Optimal Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: New insights from the randomized ARMYDA-
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Percutaneous coronary intervention (PCI) with stenting has been shown to enhance platelet aggregation.1 Accordingly, optimization of antiplatelet therapy has a crucial role in patients undergoing percutaneous revascularization and even more “aggressive” antiplatelet therapies have been employed to prevent postprocedural thrombotic complications.2,3
Dual oral antiplatelet pretreatment with aspirin plus ticlopidine has dramatically reduced the occurrence of subacute thrombosis and early adverse events after coronary stenting.4 Clopidogrel is an antiplatelet agent extensively used in clinical practice; it inhibits the adenosine diphosphate (ADP) receptor and affects intracellular signaling events that modulate the ADP-induced platelet activation. Administration of clopidogrel has been associated with better safety profile than ticlopidine, as well as at least similar clinical efficacy.5,6 Moreover, in the Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) study7 on patients with acute coronary syndromes (ACS) enrolled in the randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial and receiving PCI, pretreatment with 300-mg clopidogrel loading dose at a mean of 6 days before the procedure was associated, as compared with placebo, with a 30% relative risk reduction of death, myocardial infarction (MI) and repeat revascularization (p = 0.03). Moreover, the recent randomized Clopidogrel for the Reduction of Events (CREDO) trial8 on patients undergoing elective or urgent PCI has shown that pretreatment with a 300-mg loading dose of clopidogrel at least 6 hours before the procedure is associated with 38% relative risk reduction of death, MI and urgent target vessel revascularization (TVR) at 28 days versus assumption of clopidogrel, without loading dose, at the time of the procedure (p = 0.05). Accordingly, the 300-mg loading dose of clopidogrel, given at least 6 hours before the procedure plus aspirin, represents the conventional antiplatelet therapy in patients with ACS, as well as in those undergoing elective percutaneous intervention.8,9 However, the rationale for using a 300-mg loading dose of clopidogrel derives from dose-finding data on healthy volunteers.10 Conversely, in patients with coronary artery disease (CAD), there is an enhanced platelet reactivity as compared with healthy individuals,11 possibly requiring a more aggressive platelet inhibition.
A higher loading dose with 600 mg of clopidogrel causes an earlier and stronger inhibition of ADP-induced platelet activation than a 300 mg dose. In particular, the higher regimen has been associated with about 30% of ADP-induced platelet aggregation rate at 6 hours and 25% at 24 hours, versus about 45% and 40% after conventional regimen.12 Moreover, in the CREDO trial, a time-dependence in the clinical benefit of a 300-mg clopidogrel loading dose has been demonstrated, with at least 15 hours of pretreatment required to significantly decrease adverse events.13 Conversely, in vitro studies have shown that a 600-mg clopidogrel loading regimen is associated with maximal platelet inhibition 2 hours after drug administration.14 Data from ISAR-REACT trial on patients at low-to-intermediate risk undergoing PCI have confirmed that increasing the pretreatment interval beyond 2 to 3 hours with a 600-mg clopidogrel loading dose is not associated with significant clinical benefit.15 Thus, as long as a higher “antithrombotic status” remains the goal of drug therapy in the setting of PCI, a more rapid and intense suppression of platelet activation represents the rationale for pretreatment with a 600-mg loading regimen for reduction of early ischemic events. This is accomplished by decreasing procedural ischemia and distal embolization, protecting the microvascular bed and counterbalancing post procedural activation of coagulation.
Previous observational data16 have suggested a beneficial effect of a 600-mg clopidogrel loading dose in patients undergoing coronary stenting, with about a 45% risk reduction of adverse cardiac events at one month. A recent randomized trial17 has employed pretreatment with a 600-mg clopidogrel loading dose before PCI in patients with stable coronary artery disease. Data demonstrated that this regimen obviates the need for periprocedural glycoprotein IIb/IIIa infusion, with similar occurrence of the primary endpoint (death, MI, urgent TVR) at 30 days: 4% both in the placebo and abciximab group (p = 0.82). Moreover, recent data18 did not show a significant impact of abciximab on the risk of death and MI in diabetic patients undergoing elective percutaneous intervention after pre-treatment with a 600-mg loading dose of clopidogrel before the procedure. However, these two trials17,18 were not focused on clinical evaluation of a high clopidogrel loading dose versus conventional regimen, and no previous randomized study has specifically evaluated whether the enhanced anti-aggegation due to the 600-mg dose also translates into an independent clinical benefit.
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