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Ann Thorac Surg 2005;80:768-779
© 2005 The Society of Thoracic Surgeons
Cardiovascular Division and Division of Cardiac Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, Division of Cardiology, Department of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
* Address reprint requests to Dr Cannon, TIMI Study Group, 350 Longwood Ave, First Floor, Boston, MA02115 (Email: cpcannon{at}partners.org).
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Abstract |
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 Top Abstract IntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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Introduction |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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| Doctors Cannon, Mehta, and Aranki disclose that they have a financial relationship with Bristol-Myers Squibb Company, and Sanofi-Aventis.
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Coronary artery bypass graft (CABG) is the most frequent cardiac surgery procedure, with more than 500,000 operations conducted annually in the United States alone, and nearly 1 million worldwide. Despite improvements in surgical technique, hemodynamic monitoring and intensive care, cardiovascular morbidity following CABG surgery remains problematic, particularly in high-risk patient groups [1]. Organ reperfusion after coronary revascularization, particularly when conducted in conjunction with cardiopulmonary bypass, is associated with a diffuse inflammatory response, marked by the release of proinflammatory cytokines, activation of complement neutrophils and platelets, and initiation of intravascular thrombosis [2, 3]. This inflammatory cascade triggers the coagulation disturbances, enhanced vascular permeability, and multisystem ischemic organ injury that characterize the postbypass period [4]. In addition, underlying diffuse atherothrombotic involvement, coupled with the tendency for acute vein graft thrombosis, sets up a population at high risk for graft failure, stroke, and recurrent cardiac events [5–7].
Antiplatelet therapy forms the mainstay of primary and secondary prevention in atherothrombotic disease, and there is broad consensus about the value of long-term aspirin therapy in reducing the risk of death, myocardial infarction, and stroke in patients at high risk of occlusive vascular disease, [8] as well as in preventing ischemic complications [9] and maintaining early and late vein-graft patency after CABG [10–12]. However, the enhanced antiaggregatory effects of the newer, more potent oral antiplatelet agents (such as the thienopyridines) raises concern about possible hemorrhagic complications arising from their use in immediate proximity to cardiac surgery. This is reflected in the practice of avoiding or discontinuing oral antiplatelet agents and abruptly reversing anticoagulant therapy before surgery [13–15].
In this article we review the frequency and nature of the ischemic and bleeding complications associated with CABG surgery, the influence of oral antiplatelet therapy on perioperative bleeding, and the strategies that can be adopted to minimize the risk of bleeding. The hemorrhagic risks are set against the established clinical benefits of administering oral antiplatelet therapy in the perioperative setting. The article is based upon the results of a comprehensive MEDLINE search (1970 to 2003), supplemented by review of article bibliographies, that was conducted for relevant English language articles on CABG surgery and its complications, with a focus on the hemorrhagic risks associated with perioperative use of the oral antiplatelet agents aspirin and clopidogrel (selective and irreversible inhibitors of collagen- and ADP-induced platelet aggregation, respectively). Accordingly, the intravenous antiplatelet agents (glycoprotein IIb/IIIa receptor antagonists) and the problem of emergency CABG-related bleeding following intravenous antiplatelet therapy fall outside the scope of this review.
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Benefits of Oral Antiplatelet Therapy in CABG Surgery |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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Platelets are also implicated in the pathogenesis of graft occlusion post-CABG. On initial exposure to blood, the vascular graft is susceptible to surface clot formation, consisting of platelet aggregates, fibrin (generated from activation of the coagulation cascade), and entrapped erythrocytes. This initial phase of pseudointimal hyperplasia is followed by smooth muscle cell infiltration, and the resulting intimal hyperplasia can evolve into stenotic thickening, with a gradual reduction in graft patency. Aortocoronary grafts are susceptible to acute thrombotic occlusion during the first month after CABG surgery and, subsequently, to atherosclerotic obstruction [5]. Cumulative saphenous vein graft occlusion rates in the first year after CABG surgery are 
10% to 15%; annual graft occlusion rates are typically 1% to 2% between years 1 and 6; and 4% between years 6 and 10 after surgery [5]. Consequently, by 10 years post-CABG, only 60% of vein grafts remain patent, and only 50% of patent grafts are free of significant stenosis [5].
