Antiplatelet drugs: mechanisms and risks of bleeding following cardiac operations

Preoperative antiplatelet drug use is common in patients undergoing coronary artery bypass grafting (CABG). The impact of these drugs on bleeding and blood transfusion varies. We hypothesize that review of available evidence regarding drug-related bleeding risk, underlying mechanisms of platelet dysfunction, and variations in patient response to antiplatelet drugs will aid surgeons as they assess preoperative risk and attempt to limit perioperative bleeding. The purpose of this review is to (1) examine the role that antiplatelet drugs play in excessive postoperative blood transfusion, (2) identify possible mechanisms to explain patient response to antiplatelet drugs, and (3) formulate a strategy to limit excessive blood product usage in these patients. We reviewed available published evidence regarding bleeding risk in patients taking preoperative antiplatelet drugs. In addition, we summarized our previous research into mechanisms of antiplatelet drug-related platelet dysfunction. Aspirin users have a slight but significant increase in blood product usage after CABG (0.5 U of nonautologous blood per treated patient). Platelet adenosine diphosphate (ADP) receptor inhibitors are more potent antiplatelet drugs than aspirin but have a half-life similar to aspirin, around 5 to 10 days. The American Heart Association/American College of Cardiology and the Society of Thoracic Surgeons guidelines recommend discontinuation, if possible, of ADP inhibitors 5 to 7 days before operation because of excessive bleeding risk, whereas aspirin should be continued during the entire perioperative period in most patients. Individual variability in response to aspirin and other antiplatelet drugs is common with both hyper- and hyporesponsiveness seen in 5 to 25% of patients. Use of preoperative antiplatelet drugs is a risk factor for increased perioperative bleeding and blood transfusion. Point-of-care tests can identify patients at high risk for perioperative bleeding and blood transfusion, although these tests have limitations. Available evidence suggests that multiple blood conservation techniques benefit high-risk patients taking antiplatelet drugs before operation. Guidelines for patients who take aspirin and/or thienopyridines before cardiac procedures include some or all of the following: (1) preoperative identification of high-risk patients using point-of-care testing; (2) withdrawal of aspirin or other antiplatelet drugs for a few days and delay of operation in patients at high risk for bleeding if clinical circumstances permit; (3) selective perioperative use of evidence-based blood conservation interventions (e.g., short-course erythropoietin, off-pump procedures, and use of intraoperative blood conservation techniques), especially in high-risk patients; and (4) platelet transfusions if clinical bleeding occurs.     

噻吩并吡啶类药物代谢的研究进展

抗血小板治疗因其强有效的降低动脉血栓的能力,成为了缺血性心脑血管疾病患者治疗的基础。噻吩并吡啶类药物是第一批被开发的血小板ADP受体拮抗剂,其母体药物均为无活性的前药,需经体内代谢转化为活性产物后才能对ADP受体P2Y12发挥抑制作用。对噻吩并吡啶类药物的代谢途径、代谢产物及其临床相互作用进行了综述。     

噻吩并吡啶类抗血小板聚集药物研究概况

心脑血管疾病严重威胁人类健康,抗血小板治疗已经被证明可以有效预防和改善心脑血管疾病.噻吩并吡啶类药物是以二磷酸腺苷受体为靶点的一类抗血小板药物,包括噻氯匹定、氯吡格雷和普拉格雷,是目前临床上应用最为广泛、有效的抗血小板聚集、抗血栓药物,极大地改善了全球心脑血管患者的健康状况.概括介绍噻吩并吡啶类药物的代谢与起效模式、作用机制、临床应用及药物相互作用等方面的研究进展.     

Pharmacogenetics and pharmacogenomics of thienopyridines: clinically relevant?

Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines.     

Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel

Summary. Background: The thienopyridine P2Y₁₂ receptor antagonist clopidogrel reduces the risk of arterial thrombosis and individual pharmacodynamic responses to clopidogrel are believed to reflect the levels of active metabolite (AM) generated. Rifampicin increases the inhibitory effect of clopidogrel on platelet aggregation (PA). We studied the response to clopidogrel before and during administration of rifampicin in order to study the relationship between individual AM levels and P2Y₁₂ blockade. Methods: Healthy volunteers received a 600‐mg loading dose of clopidogrel followed by 75 mg daily for 7 days and, after a washout period and treatment with rifampicin [300 mg twice a day (b.i.d.)], received the same regimen of clopidogrel. Clopidogrel AM levels were determined over 4 h after the clopidogrel loading dose and unblocked P2Y₁₂ receptor number was assessed using a ³³P‐2MeSADP binding assay. PA was measured by optical aggregometry with ADP and TRAP. Results: Rifampicin enhanced clopidogrel AM production [area‐under‐the‐curve (AUC): clopidogrel 89 ± 22 ng h mL^?1, clopidogrel + rifampicin 335 ± 86 ng h mL^?1, P < 0.0001], and P2Y₁₂ blockade (unblocked receptors: clopidogrel 48 ± 24, clopidogrel + rifampicin 4 ± 2, P < 0.0001) and reduced PA (5 μmol L^?1 ADP: clopidogrel 20 ± 4, clopidogrel + rifampicin 5 ± 2, P < 0.01). Increasing numbers of unblocked receptors were required for an aggregation response with a decreasing concentration of ADP. PA induced by ADP 2 μmol L^?1 was particularly sensitive to low levels of receptor blockade. Conclusion: Potentiation of clopidogrel AM production by rifampicin leads to greater P2Y₁₂ blockade and consequently greater inhibition of PA. PA responses to low concentrations of ADP are more sensitive to P2Y₁₂ blockade.     

噻吩并吡啶类抗血小板聚集药物研究概况

心脑血管疾病严重威胁人类健康,抗血小板治疗已经被证明可以有效预防和改善心脑血管疾病。噻吩并吡啶类药物是以二磷酸腺苷受体为靶点的一类抗血小板药物,包括噻氯匹定、氯吡格雷和普拉格雷,是目前临床上应用最为广泛、有效的抗血小板聚集、抗血栓药物,极大地改善了全球心脑血管患者的健康状况。概括介绍噻吩并吡啶类药物的代谢与起效模式、作用机制、临床应用及药物相互作用等方面的研究进展。     

Does Clopidogrel Increase the Degree of Platelet Inhibition When a Platelet Glycoprotein IIb/IIIa Inhibitor Has Been Given? Insights From an Optical Platelet Aggregometry Study

Introduction: While the CURE trial demonstrated the benefits of clopidogrel in acute coronary syndromes, patients receiving glycoprotein IIb/IIIa antagonists were excluded. Given the frequent coadministration of these two medications, we sought to examine their interaction and their combined effect on platelet inhibition.Methods: Ten patients admitted to the hospital with stable or unstable angina underwent phlebotomy prior to, three hours and six hours after administration of a standard oral loading dose of clopidogrel. The samples were then treated in vitro with incremental concentrations of tirofiban (0, 10, 20, 40, 60, and 80 ng/mL), and optical platelet aggregometry was performed utilizing ADP and TRAP as agonists. We analyzed the combined effects of these agents using a mixed effects model with time and tirofiban concentration as fixed effects, and subject and timing of phlebotomy as random effects.Results: There was no evidence of additional inhibition of platelet aggregation due to clopidogrel regardless of the concentration of tirofiban or the study agonist (ADP 20 M or iso-TRAP). Specifically, there was no difference in the tirofiban dose-response curves with either platelet agonist for any of the three time points (before, and three and six hours after, clopidogrel administration).Discussion: There is no evidence that the combination of clopidogrel and tirofiban achieves greater inhibition of platelet aggregation than tirofiban alone.