Intravenous P2Y12 Platlet Receptor Antagonist for PCI Patients
Background: Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y₁₂ receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI.
Methods: In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-µg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 µg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times.
Results: Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 µmol/L ADP at steady state was 100% for both cangrelor 4 µg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor.
Conclusions: This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y₁₂ platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.

Platelet-initiated thrombosis is fundamental in the pathophysiology of acute coronary syndromes and for the clinical complications (subacute thrombosis and myocardial necrosis secondary to embolization) during treatment with percutaneous coronary intervention (PCI). Intravenous treatment with platelet glycoprotein IIb/IIIa (GpIIb-IIIa) (receptor antagonists are associated with reductions in composite adverse events during PCI, particularly myocardial necrosis and the need for urgent reintervention. Similarly, oral administration of clopidogrel, a relatively weak adenosine diphosphate (ADP) receptor antagonist via binding to the P2Y₁₂ platelet receptor subtype, has been shown to prevent thrombotic complications after intracoronary stent placement.

The P2Y₁₂ receptor belongs to a superfamily of at least 3 purinoreceptors the endogenous ligand of which is adenosine. The P2Y₁₂ receptor subtype is predominately located on platelets and, through signal activation by ADP, reduces levels of cyclic adenosine monophosphate promoting platelet activation. Blockade of the P2Y₁₂ receptor is felt to prevent initial activation and amplification of the responses to platelet stimuli while leaving the final common pathway of platelet aggregation intact.

N-[2-(methylthio)ethyl]-2-[3,3,3-triflouropropyl)thiol]-5′-adenylic acid (cangrelor; formerly AR-C69931MX) is an intravenous, selective, and specific antagonist of P2Y₁₂ receptor–mediated platelet activation. In 2 small phase II studies in patients presenting with acute coronary syndromes without persistent ST-segment elevation and not undergoing PCI, cangrelor given in conjunction with aspirin and heparin was found to be safe and well tolerated to a dose of 4 µg/kg per minute, achieving >95% platelet inhibition. Because of the increased risk of bleeding associated with percutaneous revascularization, the primary objectives of this 2-part study were to assess the safety and pharmacodynamics of cangrelor and compare them with abciximab in patients undergoing PCI.