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Novel antiplatelet strategies in acute coronary syndromes

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References

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 P2Y 12 receptor such as cangrelor would obviate this concern.

THROMBIN INHIBITORS

Thrombin plays an important role in platelet activation, and thrombin receptor antagonists may represent a safer means of inhibiting platelet activation relative to traditional antiplatelet agents. This theoretical safety advantage stems from the notion that blocking the action of platelets at the thrombin receptor would preserve platelets’ function as mediators of primary hemostasis. Because thrombin’s activation of platelets should occur only during clot formation, blocking platelet activation at the thrombin receptor would interrupt thrombin’s ability to propagate platelet activation during formation of coronary artery clots.

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