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Aspirin |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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100 mg/day) initiated either on the day preceding CABG surgery [17] or in the immediate postoperative period (1 hour to 5 days after surgery) [10, 12, 18, 19]. The American College of Chest Physicians currently recommends that aspirin (325 mg/day) should be initiated 6 hours after CABG surgery and maintained for 1 year to reduce the risk of saphenous vein bypass graft closure [20]. Furthermore, initiation of aspirin in the first 48 hours after CABG surgery has been reported to reduce substantially the risk of in-hospital mortality (68% lower) and ischemic myocardial, cerebral, renal, and intestinal complications ( 40% to 70% lower) [9]. Aspirin use during this early postoperative period was a significant predictor of in-hospital survival (ie, from 48 hours to hospital discharge) [9]. Preoperative aspirin use in CABG patients appears to reduce the risk of perioperative myocardial infarction and in-hospital mortality [21, 22]. In a case-control study of patients undergoing isolated CABG (n = 8,641), aspirin administration within the 7-day period immediately preceding surgery reduced in-hospital mortality by 27% (or by 45% when adjusted for disease severity and comorbid factors) [22]. Similarly, preoperative oral antiplatelet therapy was linked to 30% reduction in perioperative mortality among the 80,881 patients on the Society of Thoracic Surgeons National Database who underwent CABG surgery between 1980 and 1990 [23]. Conversely, in a prospective evaluation of 5,065 patients undergoing CABG surgery, preoperative discontinuation of aspirin was reported to increase the risk of in-hospital mortality; this effect was evident regardless of whether or not perioperative antifibrinolytic therapy or postoperative platelet transfusion were performed [9].
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Clopidogrel |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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To date, specific assessment of the efficacy of clopidogrel in CABG surgery is confined to an analysis of results for patients with non-ST segment elevation acute coronary syndromes undergoing surgical revascularization within the wider context of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial (see below) [28]. According to this analysis, the dual antiplatelet combination conferred similar relative benefit among the subset of patients undergoing CABG surgery (n = 2,072) as in the overall CURE trial population (n = 12,562) [28]. Aspirin plus clopidogrel produced a 19.0% reduction relative to aspirin alone (13.4% vs 16.4%) in the risk of cardiovascular death, myocardial infarction or stroke among those patients who underwent CABG surgery during the initial hospitalization (n = 1,013) and a 11.0% relative risk reduction (14.5% vs 16.2%) among patients who underwent CABG surgery at any time during the treatment period [28]. Overall, patients were randomized to clopidogrel treatment a median of 26 days before CABG surgery; for those patients undergoing surgery during the initial hospitalization, the corresponding figure was 12 days. (The timing of discontinuation of clopidogrel before surgery was variable, being dictated by the local surgeon rather than by the study protocol.) The clinical benefits of aspirin plus clopidogrel were mainly manifest during the preoperative period, as reflected in relative risk reductions (vs aspirin alone) in the primary endpoint of 18% and 3% before and following CABG surgery, respectively. Thus, initiation of clopidogrel in the emergency department effectively prevented the early (preoperative) occurrence of approximately 10 ischemic events in every 1,000 patients proceeding to CABG surgery. However, attempts to demonstrate a treatment effect after surgery were compromised by the decision to withhold clopidogrel (for a median of 10 days) postoperatively and the failure to resume treatment in all patients.
