Is it naive to load only clopidogrel-naive patients prior to PCI?

Percutaneous coronary intervention (PCI) has become the predominant form of coronary revascularization in Europe and the USA. Although overall a safe procedure, PCI may be complicated by adverse events, with myocardial infarction (MI) and bleeding being the most frequent and important contributors to mortality and morbidity after the procedure. It is estimated that 25% of patients undergoing PCI may have significant post-procedural myonecrosis, as identified by creatinine kinase (CK) and CK-MB isoenzyme elevations, and that up to 50% of PCI patients develop post-procedural troponin elevations. The development of strategies that help prevent post-procedural MI has therefore been a major research interest in the field of interventional cardiology. Ever since the late 1990s, it is generally accepted that platelets, adhering and aggregating at sites of endothelial injury and mechanical plaque disruption, are the key determinants of PCI-related myocardial necrosis. Accordingly, several trials, including the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, demonstrated that dual antiplatelet therapy with aspirin plus thienopyridines is efficient in reducing post-PCI ischaemic complications. Since then, dual antiplatelet therapy with the thienopyridine clopidogrel and aspirin has become an integral part of PCI treatment of patients presenting with various forms of coronary artery disease—ST elevation myocardial infarction (STEMI), non-ST elevation acute coronary syndrome (NSTE ACS), and stable angina. An important limitation of clopidogrel, however, lies in its pharmacokinetic and pharmacodynamic properties. Clopidogrel is a prodrug that has to undergo two sequential cytochrome P-450 (CYP)-dependent oxidation steps after intestinal absorption in order to be converted into its active metabolite. This leads to delayed onset of action and interindividual variability in the platelet response to clopidogrel. In an effort to reduce this limitation, a high loading dose of clopidogrel has been used prior to PCI in previous studies, showing clinical advantages as compared with placebo. 6 The optimal loading dose of clopidogrel has been the focus of several recent studies, which support the superiority of the 600 mg dose. Currently, a high loading dose of clopidogrel is recommended by the guidelines of the European Society of Cardiology to be administered in all patients undergoing PCI. In addition to improved antiplatelet regimens, another significant milestone in the recent history of PCI was the development of the drug-eluting stent (DES), substantially reducing coronary restenosis, the major limitation of PCI in the bare metal stent (BMS) era. Although DES have indisputably improved patient outcomes, they require a protracted dual antiplatelet therapy compared with BMS. As a result of the broad application of DES, large numbers of patients presenting for PCI to interventional cardiology centres in Europe and the USA nowadays are no longer clopidogrel naı̈ve, but are already on chronic clopidogrel therapy. An important yet unanswered question is therefore whether patients on maintenance therapy with clopidogrel should also be given a booster load, similar to clopidogrel-naı̈ve subjects. Intuitively, one would expect that patients treated chronically with clopidogrel might not necessarily benefit from reloading prior to a repeat PCI. However, recent studies have suggested that—most probably due to interindividual variability in P450-dependent biotransformation—residual platelet aggregation persists in a substantial number of patients despite chronic clopidogrel treatment, affecting cardiovascular outcomes after repeat PCI. On average, the magnitude of maximal inhibition of platelet aggregation in patients who receive a dose of 75 mg/day is 30–50%. Correspondingly, further platelet inhibition can be achieved with clopidogrel loading in patients on the currently recommended maintenance dose of 75mg/day. Recent studies evaluating clopidogrel loading dose such as the current Clopidogrel Optimal Dose Usage to Reduce Recurrent Events (CURRENT-OASIS 7) trial, included both clopidogrel-naı̈ve patients and patients on clopidogrel maintenance therapy. Nevertheless, the clinical benefit of