Orlando, Fla.—The new, reversible antiplatelet drug cangrelor was not superior over clopidogrel in reducing the composite of death, MI or ischemic revascularization 48 hours after PCI, nor did the investigative drug prove superior over placebo for combined endpoint of MI, all-cause mortality and revascularization. Y et, the drug may have some benefits for stent thrombosis. Two randomized, controlled trials demonstrated these results, which were presented Sunday at the American Heart Association late breaking clinic al trials session.
Both CHAMPION ( Cangrelor versus standard tHerapyto Achieve optim al Management of Platel et InhibitION) trials were conducted in a parallel fashion with different primary endpoints. The Medicines Company’s cangrelor is a potent, direct and reversible inhibitor of the P2Y12 receptor and is the first such drug to be administered intravenously.
In CHAMPION PCI, a phase III, multination al (200 sites, 18 countries), randomized, double-blind, placebo-controlled trial, researchers assessed whether cangrelor provides superior, or at least non-inferior performance compared to a 600 mg dose of clopidogrel during the 48 hours after PCI. Those in the cangrelor group received 30 mcg of the drug per kilogram of body weight intravenously, followed by a 4 mcg/kg/per minute infusion for at least two hours. After PCI, all patients received 600 mg of clopidogrel.
Investigators of CHAMPION PCI planned to enroll 9,000 patients, but the trial was stopped early (May) with 8,820 enrolled after an interim review panel concluded it was unlikely to meet its primary endpoint.
There was no statistically significant difference in the primary composite endpoint (death, MI, ischemic revascularization at 48 hours), which affected 7.5 percent of the cangrelor group versus 7.1 percent, said CHAMPION PCI princip al investigator and study presenter Robert A. Harrington, MD, director of the Duke Clinic al Research Institute in Durham, N.C. Y et, in form al non-inferiority 1160 testing, cangrelor appeared to maintain more than 60 percent of the benefit of 600 mg clopidogrel over placebo, he added.
CHAMPION PLATFORM, a phase III tri al, included 5,362 stented patients randomized to receive either a placebo or cangrelor during PCI. The tri al, which began enrolling a different patient group in 2006, ended when an interim review committee concluded that cangrelor would fail to show superiority over clopidogrel for its primary endpoint (composite of all-cause death, MI and the need for coronary revascularization.
“There was no statistically significant difference between the two arms of the tri al at our 48-hour endpoint,” said CHAMPION PLATFORM princip al investigator Deepak L. Bhatt, MD, chief of cardiology at the VA Boston Healthcare System. “However, a number of secondary endpoints had informative findings.” For instance, all-cause death as a stand-alone endpoint was reduced significantly from 0.7 percent in controls to 0.2 percent (67 percent) in the cangrelor group.
“It is intriguing, but it is a secondary endpoint and needs to be interpreted with some caution given that the primary endpoint was not m et and the number of deaths overall was low,” said Bhatt. However, minor bleeding events occurred significantly more often in the cangrelor group, compared with placebo (5.4 vs. 3.4 percent).
Both trials were simultaneously published in the New England Journal of Medicine, along with an accompanying editori al by Adnan Kastrati, MD, et al from Deutsches Herzzentrum, Technische Universität München in Munich, Germany, who wrote that a better study design and reporting for the drug should probably be used in the future because cangrelor may not have been given “an optim al chance to show its assumed benefits.” He questioned the clopidogrel loading dose of 600 mg, compared with the guideline-recommended 300 mg.
Despite these complications, cangrelor showed a reduction in acute stent thrombosis. In CHAMPION PLATFORM, “acute stent thrombosis was reduced from 0.6 percent in controls to 0.2 percent in the cangrelor group (69 percent reduction), a significant benefit,” Bhatt said.
“When CHAMPTION PCI’s findings are combined with those from the companion tri al, CHAMPION PLATFORM, it may suggest that cangrelor reduces the risk of some clinically meaningful ischemic events in patients under going PCI,” said Harrington. “That includes a possible reduction in Q wave infarction and stent thrombosis.”