In the nonsurgical setting, the clinical benefits of long-term clopidogrel therapy in preventing recurrent ischemic events in patients with atherothrombotic disease are well established (Table 1). The clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) study, a randomized trial in patients with established atherothrombosis (n = 19,185), reported a significant relative risk reduction in the primary composite endpoint (first occurrence of ischemic stroke, myocardial infarction or vascular death) of 8.7% in favor of clopidogrel (75 mg/day) over aspirin (325 mg/day) over a treatment period of (mean) 1.9 years [29]. Patients who had previously undergone cardiac surgery (n = 1,480) derived particular benefit from clopidogrel, as reflected in significant risk reductions relative to aspirin in vascular death (39%), myocardial infarction (38%), all-cause rehospitalization (25%), and rehospitalization for ischemia or bleeding (27%) [30].
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The clopidogrel for the reduction of events during observation (CREDO) trial evaluated the short-term benefits of combined aspirin and clopidogrel pretreatment and the long-term benefits of sustained therapy in the setting of percutaneous coronary intervention (PCI) [33]. Coadministration of a loading dose of clopidogrel (300 mg) with aspirin (325 mg) in the period 6 to 24 hours before PCI resulted in a significant 38.6% risk reduction relative to aspirin in the composite endpoint of death, myocardial infarction or urgent target vessel revascularization in the first month post-PCI. Treatment 3–6 hours pre-PCI did not reduce events. After 12 months of treatment, patients receiving clopidogrel (75 mg/day) plus aspirin (81 to 325 mg/day) had a significant 26.9% relative risk reduction in the combined endpoint of death, myocardial infarction or stroke.
On the basis of the demonstrated benefits of ticlopidine on graft patency, and the established safety advantage of clopidogrel over ticlopidine, the American College of Chest Physicians recommends that clopidogrel (300 mg loading dose) should be initiated 6 hours after CABG surgery, and continued as long-term therapy (75 mg/day) to maintain graft patency in patients who are allergic to aspirin [20]. It remains to be determined whether clopidogrel should be used as an alternative to aspirin or in combination with aspirin, in the early postoperative period, although current thinking tends to favor the latter approach. The recent joint American College of Cardiology and American Heart Association (ACC/AHA) guidelines for medical management of acute coronary syndromes do, however, recommend that clopidogrel should be administered with aspirin on hospital admission and continued for up to 9 months [34].
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Bleeding Complications in CABG Surgery |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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1 L, [35] with some 30% of patients experiencing blood loss in excess of this amount [36]. The incidence of significant bleeding (variously defined as > 10 U of blood transfused in the perioperative period or blood loss > 100 mL/hour for 2 consecutive hours) is generally 3% to 5% [37], although it can be as high as 19% in patients undergoing emergent CABG after thrombolysis [38].
Major bleeding (according to the standard thrombolysis in myocardial infarction [TIMI] definition, blood loss with a 15% absolute decrease in hematocrit or a 5 g/dL in hemoglobin, or intracranial hemorrhage [39], the equivalent of 5 U of transfused blood with no change in hematocrit) is reported to occur in 10% of patients in the first month after CABG surgery [40]. Surgical re-exploration for hemorrhagic complications (generally indicated when blood loss exceeds 10 mL/kg in the first hour or 5 mL/kg on average over the first 3 hours postoperatively, or when bleeding occurs after cessation of chest tube drainage) is required in an estimated 2% of patients undergoing initial CABG and 3% of those undergoing repeat CABG surgery [41, 42]. Excessive bleeding (with or without surgical re-exploration), although not usually fatal, results in increased blood transfusion rates, risk of infection, and additional hospital costs [43]. Furthermore, surgical re-exploration secondary to bleeding confers added risk of anesthetic complications, prolongs mechanical ventilation and hospital stay, and is associated with an increased mortality rate [44].
