Pharmacokinetics of clopidogrel in patients with stent thrombosis

In patients undergoing percutaneous coronary intervention (PCI), dual antiplatelet treatment with aspirin and clopidogrel is the therapy of choice to prevent thrombotic events after coronary interventions [1]. Despite an adequate antiplatelet treatment, stent thrombosis, a potentially life-threatening event, is still feared to occur [2]. The thienopyridine clopidogrel is an inactive prodrug that requires two-step oxidation by the hepatic cytochrome P450 (CYP) system to generate its active compound, the thiol metabolite, which targets and irreversibly inhibits the adenosine diphosphate (ADP) P2Y12 receptor [3,4]. The major circulating compound, the carboxyl metabolite of clopidogrel, completely lacks antiplatelet activity. Platelet response to loading and maintenance treatment with clopidogrel is highly variable [5]. Clinical [6,7], cellular [8] and genetic factors [9] have been associated with response variability to clopidogrel. It has been demonstrated that the pharmacodynamic response to clopidogrel and specifically the extent of ADP-receptor blockade at the time of coronary intervention is associated with the risk of major adverse cardiac events and stent thrombosis in patients receiving coronary stents [10,11]. However, pharmacokinetics of clopidogrel were never assessed specifically in patients with a history of stent thrombosis. We hypothesized that in stent thrombosis patients the high level of ADP-induced platelet aggregation in the presence of clopidogrel therapy [12] can largely be attributed to diminished metabolization of clopidogrel to its active thiol metabolite. The aim of this study was to assess the pharmacokinetics of clopidogrel and simultaneously to assess ADP-induced platelet aggregation before and after administration of a loading dose of 600 mg clopidogrel in patients under clopidogrel maintenance treatment and with a recent history of stent thrombosis following PCI and to compare these parameters with those of previously studied healthy controls [13]. Eligible for this study were seven prospectively recruited patients with coronary artery disease (CAD) and angiographically confirmed stent thrombosis in the past. All patients were treated with 75 mg day clopidogrel before the occurrence of stent thrombosis. The number of patients included in the study was based on the assumption that cmax of the active metabolite was lower (7.5 ± 3.0 ng mL) in stent thrombosis patients vs. 15.0 ± 6.0 ng mL in healthy controls. Choosing a power of 80% and a two-sided a value of 0.05 an overall sample size of at least seven per group was required. Patients were under clopidogrel maintenance treatment with 75 mg day prior to administration of an additional 600 mg clopidogrel loading dose except for one patient who was under maintenance treatment with 150 mg day (see Table 1, patient 7). All patients were concomitantly treated with aspirin (200 mg day), a statin, a beta-blocker and an ACE (angiotensin converting enzyme) inhibitor. In addition, two patients were treated with a proton-pump inhibitor and one patient with a calcium channel blocker at the time point of blood sampling. For pharmacokinetic assessments, blood samples were collected prior to administration of 600 mg clopidogrel loading and at predefined time points afterwards (20, 40, 60, 120, 240 min). Blood samples were immediately filled in tubes coated with a stabilizing agent (Pat. No. DE 1