Compared with 300 mg of clopidogrel, the more potent platelet inhibitory effect of a 600-mg dose translated to a two-thirds reduction ( P = .041) in the composite end point of death, MI, or target vessel revascularization at 30 days in a study of 255 patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI). 7 The reduction in this composite end point with high-dose clopidogrel was driven by a reduction in the incidence of periprocedural MI.
In a separate study of 292 patients with non‑ST-segment-elevation ACS who were scheduled for PCI, the superior platelet response to 600 mg versus 300 mg of clopidogrel translated to a 60% reduction in adverse thrombotic events ( P = .02), and this benefit extended beyond rates of periprocedural MI. 8
Similar results with increased maintenance dose
Similarly, emerging data suggest that raising the maintenance dose of clopidogrel can also raise response rates. In a study of 60 patients, doubling the maintenance dose of clopidogrel after PCI from 75 mg/day to 150 mg/day resulted in improved platelet inhibition as assessed by rapid platelet function analysis. 9 Likewise, a 150-mg/day maintenance dose of clopidogrel was associated with a superior antiplatelet effect compared with 75 mg/day in a study of 40 patients with type 2 diabetes. 10
Large definitive trial is under way
In the wake of these smaller trials, a large randomized trial known as CURRENT is comparing a strategy of high-dose clopidogrel with standard-dose clopidogrel in patients with ACS for whom an early invasive management strategy is planned. 11 The high-dose regimen involves a 600-mg loading dose followed by 150 mg/day for 1 week and then 75 mg/day for 3 weeks, whereas the standard-dose regimen involves a 300-mg loading dose followed by 75 mg/day for 4 weeks. Both groups are being further randomized to low-dose aspirin (75 to 100 mg/day) or high-dose aspirin (300 to 325 mg/day) for 30 days after PCI. With a target enrollment well beyond 10,000 patients, CURRENT should definitively clarify the relative efficacy and safety of high-dose clopidogrel in this setting.
Tailoring clopidogrel therapy
Investigators have explored tailoring the dosing of clopidogrel around the time of PCI based on the degree of platelet inhibition. In one study, administering additional loading doses of clopidogrel, up to a total of 2,400 mg, before PCI in patients with a suboptimal degree of platelet inhibition resulted in a lower rate of ischemic complications following PCI. 12
PRASUGREL, A NOVEL THIENOPYRIDINE
Prasugrel is an investigational third-generation thienopyridine currently under US Food and Drug Administration (FDA) review for use in patients with ACS being managed with PCI. Like clopidogrel, prasugrel is a prodrug that requires conversion to an active metabolite prior to binding to the platelet P2Y 12 receptor for ADP to confer antiplatelet activity. Prasugrel is metabolized more efficiently than clopidogrel, allowing for faster activation and superior bioavailability to produce a greater and more consistent antiplatelet effect. 1,13
The active metabolites of clopidogrel and prasugrel are no different in their ability to inhibit platelet aggregation, but approximately 85% of clopidogrel is inactivated by esterases, with the remaining 15% being converted to the active metabolite using the cytochrome P450 pathway via two successive oxidative steps in the liver. 14 In contrast, esterases facilitate the transformation of prasugrel to its active metabolite. 14 This activation requires only one oxidative step that can occur in either the liver or the gut through cytochrome P450.