Safety and Efficacy of Cangrelor, an Intravenous, Short-Acting Platelet Inhibitor in Patients Requiring Coronary Artery Bypass Surgery
Objective: Oral P2Y12 platelet receptor inhibitors are a cornerstone of reducing complications in patients with acute coronary syndromes or coronary stents. Guidelines advocate discontinuing treatment with P2Y12 platelet receptor inhibitors before surgery. Cangrelor, a short-acting, reversible, intravenously administered P2Y12 platelet inhibitor is effective in achieving appropriate platelet inhibition in patients who are awaiting coronary artery bypass grafting (CABG) and require P2Y12 inhibition. The objective of this study was to assess the effects of preoperative cangrelor on the incidence of perioperative complications, which are currently unknown.
Methods: Patients (n = 210) requiring preoperative clinical administration of thienopyridine therapy were randomized in a multicenter, double-blinded study to receive cangrelor or placebo while awaiting CABG after discontinuation of the thienopyridine. Optimal platelet reactivity, which was defined as <240 P2Y12 platelet reaction units, was measured with serial point-of-care testing (VerifyNow). Pre- and postoperative outcomes, bleeding values, and transfusion rates were compared. To quantify potential risk factors for bleeding, we developed a multivariate logistic model.
Results: The differences between the groups in bleeding and perioperative transfusion rates were not significantly different. The rate of CABG-related bleeding was 11.8% (12/102) in cangrelor-treated patients and 10.4% (10/96) in the placebo group (P = .763). Transfusion rates for the groups were similar. Serious postoperative adverse events for the cangrelor and placebo groups were 7.8% (8/102) and 5.2% (5/96), respectively (P = .454).
Conclusions: Compared with placebo, bridging patients with cangrelor prior to CABG effectively maintains platelet inhibition without increasing post-CABG complications, including bleeding and the need for transfusions. These data suggest cangrelor treatment is a potential strategy for bridging patients requiring P2Y12 receptor inhibition while they await surgery.
Aguirre FV, Topol EJ, Ferguson JJ, et al, for the EPIC Investigators. 1995. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 91:2882-90.nAngiolillo DJ, Firstenberg MS, Price MJ, et al, for the BRIDGE Investigators. 2012. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 307:265-74.nBennett-Guerrero E, Slaughter TF, White WD, et al. 2005. Preoperative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery. J Thorac Cardiovasc Surg 130:1567-72.nBhatt DL, Lincoff AM, Gibson CM, et al, for the CHAMPION PLATFORM Investigators. 2009. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361:2330-41.nBiancari F, Airaksinen KE, Lip GY. 2011. Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies. J Thorac Cardiovasc Surg 143:665-75.e4.nBonello L, Tantry US, Marcucci R, et al, Working Group on High On-Treatment Platelet Reactivity. 2010. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919-33.nChen ZM, Jiang LX, Chen YP, et al; COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. 2005. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1607-21.nCollet JP, Montalescot G, Blanchet B, et al. 2004. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 110:23610-7.nEsposito RA, Culliford AT, Colvin SB, Thomas SJ, Lackner H, Spencer FC. 1983. Heparin resistance during cardiopulmonary bypass. The role of heparin pretreatment. J Thorac Cardiovasc Surg 85:346-53.nGao C, Boylan B, Fang J, Wilcox DA, Newman DK, Newman PJ. 2011. Heparin promotes platelet responsiveness by potentiating IIb 3-mediated outside-in signaling. Blood 117:4946-52.nGiugliano RP, White JA, Bode C, et al, for the EARLY ACS Investigators. 2009. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 360:2176-90.nGurbel PA, Bliden KP, Hiatt BL, O'Connor CM. 2003. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107:2908-13.nHarrington RA, Stone GW, McNulty S, et al. 2009. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361:2318-29.nLewis BS, Mehta SR, Fox KA, et al, for the CURE trial investigators. 2005. Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Am Heart J 150:1177-84.nMalinin A, Pokov A, Swaim L, Kotob M, Serebruany V. 2006. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol 28:315-22.nMarcucci R, Gori AM, Paniccia R, et al. 2009. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 119:237-42.nMichelson AD. 2004. Platelet function testing in cardiovascular diseases. Circulation 110:489-93.nNijjer SS, Watson G, Athanasiou T, Malik IS. 2011. Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: a meta-analysis of 34 studies. Eur Heart J 32:2970-88.nNorgard NB. 2009. Cangrelor: a novel P2Y12 receptor antagonist. Expert Opin Investig Drugs 18:1219-30.nPatti G, Nusca A, Mangiacapra F, Gatto L, D'Ambrosio A, Di Sciascio G. 2008. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 52:1128-33.nPrice MJ, Endemann S, Gollapudi RR, et al. 2008. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 29:992-1000.nSabatine MS, Cannon CP, Gibson CM, et al, for the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. 2005. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179-89.nSambu N, Warner T, Curzen N. 2011. Clopidogrel withdrawal: is there a "rebound" phenomenon? Thromb Haemost 105:211-20.nWright RS, Anderson JL, Adams CD, et al. 2011. ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol 57:e215-367.nYusuf S, Zhao F, Mehta SR, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. 2001. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494-502.n