In the great majority of cases, CABG-related bleeding can be attributed either to defective surgical hemostasis or to acquired hemostatic defects, most commonly those related to transient platelet dysfunction [37, 45]. Thrombocytopenia and impaired platelet function are frequent sequelae of the cardiopulmonary bypass procedure: platelet counts are reduced to 50% of preoperative levels by sequestration and hemodilution [46], while platelet function is markedly impaired by hypothermia and mechanical filtering [46–48]. Platelet adhesion to foreign surfaces in the extracorporeal circuit, mediated by interaction between platelet glycoprotein IIb/IIIa receptors and surface-bound fibrinogen in the oxygenator and bypass tubing [49], is followed by platelet activation, the release of platelet contents and conformational changes resulting in loss of platelet aggregatory responses to ADP and collagen [50]. Platelet dysfunction may also be related to activation of coagulation or fibrinolysis during cardiopulmonary bypass [51, 52]. The platelet defect increases progressively with duration of cardiopulmonary bypass, but it is nevertheless a transient phenomenon, with bleeding time normalizing 2 to 4 hours postoperatively [37]. However, physiologic hemostasis results in a secondary fall in platelet numbers during the early postoperative period and complete recovery usually takes several days [53].
Risk factors for postoperative bleeding and perioperative use of blood products are multifactorial and include advanced age, female gender, chronic renal disease, diabetes, low hematocrit, prolonged cardiopulmonary bypass time, reoperation, emergency operation, the proximity of antiplatelet/thrombolytic therapy to CABG surgery, and the use of anticoagulants during the CABG procedure [46, 54, 55]. Similarly, advanced age, renal failure, longer time on cardiopulmonary bypass, higher numbers of distal anastomoses, and use of internal mammary artery grafts are risk factors for re-exploration [44].
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Effect of Antiplatelet Therapy on Post-CABG Bleeding |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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2 days before surgery) of aspirin ( 75 mg/day) increases blood loss, transfusion requirements, and re-exploration rates for bleeding in CABG patients (Table 2) [11, 13, 56–62]. Hemorrhagic effects of aspirin variously include a twofold increase in mediastinal blood loss, increased chest tube blood loss and the need for prolonged chest tube drainage [57], a twofold increase in erythrocyte, platelet and fresh-frozen plasma requirements [58], and a fourfold increase in the incidence of surgical re-exploration for control of bleeding (6.6% vs 1.7%) [59]. In addition, preoperative aspirin has been identified as an independent multivariate predictor of postoperative blood transfusion in high-risk patients [63].
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Importantly, perioperative transfusion requirements have been found to depend on the aspirin-free interval: in first-time CABG surgery patients, increased allogenic erythrocyte transfusion requirements were confined to those who discontinued aspirin less than 2 days before surgery; patients who stopped aspirin 3 to 7 days preoperatively had little or no increased transfusion requirement [68]. Moreover, initiation of aspirin therapy in the first 48 hours after CABG surgery did not increase bleeding in the period before hospital discharge [9].
Clopidogrel
Several recent, small-scale observational studies in nonrandomized series of patients have indicated that preoperative use of combined clopidogrel and aspirin in CABG patients increases the risk of postoperative bleeding [42, 66, 69]; however, the impact on transfusion requirements and surgical re-exploration rates in the perioperative and immediate postoperative ( 48 hours) period is less clear [42, 66, 69–72]. The relationship between oral antiplatelet drug use and perioperative bleeding/blood product transfusion requirements is likely confounded by multiple factors, such as patient comorbidity, the CABG procedure (elective or emergent/urgent), preoperative anticoagulation and thrombolysis, and autologous whole blood use. Unstable patients undergoing emergency CABG might be expected to receive more intensive perioperative support and blood product transfusions than elective CABG patients. Moreover, the relative contribution of clopidogrel to any observed bleeding with dual antiplatelet therapy is uncertain in observational studies.
