Invited Commentary

Abstract

Given the efficacy of platelet inhibition by thienopyridine (adenosine 5′-diphosphate [ADP] receptor antagonists) anticoagulants (ie, clopidogrel, ticlopidine, and prasugrel) to reduce morbidity associated with acute coronary syndromes and other thrombotic disorders, the number of patients requiring cardiac operations after exposure to these drugs continues to increase. After ingestion, thienopyridines undergo metabolism to an active form that irreversibly inhibits platelet P2Y12 ADP receptors [1Patrono C. Rocca B. The future of antiplatelet therapy in cardiovascular disease.Annu Rev Med. 2010; 61: 49-61Crossref PubMed Scopus (22) Google Scholar]. In general, reversal of thienopyridine-mediated anticoagulant effects requires 4 to 10 days and proves dependent on the introduction of new platelets from the marrow and extramedullary sources; however, a common polymorphism of cytochrome P450, termed CYP2C19, reduces concentration of the active metabolite and may limit anticoagulant activity as well [1Patrono C. Rocca B. The future of antiplatelet therapy in cardiovascular disease.Annu Rev Med. 2010; 61: 49-61Crossref PubMed Scopus (22) Google Scholar]. Although bleeding risk attributable to thienopyridine anticoagulants in nonsurgical patients appears limited, evidence suggests that patients undergoing cardiac operations that require cardiopulmonary bypass (CPB) experience excess bleeding and transfusion exposures. In a recent multicenter retrospective cohort analysis, patients undergoing CPB within 5 days of clopidogrel exposure experienced increased risk for reoperation, major bleeding, and prolonged length of stay [2Berger J.S. Frye C.B. Harshaw Q. Edwards F.H. Steinhubl S.R. Becker R.C. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: a multicenter analysis.J Am Coll Cardiol. 2008; 52: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. Similarly, a structured literature review incorporating 23 studies and more than 3500 patients reported that coronary artery bypass graft (CABG) operations within 7 days of clopidogrel exposure was associated with an increase in major bleeding and transfusion requirements [3Pickard S.A. Becker R.C. Schumock G.T. Frye C.B. Clopidogrel-associated bleeding and related complications in patients undergoing coronary artery bypass grafting.Pharmacotherapy. 2008; 28: 376-392Crossref PubMed Scopus (67) Google Scholar]. Although current practice guidelines recommend discontinuation of thienopyridines 5 to 7 days before cardiac operations, patient-to-patient variability in anticoagulant duration of these drugs suggests a potential for laboratory-based monitoring of the thienopyridine anticoagulant effect to influence surgical planning. In this issue of The Annals, Ranucci and colleagues [4Ranucci M. Baryshnikova E. Soro G. Ballotta A. De Benedetti D. Conti D. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines.Ann Thorac Surg. 2011; 91: 123-130Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar] report that preoperative screening of ADP-mediated platelet aggregation using multiple electrode whole-blood aggregometry successfully categorized patients for bleeding risk after recent thienopyridine exposure. Preoperative assessment of bleeding risk proves challenging, given the potential for CPB to adversely affect coagulation. CPB-related hyperfibrinolysis, hemodilution, and hypothermia contribute to bleeding after cardiac operation and confound identification of preoperative predictors, as reflected by the limited positive predictive power commonly associated with preoperative testing of coagulation. In contrast, the negative predictive value (ie, 92%) associated with Ranucci and colleagues' approach suggests the potential to identify patients at low risk for excess bleeding after thienopyridine therapy. For elective cardiac operations, multiple electrode whole-blood aggregometry testing may provide a mechanism to reduce unnecessary surgical delays by assessing thienopyridine effect on platelet function and identifying those patients unlikely to bleed excessively due to thienopyridine exposure. Similarly, operations might be delayed beyond 5 days in the subset of patients experiencing prolonged platelet inhibition after thienopyridine discontinuation. Even in settings where the operation cannot be delayed, preoperative testing may prove useful in directing transfusion therapy postoperatively. Although ADP-based platelet aggregation testing appears logical for assessing platelet inhibitory effects of thienopyridines, the role for platelet function testing in directing overall postoperative transfusion therapy remains unclear. Given potential for platelet activation by multiple receptors and pathways, as yet no single measure of platelet function has proved superior [5Lippi G. Favaloro E.J. Salvagno G.L. Franchini M. Laboratory assessment and perioperative management of patients on antiplatelet therapy: from the bench to the bedside.Clin Chim Acta. 2009; 405: 8-16Crossref PubMed Scopus (30) Google Scholar]. Multiple Electrode Whole-Blood Aggregometry and Bleeding in Cardiac Surgery Patients Receiving ThienopyridinesThe Annals of Thoracic SurgeryVol. 91Issue 1PreviewPreoperative treatment with thienopyridines is associated with increased postoperative bleeding in cardiac surgery patients. Patients under treatment with thienopyridines have different levels of platelet dysfunction and the effects of discontinuation are not totally predictable. The present study aimed to determine if a preoperative assessment of platelet function in these patients could provide clinically relevant information regarding the risks of excessive postoperative bleeding and transfusion requirements. Full-Text PDF