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Müller, Barbara (2010): Die hemmende Wirkung von Clopidogrel auf die Aggregation humaner Thrombozyten. Dissertation, LMU München: Faculty of Veterinary Medicine
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Abstract

Platelets are major players in pathophysiology of cardiovascular diseases in man and animals. Therefore, antiplatelet strategies are an important element in human medicine (e.g., for prevention of thrombotic events after vascular interventions). Current guidelines recommend dual antiplatelet therapy with clopidogrel 75 mg qd and acetylsalicylic acid 100mg qd in patients undergoing elective coronary stent implantation. However, several studies demonstrated a high interindividual variability in antiplatelet response to clopidogrel with a significant impact on clinical outcome. For instance, the EXCELSIOR study showed that patients with an insufficient response to clopidogrel (defined as >14% aggregation after stimulation with ADP 5 µM) after loading with clopidogrel 600 mg had a 3-fold higher incidence of death and non-fatal myocardial infarction within one year after elective coronary stenting. Therefore, the current prospective study aimed to investigate if high on-treatment platelet reactivity with a standard dosing of clopidogrel can be overcome by an increased dosing regimen. Antiplatelet effects of clopidogrel were assessed by light transmission aggregometry (stimulation with ADP 5 µmol/L) at day 1 after loading with clopidogrel 600 mg and subsequent elective coronary stenting. Out of the 117 patients enrolled, 39 were identified having a residual platelet reactivity >14%. These patients received an additional bolus of clopidogrel 300 mg and an intensified maintenance dosing regimen of clopidogrel 150 mg per day. Patients with residual platelet reactivity ≤14% were treated according to the labelled standard dosing regimen of clopidogrel (75 mg qd). Platelet reactivity was assessed 2 and 4 weeks after PCI. Data from 57 patients without any adjustment of clopidogrel dose served as control. The intensified dosing regimen of clopidogrel decreased residual platelet reactivity significantly compared to baseline assessments despite a persisting substantial inter-individual variability. Median platelet reactivity in the group of patients with dose adaption was slightly but significantly higher compared to patients with adequate initial response and treatment with clopidogrel 75 mg qd throughout. These results were confirmed by additional tests such as aggregometry with higher concentrations of ADP (20 µM) and analysis of surface protein expression of platelets. After increasing the dose of clopidogrel, no dose-related increase in systemic exposure to parent clopidogrel or the inactive metabolite carboxy-clopidogrel could be determined which most likely can be attributed to the large variability in pharmacokinetics of clopidogrel. The higher dose of clopidogrel 150 mg qd was not associated with any evidence of an increased incidence of bleeding. However, the present study was not sufficiently powered to detect differences with regards to safety. In conclusion, selective dose adaptation of clopidogrel is a feasible way to achieve a better platelet inhibition in patients with insufficient response to clopidogrel. These findings open the field for large scale clinical studies investigating the impact of tailored and individualized antiplatetet therapy on clinical outcome in patients undergoing percutaneous coronary interventions.