Novel antiplatelet strategies in acute coronary syndromes

AZD6140, A REVERSIBLE P2Y₁₂ RECEPTOR ANTAGONIST

AZD6140, another investigational antiplatelet agent, is an orally active reversible P2Y₁₂ 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 P2Y₁₂ RECEPTOR ANTAGONIST

Cangrelor (formerly known as AR-C69931MX) is an intravenously (IV) administered P2Y₁₂ 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

If approved by the FDA, cangrelor would be administered similar to the way that glycoprotein IIb/IIIa inhibitors are, as it would be used primarily in the catheterization laboratory and then discontinued after the procedure, at which point transition to a long-term oral therapy would be necessary.

Clinical effects relative to abciximab

Cangrelor has been compared with the glycoprotein IIb/IIIa inhibitor abciximab and placebo in 249 patients undergoing elective or urgent PCI.²² Rates of the combined end point of death, MI, or need for repeat revascularization at 30 days were similar with cangrelor and abciximab (5.7% vs 5.4%, respectively; P = NS), both of which were lower than the rate with placebo (10.0%). Major or minor bleeding through 7 days occurred in numerically fewer cangrelor recipients compared with abciximab recipients (7.0% vs 9.0%), although the small sample size precluded evaluation for statistical significance.

Clinical effects relative to clopidogrel—the CHAMPION trials

A phase 3 trial program consisting of two multinational studies of cangrelor—the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) program—is currently under way.

CHAMPION-PCI is enrolling 9,000 patients presenting with ACS who are being randomized in a double-blind fashion at the start of PCI to a 600-mg loading dose of clopidogrel or to cangrelor given as an IV bolus of 30 μg/kg followed by an IV infusion of 4 μg/kg/min. The primary end point is a composite of all-cause mortality, MI, or ischemia-driven revascularization in the 48 hours following randomization. Secondary end points include rates of all-cause mortality and MI at 48 hours.²³

CHAMPION-PLATFORM is enrolling 4,400 patients scheduled for PCI as a result of ACS who are being randomized in a double-blind, double-dummy manner to (1) cangrelor bolus and infusion plus oral placebo or (2) oral clopidogrel plus placebo bolus and infusion before their index procedures. Dosages of the two agents are the same as in CHAMPION-PCI. The primary end point is a composite of death, MI, or urgent target vessel revascularization at 48 hours. Secondary end points include 30-day and 1-year clinical outcomes.²³

The rationale for the CHAMPION investigations stems from the need to initiate clopidogrel before a patient is taken to the catheterization laboratory, owing to the inability to achieve a high degree of platelet inhibition until 4 to 6 hours after clopidogrel administration. Although this strategy can be undertaken without complication for most patients, a subset of patients with three-vessel disease or left-main disease will require CABG, which then must be delayed several days until clopidogrel’s platelet-inhibiting effect diminishes. A rapid-acting IV inhibitor of the P2Y₁₂ receptor such as cangrelor would obviate this concern.