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Observational Studies |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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An observational study of 224 patients undergoing nonemergency first-time CABG surgery reported that patients exposed to clopidogrel in the 7 days preceding surgery (86% of whom received concomitant aspirin) had significantly higher mean chest tube outputs (8 and 24 hours post-CABG) and blood product (erythrocyte, platelet, and fresh frozen plasma) requirements, and a higher incidence of reoperation for bleeding (6.8% vs 0.6%) than those unexposed to clopidogrel (47% of whom received aspirin) [66]. It should be noted, however, that the nonclopidogrel group had less severe coronary artery disease than the clopidogrel group and that the reoperation rate for bleeding in the nonclopidogrel group was considerably lower than that reported in previous observational studies [42]. Although reoperations for bleeding were confined to those patients exposed to clopidogrel in the 3 days preceding surgery, 24-hour chest tube output correlated poorly with the clopidogrel-free interval before surgery (Fig 1).
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7 days previously [n = 7]) revealed significantly greater packed red blood cell (10.8 vs 1.7 U), fresh frozen plasma (7.7 vs 1.7 U), and platelet (9.0 vs 0.2 U) requirements in the former group [69]. Similarly, another retrospective observational study, involving 659 patients undergoing first CABG surgery, indicated that administration of clopidogrel or clopidogrel + aspirin within the 7-day period immediately preceding surgical revascularization led to increased blood product requirements in the perioperative period [70]. When compared with those patients who received neither drug (n = 497), patients exposed to clopidogrel (n = 11) or clopidogrel + aspirin (n = 46) received significantly more units of packed red blood cells (2.9 and 2.4, respectively, vs 1.4), platelets (3.6 and 3.7, respectively, vs 1.0), and fresh frozen plasma (2.5 and 3.1, respectively, vs 1.6) during CABG surgery and in the second postoperative day. In addition, the associated risk of excessive blood product transfusion was highest among recipients of the antiplatelet combination (adjusted odds ratio 2.2; 95% confidence interval = 1.1 to 4.3) [70]. In contrast, a retrospective analysis of 153 consecutive patients undergoing conventional CABG surgery indicated that clopidogrel exposure in the 48-hour preoperative period had no significant impact on blood transfusion requirements or surgical re-exploration rates [71]. While clopidogrel-treated patients tended to exhibit higher chest tube drainage than the nonclopidogrel-treated patients at 6 and 24 hours post-CABG (355 vs 266 mL and 760 vs 580 mL, respectively), erythrocyte and platelet transfusion rates as well as re-exploration rates for bleeding were similar in the two groups. In this study preoperative aspirin use was only marginally higher in the clopidogrel than in the nonclopidogrel group (98% vs 86%), and in all other respects (age, gender, preoperative heparin use, hematocrit, platelet count and coagulation measurements, and cross-clamp and bypass times) the groups appeared similar. Likewise, a recent prospective evaluation of 1,628 consecutive patients undergoing (predominantly elective) CABG surgery found that preoperative clopidogrel use (n = 48) did not increase blood transfusion requirements or surgical re-exploration rates [72]. Neither in elective nor in nonelective CABG surgery did clopidogrel pretreatment significantly influence chest tube output, the need for blood/blood product transfusions or surgical re-exploration, or the duration of intensive care or hospital stay [72]. The fact that the clopidogrel-pretreated group contained a higher proportion of nonelective cases (25% vs 10%) than the nonclopidogrel group makes the findings of comparable bleeding rates in the two groups even more impressive. These observational studies are limited, however, by the fact that any observed difference in postoperative bleeding might be due to patient/procedural factors other than clopidogrel treatment.
