Routine pre-treatment with clopidogrel before diagnostic coronary angiography: the question is right, but what about the answer?

Dual antiplatelet therapy is the mainstay of antiplatelet treatment in percutaneous coronary interventions (PCIs) with stent implantation, as well as in acute coronary syndromes (ACS) with and without ST segment elevation. 3 In ACS, dual antiplatelet therapy has been shown to reduce the risk of death and myocardial infarction (MI), both at the initial phase and in the long term. In the setting of stent implantation, dual antiplatelet therapy has been shown to reduce the risk of major adverse cardiac events (MACEs) and stent thrombosis, as compared with various other antithrombotic regimens. Ticlopidine was the first thienopyridine to be used in the setting of stent implantation, but, over time, clopidogrel has proven to be better tolerated and more efficacious. However, clopidogrel is a prodrug, which requires a two-step metabolism in the liver to be transformed into its active metabolite. Its onset of action is quite slow, and the level of inhibition of platelet aggregation (IPA) achieved with the recommended regimen is quite low compared with other compounds. This implies that if clopidogrel is administered at the time of stent implantation, the level of IPA could be quite low during the critical 3–4 h after the procedure. Two solutions have been proposed to overcome this problem. The first is to administer clopidogrel long before the procedure. This strategy has been shown to be efficacious in three different settings. In the CREDO study, it was shown that better outcome following stent implantation could be achieved if clopidogrel was administered .14 h before the procedure. In PCI-CURE and CLARITY, pre-treatment with clopidogrel was shown to lead to better efficacy. The risk reduction for death or MI at 30 days following PCI was in the range of 25% when data from CREDO, PCI-CURE, and CLARITY were pooled. 11 In addition, no significant increase in the bleeding risk was observed in this meta-analysis, where the odds ratio for major or minor bleeding was 1.21 (95% CI 0.85–1.72, P 1⁄4 0.29) for pre-treatment vs. no pre-treatment. Based on these data, the most recent guidelines make clopidogrel pre-treatment a class I recommendation (300 mg at least 6 h before PCI). The other possible solution is to deliver higher doses of clopidogrel. Loading doses of 600 mg and even 900 mg have been tested on surrogate end-points exploring platelet function. These doses have been shown to lead to faster onset of action, and a higher level of IPA. Although neither of these doses is currently approved, the 600 mg dose is widely used in routine practice, and has been shown to be more efficacious than the standard 300 mg loading dose in small trials, mostly with surrogate end-points. In this context, the study by Widimsky and collaborators addresses an important issue frequently encountered in routine practice, namely administration of a loading dose of clopidogrel to patients scheduled for diagnostic coronary angiography with intent to perform PCI, if the lesions are amenable to angioplasty. This means that many of the patients who receive a loading dose of clopidogrel will not undergo stent implantation, and will thus be exposed to the potential risk of this strategy, particularly bleeding at the puncture site, without the perspective of a beneficial effect. This type of strategy—namely patients submitted to diagnostic procedures ‘loaded’ with clopidogrel—has never been compared with a strategy of elective administration of a high loading dose of clopidogrel in the catheterization laboratory in the case of PCI. For this reason, the authors’ intent is sound, and the message for the cardiological community is important, i.e. to determine whether or not elective administration of a high loading dose at the time of PCI will lead to fewer bleeding