Stent thrombosis. A subanalysis of TRITON-TIMI 38 examined the risk of stent thrombosis in the 12,844 patients enrolled in the trial who had stents implanted. 17 Stent thrombosis was assessed using the Academic Research Consortium definitions of definite, probable, and possible stent thrombosis. 18 The risk of definite or probable stent thrombosis was halved (hazard ratio = 0.48; P < .0001) with the use of prasugrel compared with clopidogrel, and the reduction was highly significant regardless of the type of stent implanted or the way stent thrombosis was defined. Significant reductions in both early (within the first 30 days) stent thrombosis ( P < .0001) and late (beyond 30 days) stent thrombosis ( P = .03) were observed in the prasugrel arm compared with the clopidogrel arm. 17
AZD6140, A REVERSIBLE P2Y 12 RECEPTOR ANTAGONIST
AZD6140, another investigational antiplatelet agent, is an orally active reversible P2Y 12 receptor antagonist, in contrast to the thienopyridines, which are irreversible inhibitors. A member of the cyclo-pentyl-triazolo-pyrimidine (CPTP) class, AZD6140 has a rapid onset of action (≤ 2 hours) and does not require metabolic activation. Its plasma half-life is approximately 12 hours, which translates to twice-daily dosing.
Inhibition of platelet aggregation relative to clopidogrel
In a study of clopidogrel-naïve patients with ACS, inhibition of platelet aggregation 12 hours after administration of AZD6140 was approximately 75% with 90-mg, 180-mg, and 270-mg doses, significantly greater than the 30% inhibition achieved after administration of 300 mg of clopidogrel ( P < .0002 for all doses of AZD6140 vs clopidogrel). 19 Whereas steady state was achieved in approximately 4 to 6 hours with clopidogrel, it was achieved in approximately 2 hours or less with AZD6140.
Clinical safety and efficacy relative to clopidogrel
In a dose-ranging study of AZD6140, adjudicated bleeding rates were similar among two different doses of AZD6140 (90 mg twice daily and 180 mg twice daily) and clopidogrel 75 mg once daily, with no evidence of a dose effect for major bleeding with AZD6140. 20 Although this study, conducted in 990 patients with ACS, was underpowered for efficacy end points, rates of adjudicated MI were numerically lower in each of the AZD6140 groups than in the clopidogrel group.
A more definitive evaluation of the relative effcicacy and safety of AZD6140 is expected from the ongoing PLATO trial, which is comparing 90 mg of AZD6140 twice daily with clopidogrel 75 mg/day among 18,000 patients randomized to one of the two treatments within 24 hours of an index ACS event. 21
CANGRELOR, A RAPID PARENTERAL P2Y 12 RECEPTOR ANTAGONIST
Cangrelor (formerly known as AR-C69931MX) is an intravenously (IV) administered P2Y 12 receptor antagonist under investigation for treatment of ACS and use during PCI and other coronary procedures. The compound is an adenosine triphosphate analogue with a plasma half-life of 5 to 9 minutes. Cangrelor is highly reversible, as platelet function returns to normal within 20 minutes of dosing. Within 15 minutes of initiation, cangrelor produces profound platelet inhibition and rapidly achieves steady state; peak effect occurs within minutes. 22 The response to cangrelor is highly consistent, with virtually all recipients achieving the same degree of platelet inhibition. Platelet response approaches baseline 15 minutes after termination. 22