Cangrelor: a review on pharmacology and clinical trial development

Abstract

Dual antiplatelet therapy with aspirin and an oral ADP P2Y12 receptor antagonist is the standard-of-care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention (PCI). However, currently available ADP P2Y12 receptor antagonists have several limitations, such as interindividual response variability, drug-drug interactions, slow onset/offset and only oral availability. Cangrelor is a reversible, potent, intravenous, competitive inhibitor of the ADP P2Y12 receptor that rapidly achieves near complete and predictable platelet inhibition. Along with reversible binding to the receptor cangrelor also has a very short half-life (3-5 min), which in turn results in a rapid offset of action. These properties make cangrelor a promising drug for clinical use in patients undergoing PCI or patients waiting for major surgery but still require antiplatelet protection. This manuscript provides an update of the current status of knowledge on cangrelor, focusing on its pharmacologic properties and clinical trial development, including the BRIDGE and CHAMPION-PHOENIX trials.

Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials

“…Therefore, defining the impact of cangrelor overdosing on adverse events, in particular bleeding complications, is of clinical interest. Cangrelor is the first IV P2Y 12 receptor inhibitor that induces potent platelet inhibitory effects within minutes of administration [8][9][10]. Compared with control, cangrelor reduces periprocedural thrombotic complications in patients undergoing PCI without any increase in major bleeding, although minor bleeding is increased [11][12][13][14].…”

“…Cangrelor is a direct-acting (no metabolism required) drug which exhibits reversible binding with the P2Y 12 receptor. Moreover, cangrelor has a very rapid offset with a half-life of 3-6 min and a return to baseline platelet reactivity within 60 min [8][9][10]. These pharmacological properties are distinct from oral P2Y 12 receptor inhibitors.…”

“…Although ticagrelor is a direct acting reversible binding agent, *30 % of its antiplatelet effects are exerted from a metabolite derived from hepatic metabolism that presents a similar pharmacological profile of the parent compound; also the half-life of ticagrelor and its major metabolite is *8-12 h, and 3-5 days are warranted for a return to baseline platelet reactivity after drug discontinuation [8]. Moreover, cangrelor is rapidly metabolized in the circulation, and its half-life is not dependent on dose [8][9][10]. When used at therapeutic doses, cangrelor is associated with near complete P2Y 12 receptor blockade.…”

“…Cangrelor is a novel, intravenous (IV), direct-acting P2Y 12 receptor antagonist that provides fast-onset, potent, and consistent platelet inhibition, with reversible binding and a half-life of 3-6 min [9,10]. The CHAMPION (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) program consisted of three randomized (1:1), double-blind, double-dummy trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) designed to test whether a P2Y 12 treatment strategy of IV cangrelor at the time of PCI (30 lg/kg bolus, followed immediately by a 4 lg/kg per minute infusion for 2-4 h or until the conclusion of the index PCI, whichever was longer), followed by transition to oral clopidogrel is superior to control (placebo or oral clopidogrel), given at the beginning or the end of PCI, at reducing the rate of thrombotic events during and immediately after PCI [11][12][13].…”

How to manage prasugrel and ticagrelor in daily practice

“…alternative to anti-GPIIb/IIIa bridging [78]. Indeed, cangrelor has a very short lasting inhibitory action allowing a full recovery of P2Y12 activity 60 min after infusion is stopped.…”