AHA: Cangrelor fails to become a CHAMPION in two randomized, controlled trials
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. Yet, 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 clinical trials session.
Both CHAMPION (Cangrelor versus standard tHerapyto Achieve optimal Management of Platelet 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, multinational (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 principal investigator and study presenter Robert A. Harrington, MD, director of the Duke Clinical Research Institute in Durham, N.C. Yet, in formal 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 trial, included 5,362 stented patients randomized to receive either a placebo or cangrelor during PCI. The trial, 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 trial at our 48-hour endpoint,” said CHAMPION PLATFORM principal 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 met 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 editorial 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 optimal 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 trial, 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.”
“Although the results of the two trials are disappointing in that they failed to meet the primary endpoint, there is enough suggestion in these data of potential benefit that it warrants further investigation,” Harrington said.
Kastrati, who questioned the need to stop the trials, concurred with the investigators' recommendation for trialing, despite the “negative results” of these trials. “The most important lesson from the two CHAMPION trials is that in patients with acute coronary syndromes in whom the administration of an ADP-receptor antagonist was deferred until diagnostic angiography had established the indication for PCI, IV cangrelor did not provide additional advantages to those achieved with 600 mg of clopidogrel,” he wrote.
However, Kastrati added that “cangrelor is a potent intravenous ADP-receptor antagonist with a rapid onset and offset of action. These valuable qualities certainly warrant further study aimed at identifying more suitable clinical niches for cangrelor and more appropriate approaches to its use.”
Both CHAMPION trials were funded by The Medicines Company, and statistical analyses were performed by the Duke Clinical Research Institute.
Both CHAMPION (Cangrelor versus standard tHerapyto Achieve optimal Management of Platelet 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, multinational (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 principal investigator and study presenter Robert A. Harrington, MD, director of the Duke Clinical Research Institute in Durham, N.C. Yet, in formal 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 trial, included 5,362 stented patients randomized to receive either a placebo or cangrelor during PCI. The trial, 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 trial at our 48-hour endpoint,” said CHAMPION PLATFORM principal 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 met 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 editorial 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 optimal 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 trial, 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.”
“Although the results of the two trials are disappointing in that they failed to meet the primary endpoint, there is enough suggestion in these data of potential benefit that it warrants further investigation,” Harrington said.
Kastrati, who questioned the need to stop the trials, concurred with the investigators' recommendation for trialing, despite the “negative results” of these trials. “The most important lesson from the two CHAMPION trials is that in patients with acute coronary syndromes in whom the administration of an ADP-receptor antagonist was deferred until diagnostic angiography had established the indication for PCI, IV cangrelor did not provide additional advantages to those achieved with 600 mg of clopidogrel,” he wrote.
However, Kastrati added that “cangrelor is a potent intravenous ADP-receptor antagonist with a rapid onset and offset of action. These valuable qualities certainly warrant further study aimed at identifying more suitable clinical niches for cangrelor and more appropriate approaches to its use.”
Both CHAMPION trials were funded by The Medicines Company, and statistical analyses were performed by the Duke Clinical Research Institute.