Platelet Aggregometry and Aspects of Residual Platelet Reactivity in Patients with Coronary Artery Disease Treated with Aspirin and Clopidogrel
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AbstractDual Antiplatelet therapy with aspirin and clopidogrel is a cornerstone in treatment of patients with acute coronary syndromes (ACS) and after percutaneous coronary intervention (PCI), and aspirin is established as antiplatelet monotherapy in stable coronary artery disease (CAD). Despite the fact that treatment with aspirin and clopidogrel attenuates platelet activity, thrombotic events still occur, and the terms aspirin- and clopidogrel “resistance” or “non-responsiveness” - denoting inadequate responses to these drugs, have emerged. Before the work on this thesis was initiated, several studies had demonstrated in vitro on-treatment residual platelet activity, and it was hypothesized that patients who respond inadequately to antiplatelet therapy might be identified by routine in vitro platelet function testing. However; partly due to lacking consensus on definitions, methods and terminology, the prevalence and clinical significance of aspirin- and clopidogrel resistance was controversial – and further research was needed. In order to evaluate the prevalence of aspirin and clopidogrel resistance and to explore and compare two different platelet aggregatory methods we performed three aggregometric studies.
In our first study we explored the prevalence of COX-1 related aspirin resistance among 289 patients with stable CAD who were treated with aspirin. For this purpose we performed in vitro testing using arachidonic acid (AA) stimulated light transmission aggregometry (LTA) and parallel measurements of plasma thromboxane B2 (TXB2). These tests were initially performed on two occasions 2-4 weeks apart and prior to coronary angiography. According to LTA aggregation findings, 11 patients showed signs of inadequate aspirin response on at least one of the two occasions. However, none of these 11 patients showed signs of residual platelet reactivity at a third examination. In conclusion, none of our patients presented persistent COX-1 related aspirin resistance.
In the second study we wanted to explore between- and within-subject variability in ADP-stimulated aggregation before and after initiation of clopidogrel therapy. For this purpose, we performed ADP-stimulated LTA in the 79 of the 289 patients from our first study who underwent PCI and consequently were treated with clopidogrel in addition to aspirin after the procedure. ADP-stimulated LTA was performed on two occasions before - and one after – initiation of clopidogrel therapy. As expected, large between-subject variability in aggregation was found both before and during treatment with clopidogrel. Besides, there were substantial within-subject variations over time before clopidogrel treatment and in clopidogrel naïve controls. Although the correlation between pre- and post clopidogrel aggregation was significant, reliable predictions of aggregometry responses during clopidogrel therapy could not be made based on pre-treatment testing.
Not only the substantial between-subject variability in ADP-stimulated LTA during clopidogrel therapy, but also within-subject variability in aggregation over time before clopidogrel, suggested that clinically significant within-subject variations in on-treatment aggregation over time might be present. This merited further studies, and in addition we wanted to compare the relatively slow LTA method with the much faster Multiplate Electrode Aggregometry (MEA) method. In our last study we therefore performed repeated, parallel ADP-stimulated LTA and MEA aggregation measurements with 3 different ADP-concentrations in order to explore the agreement between the two methods. The patient population consisted of 31 patients who were on dual antiplatelet therapy with aspirin and clopidogrel after NSTEMI and were treated with PCI; aggregometry was performed on three occasions 6 weeks apart, the first at the time of PCI. As aspirin-and clopidogrel treatment aims to inhibit arterial platelet reactivity while blood sampling acquired for aggregation measurements usually are venous; we also wanted to compare LTA and MEA aggregation in venous and arterial blood. We found that despite substantial between-subject variability, on-treatment aggregation was quite stable over time in most patients when assessed by both LTA and MEA, and that the agreement between LTA and MEA was good and stable. ADP concentrations had impact on both MEA and LTA assessments, and should therefore be taken into consideration when comparing results based on different ADP concentrations. We also found that parallel testing in arterial and venous blood showed similar aggregation results both for LTA and MEA – suggesting that venous blood sampling is sufficient for LTA- and MEA assessments.
List of papers. The papers are removed from the thesis due to publisher restrictions.
Paper I: Øystein Meen, Frank Brosstad, Hassan Khiabani, Erik Gjertsen, May Ellen Lauritsen, Turid Margrethe Pedersen, Stine Bjørnsen, Nina Malja Schjelderup, Wivi Ameln, Ee Chye Ng, Marianne Wettergreen, Shazia Parveen Siddique, Gunnar Erikssen. No case of COX-1 related aspirin resistance found in 289 patients with symptoms of stable CHD remitted for coronary angiography. Scandinavian Journal of clinical & Clin Laboratory Investigation 2008; 68:185-191. doi:10.1080/00365510701601673
Paper II: Øystein Meen, Frank Brosstad, Stine Bjørnsen, Turid Margrethe Pedersen and Gunnar Erikssen. Variability in aggregometry response before and after initiation of clopidogrel therapy. Scandinavian Journal of Clinical & Laboratory Investigation 2009; 69: 673-679. doi:10.1080/00365510902971875
Paper III: Øystein Meen, Frank Brosstad, Knut Liestøl, Gabor Kunszt, Bjørn Bendz, Marianne Wettergreen, Nina Malja Schjelderup, Trine Andreassen, Gunnar Erikssen. Sequential ADP-stimulated light transmission and multiple electrode aggregometry in patients taking aspirin and clopidogrel after non ST-elevation myocardial infarction. Scandinavian Journal of Clinical & Laboratory Investigation 2012; 72: 318-325. doi:10.3109/00365513.2012.666565