Osobitosti otpornosti na antitrombocitne lijekove u bolesnika s akutnim infarktom miokarda sa ST-elevacijom liječenih standardnim dozama acetilsalicilne kiseline i klopidogrela [The characteristics of resistance to antiplatelet drugs in patients with acute ST-segment elevation myocardial infarction treated with standard doses of acetylsalicylic acid and clopidogrel]

The central role of platelets in the pathophysiology of acute coronary syndromes is stressed in every cardiology textbook and many pages have been written to describe the doubtless benefit from contemporary pharmacotherapy that includes simultaneous administration of several potent antiplatelet drugs. In the effort to oppose pathologic coronary thrombosis, the more and more aggressive antiplatelet treatment brings us closer to other, though equally dangerous extreme of pathologic hemostasis – the hemorrhage. Why is that some of the patients are more prone to the development of new thrombotic cardiovascular incident while others are more likely to develop bleeding during identical antiplatelet treatment? Although cardiovascular adverse events are not of unambiguous etiology but rather present multifactorial phenomena, there is no doubt that atherothrombosis plays the utmost role in their evolution. Like we use to measure the blood glucose or LDL cholesterol concentrations to estimate the level of cardiovascular risk, as well as to adjust anti-diabetic or hypolipemic treatment, it can be presumed that the assessment of platelet reactivity and the response to antiplatelet drugs may help us to predict new thrombotic events or hemorrhagic complications. This thesis sought to study the characteristics of platelet response to standardized antiplatelet treatment in patients with acute ST-elevation myocardial infarction (STEMI) - the most hazardous population with coronary artery disease that has also been the least studied with regard to platelet responsiveness to both aspirin and clopidogrel. We have shown that the earliest phase of response to antiplatelet treatment in STEMI is a very dynamic process and that the antithrombotic effect of both aspirin and clopidogrel stabilizes after the fourth day of treatment. We have also demonstrated that the pretreatment ADP- but not the arachidonic acid-dependent platelet reactivity is associated with major adverse cardiovascular outcome. This is the first study that provided evidence for correlation between posttreatment arachidonic acid-dependent platelet aggregation in patients previously treated with aspirin and the occurrence of spontaneous recanalisation of infarct related coronary artery that carries a very favourable prognosis. Finally, the most important observation from our study was the finding that the relative reduction and not the absolute level of platelet reactivity after the introduction of antiplatelet treatment as a marker of platelet response is strongly associated with long-term cardiovascular prognosis including cardiovascular death, stent thrombosis, target vessel revascularization and stroke. Patients with STEMI at particularly high cardiovascular risk were those with so called dual resistance to antiplatelet therapy. This thesis represents a part of continuous and intensive efforts aiming to examine the prognostic value of measuring platelet reactivity and response to antiplatelet drugs, as well as to investigate the possible benefit from individualization of antiplatelet treatment (type and dosage of antiplatelet drugs) according to such measurements.