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Randomized Studies |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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5 days before surgery (n = 912), major bleeding in the 7-day period following surgery tended to be more frequent in the clopidogrel + aspirin arm than in the aspirin arm (9.6% vs 6.3%) [31]. In contrast, there was no excess of major bleeding in those patients (n = 910) who underwent CABG surgery more than 5 days after the last clopidogrel dose (4.4% vs 5.3%) [31]. Analysis of bleeding episodes within the first 7 days following CABG surgery revealed an absolute excess of 2.8% in the incidence of life-threatening bleeding with clopidogrel plus aspirin over aspirin alone in those patients who underwent CABG surgery 5 days after the last clopidogrel dose, but no such excess for those discontinuing oral antiplatelet therapy more than 5 days before surgery [28]. Similarly, reoperation rates for bleeding in the acute postoperative period tended to be higher with clopidogrel + aspirin than with aspirin alone (4.1% vs 2.3%) for those patients undergoing CABG surgery 5 days after the last clopidogrel dose [28]. In contrast, there was a tendency for a lower reoperation rate with clopidogrel + aspirin versus aspirin alone (1.5% vs 2.6%) in those discontinuing clopidogrel more than 5 days before surgery [28]. Further analysis, using the validated TIMI definition of bleeding [39], revealed no significant excess of major perioperative bleeding with dual antiplatelet therapy compared with aspirin monotherapy, even when administered 5 days before CABG surgery (2.2% vs 2.4%) [28]. Likewise, the incidence of severe/life-threatening bleeding (GUSTO definition) did not differ significantly between the two treatment arms, even when antiplatelet treatment was discontinued 5 days before CABG surgery (4.0% vs 2.8%) [28]. This indicates that the excess bleeding seen with clopidogrel predominantly comprises moderate rather than major bleeding. Insight into the relative contributions of aspirin and clopidogrel to the risk of bleeding with dual antiplatelet therapy is provided by a recent posthoc analysis of the CURE trial data [73]. Although addition of clopidogrel to aspirin slightly increased the rate of major bleeding over the 12-month treatment period, the absolute risk of bleeding was largely dictated by the dose of aspirin. Indeed, the incidence of major bleeding with clopidogrel plus low-dose aspirin (75 to 100 mg/day) or medium-dose aspirin (101 to 199 mg/day) therapy (3.0% and 3.4%, respectively) was lower than that with high-dose aspirin (200 to 325 mg/day) alone (3.7%). This reduced bleeding risk with low-dose aspirin is consistent with findings from controlled studies of other aspirin-containing oral antiplatelet regimens [74]. Similarly, serious bleeding was reported to be less common with lower doses (75 to 162 mg/day) than with higher doses (162 to 325 mg/day) of aspirin (2.4% vs 3.3%) when used alone or in combination with the oral GP IIb/IIIa receptor antagonist lotrafiban [75].
In the CREDO trial (detailed above), addition of clopidogrel (75 mg/day) to aspirin (81 to 325 mg/day) monotherapy tended to elevate the incidence of major bleeding (intracranial bleeding or bleeding associated with a decrease in hemoglobin >5 g/dL or hematocrit 15%): 8.8% versus 6.7% over the 12-month treatment period [33]. Approximately three-quarters of all major bleeds occurred in the subset of patients undergoing CABG surgery, but interestingly there was no difference in the bleeding risk by treatment group (in the clopidogrel and placebo arms, 68% and 78% respectively) [33].
More recent data on the risk of bleeding with clopidogrel pre-CABG come from the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)—Thrombolysis in Myocardial Infarction (TIMI) 28, which enrolled 3491 patients with acute ST-segment elevation MI treated with thrombolysis [76]. Patients were randomized to receive either clopidogrel (300 mg loading dose, then 75 mg once daily) or placebo in the emergency department and continued up until the time of angiography (mean 3.5 days), after which it was discontinued prior to CABG if required. Overall, a highly significant benefit on patency of the infarct related artery was observed (36% improvement, p = 0.00000036). Following thrombolysis, 136 patients underwent CABG during their index hospitalization, and in this group, treatment with clopidogrel was not associated with a significant excess in major bleeding through 30 days (7.5% with clopidogrel vs. 7.2% with placebo, p = 1.00), even in those who underwent CABG within 5 days of discontinuation of study medication (9.1% vs. 7.9%, respectively, p = 1.00). These new data suggest that with a strategy of stopping clopidogrel immediately post catheterization, the apparent increase in bleeding may be avoided.
