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Cangrelor Is Not the New Champion

Unexpected setbacks for a promising new antiplatelet agent illustrate the gap between laboratory results and clinical efficacy.

Cangrelor, an investigational intravenous agent that reversibly inhibits the platelet P2Y12 adenosine diphosphate receptor, has two potential advantages over clopidogrel: a rapid onset of action and a short half-life that allows normalization of platelet function within 60 minutes of discontinuation. In two manufacturer-sponsored studies, investigators assessed cangrelor's efficacy in patients undergoing percutaneous coronary intervention. Both trials were terminated early based on findings from interim analyses.

In the CHAMPION PLATFORM trial, 5301 patients undergoing PCI for acute coronary syndromes were randomized to receive cangrelor or placebo for 2 to 4 hours during the procedure and clopidogrel (600 mg) at the end of the procedure. Glycoprotein (GP) IIb/IIIa inhibitors were used in 9.2% of patients. The primary composite endpoint of death, MI, or ischemia-driven revascularization within 48 hours occurred in 7% of cangrelor recipients and in 8% of placebo recipients, a nonsignificant difference. However, cangrelor was associated with significant reductions in the stent thrombosis rate (0.2%, vs. 0.6% with placebo) and mortality (0.2% vs. 0.7%). Major and minor bleeding rates were similar in the two groups, although groin hematomas occurred more frequently in cangrelor recipients. Dyspnea was more common in cangrelor recipients (1.4%) than in placebo recipients (0.5%).

In the CHAMPION PCI trial, 8877 patients undergoing PCI were randomized to receive either 600 mg of clopidogrel or cangrelor at the beginning of the procedure. GPIIb/IIIa inhibitors were used in 26.5% of patients. Cangrelor recipients received clopidogrel at the end of the infusion. The rate of the composite endpoint of death, MI, or ischemia-driven revascularization did not differ significantly between the two groups at either 48 hours or 30 days or among subgroups with stable angina, unstable angina, and ST-segment-elevation MI. Bleeding rates were similar in the two treatment groups, but dyspnea occurred in slightly more cangrelor recipients (1.0%) than clopidogrel recipients (0.4%).

Comment: Given the importance of platelet inhibition in ACS treatment and PCI, the fact that cangrelor did not improve outcomes — despite presumably achieving earlier and greater platelet inhibition than clopidogrel alone — is surprising. Study design issues, including the definition of periprocedural MI and the abrupt transition to an oral antiplatelet after cangrelor infusion, could have contributed to these negative results. However, newer oral agents with a faster onset of action and more-consistent platelet inhibition than clopidogrel are now available and will pose a further challenge to cangrelor's development.

— Howard C. Herrmann, MD

Dr. Herrmann was a site investigator for the CHAMPION PCI study but was not involved in data analysis or manuscript preparation.

Published in Journal Watch Cardiology November 15, 2009

Citation(s):

Bhatt DL et al for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009 Nov 15; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0908629)

Harrington RA et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009 Nov 15; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0908628)

Kastrati A and Ndrepepa G. Cangrelor — A champion lost in translation? N Engl J Med 2009 Nov 15; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMe0910677)