A new study, CHAMPION PHOENIX, indicates that the intravenous adenosine diphosphate (ADP) receptor cangrelor (The Medicines Company) significantly reduces the rate of ischaemic events—including stent thrombosis—compared with clopidogrel (Plavix, Bristol-Myers Squibb and Sanofi Aventis) in patients undergoing urgent or elective percutaneous coronary intervention (PCI).
The CHAMPION PHOENIX (Cangrelor versus standard therapy to achieve optimal management of platelet inhibition) study was presented at the American College of Cardiology annual meeting (9–11 March, San Francisco, USA) and was simultaneously published in the New England Journal of Medicine.
Writing in the NEJM paper, Deepak Bhatt (VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, USA) and others stated that a potent intravenous fast-acting reversible antiplatelet agent could potentially be used to address an unmet clinical need in patients undergoing PCI. They explained that clopidogrel and other P2Y12 inhibitors have limitations because, at the moment, they are administered orally, which is problematic in patients who have conditions (eg. nausea) that limit drug bioavailability. Additionally, Bhatt et al reported that there are multiple sources of variation in the pharmacokinetic and pharmacodynamic response to clopidogrel and that the effects of current intravenous drugs that are available to reduce thrombotic complications during PCI (glycoprotein IIb/IIa inhibitors), although they can be effective, “can last for several hours and cannot easily be reversed”. The authors stated that cangrelor was an “intravenous, fast-acting, potent, direct-acting platelet ADP P2Y12 inhibitor that has rapidly reversible effects” and, therefore, the purpose of CHAMPION PHOENIX was to assess if cangrelor could reduce the incidence of ischaemic complications of PCI compared with clopidogrel.
Bhatt et al randomly assigned patients who required PCI for stable angina, a non-ST-segment elevation acute coronary syndrome, or ST-segment elevation myocardial infarction (STEMI) in a double-dummy, double-blind fashion to receive cangrelor or clopidogrel before undergoing PCI. Patients received an infusion of cangrelor or matching placebo and 300mg/600mg of clopidogrel or matching placebo. After the infusion (of cangrelor or placebo), they received 600mg of clopidogrel (cangrelor group) or matching placebo (clopidogrel group). The primary endpoint was the composite rate of death from any cause, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis 48 hours after randomisation, and the primary safety endpoint was severe bleeding not related to coronary artery bypass grafting (CABG). Bhatt said in a press statement: “These are endpoints we worry about a lot in interventional cardiology and in cardiology in general.”
As 203 patients who underwent randomisation did not undergo PCI or did not receive a study drug, the authors assessed a modified intention-to-treat population of 10,942 patients (5,427 on cangrelor and 5,479 on clopidogrel)—average age 64 years, 56.1% with stable angina, 25.7% with non-ST-segment elevation acute coronary syndrome, and 18.2% with STEMI. Bhatt et al commented that the rate of the primary composite efficacy endpoint was significantly lower than in the clopidogrel group (4.7% vs. 5.9%; respectively, p=0.005) and wrote: “The number needed to treat with cangrelor to prevent one primary endpoint event is 84.” According to the authors, the reduction in acute periprocedural myocardial infarction (3.8% for cangrelor vs. 4.7% for clopidogrel; p=0.02) accounted for most of this benefit. However, they added that the rate of stent thrombosis, which was a key secondary endpoint in the study, was also significantly lower in the cangrelor group compared with the clopidogrel group—0.8% vs. 1.4%; p=0.01, respectively. At 30 days, the rate of the primary endpoint and the rate of stent thrombosis were both still significantly lower in the cangrelor group than in the clopidogrel group. The benefit with cangrelor was observed in all major subgroups and there were no differences in the rate of adverse events between the groups other than a higher rate of transient dyspnea (1.2% vs. 0.3%).
Bhatt et al stated that cangrelor may have a role beyond reducing ischaemic complications in PCI: “Cangrelor may be useful in situations in which ADP-receptor blockade is needed but a short-acting intravenous agent would be preferred. For example, in patients waiting to undergo open-heart surgery, cangrelor (at a lower dose than that used in this study) has been shown to result in consistent platelet inhibition without a significant increase in bleeding.”
Bhatt commented: “The investigators feel the data are compelling. The data we have shown are clear and consistent across all relevant subgroups or patient populations. This drug has several advantages, and nothing out there right now has quite the same biological properties.”
He told Cardiovascular News: “If approved, intravenous cangrelor might be used across the full spectrum of PCI— stable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or STEMI, as CHAMPION PHOENIX did show cangrelor was superior to clopidogrel in all three of these populations. Beyond reducing ischemic complications, a strategy of cangrelor instead of pre-treatment with an oral ADP receptor antagonist potentially avoids the situation of a patient with surgical anatomy being delayed for bypass surgery.”