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Strategies to Reduce the Risk of Antiplatelet-Associated Postoperative Bleeding |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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7 days after drug discontinuation [78]. This provides the rationale for the current ACC/AHA recommendation that, in appropriate clinical settings such as stable angina and low-risk plaque morphology, it may be prudent to discontinue aspirin 7 to 10 days before elective cardiac surgery to avoid the risk of excessive postoperative bleeding [14]. By delaying elective CABG surgery for this period after discontinuation of aspirin, complete recovery of platelet function is assured; oral antiplatelet therapy may then be resumed in the early postoperative period (generally within the first 6 hours) once bleeding has subsided [13, 59, 61]. However, since substantial recovery of platelet function occurs within 3 days of withdrawing aspirin [79], a shorter aspirin-free interval may well be sufficient. Alternatively, intraoperative administration of aprotinin, a serine protease inhibitor with antifibrinolytic activity, is an option for counteracting the bleeding risk in the aspirin-pretreated patient [80, 81]. Indeed, the reduction in postoperative bleeding obtained with high-dose aprotinin during CABG surgery is enhanced in patients receiving low-dose aspirin [21]. For patients receiving clopidogrel, the optimal delay before elective CABG surgery is unclear. The previously cited evidence from observational and randomized studies would suggest that a 5-day drug-free interval may be appropriate [31, 66]. This is reflected in the recent ACC/AHA recommendation that clopidogrel should be withheld for at least 5 days in patients scheduled for elective CABG surgery [14, 34].
Urgent and Emergent CABG Surgery
Delay of surgery until platelet function has recovered is usually not a feasible option for patients requiring urgent or emergent CABG surgery (eg, for unstable angina or failed angioplasty). Under these circumstances, prophylactic platelet transfusion during surgery may be considered for rapid reversal of any pro-hemorrhagic tendency, even when the platelet count is normal [42]. However, this approach carries the risk of acute reversal of the clinical benefits of platelet inhibition [82]. For this reason, perhaps, it may be more appropriate to reserve platelet transfusion for patients with clinical bleeding after discontinuation of extracorporeal circulation and neutralization of heparin with protamine, an approach adopted in abciximab-treated patients requiring CABG surgery [83].
Alternative approaches when immediate CABG surgery is unavoidable include the prophylactic use of aprotinin and tranexamic acid to promote hemostasis during the early reperfusion period [21, 52, 80]. Clinical experience suggests that intraoperative use of aprotinin or tranexamic acid may permit surgery to be conducted safely on patients presenting on aspirin and clopidogrel [84], although this remains to be confirmed. Aprotinin offers the advantage of reducing overall bleeding in patients exposed to aspirin while apparently preserving platelet function during cardiopulmonary bypass [45]. Earlier concern about possible prothrombotic effects of this potent hemostatic agent appear to be misfounded: aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the protease-activated receptor 1 [85], suggesting that it may instead have significant antithrombotic activity.
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Comment |
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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A proposed algorithm, based on the literature reviewed here, attempts to balance the benefits and risks of dual antiplatelet therapy in the perioperative setting (Fig 2). In summary, for the patient requiring urgent or emergent CABG surgery, any risk of bleeding associated with continuation of antiplatelet therapy is likely to be greatly outweighed by its clinical benefit in preventing further ischemic events in the period before revascularization.
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TopAbstractIntroductionBenefits of Oral Antiplatelet...AspirinClopidogrelBleeding Complications in CABG...Effect of Antiplatelet Therapy...Observational StudiesRandomized StudiesStrategies to Reduce the...CommentReferences |
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 J. W. Eikelboom and J. Hirsh Bleeding and management of bleeding Eur. Heart J. Suppl., October 1, 2006; 8(suppl_G): G38 - G45. [Abstract] [Full Text] [PDF]
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