increased platelet turnover. In study 3, we investigated if the antiplatelet effect of aspirin is sustained through the standard 24-hour dosing interval. We included 50 patients with previous definite stent thrombosis, 100 patients with stable coronary artery disease, and 50 healthy individuals. We found that platelet aggregation increased significantly through the 24-hour dosing interval, and so did cyclooxygenase-1 activity and platelet activation. The increase in platelet aggregation did not differ between groups, but patients with previous definite stent thrombosis had higher levels of platelet turnover indices and thrombopoietin. In study 4, we addressed an ongoing debate concerning potential interactions between antiplatelet drugs and proton pump inhibitors. In patients with coronary artery disease, we investigated if the antiplatelet effect of aspirin was reduced in 54 patients treated with aspirin and a proton pump inhibitor compared to 364 patients treated with aspirin only. We found increased levels of platelet aggregation and platelet activation in patients treated with aspirin and a proton pump inhibitor.