doi: 10.1161/CIRCULATIONAHA.104.524611
(Circulation. 2005;112:I-276 – I-280.)
© 2005 American Heart Association, Inc.
Surgery for Coronary Artery Disease |
Aprotinin Decreases Postoperative Bleeding and Number of Transfusions in Patients on Clopidogrel Undergoing Coronary Artery Bypass Graft Surgery
A Double-Blind, Placebo-Controlled, Randomized Clinical Trial
From the Department Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
Correspondence to Dr Jan van der Linden, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska Institute, Karolinska University Hospital, SE-17176 Stockholm, Sweden. E-mail janvan{at}ki.se
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Abstract |
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Background— Clopidogrel, an irreversible platelet inhibitor, is used to treat patients with unstable angina. These patients often present for coronary artery bypass graft surgery (CABG) and are at increased risk for perioperative bleeding. The current investigation evaluates the impact of aprotinin on bleeding and transfusion requirements in clopidogrel-treated patients undergoing CABG.
Methods and Results— Seventy-five consecutive patients with unstable angina, administered clopidogrel <5 days before CABG, were randomized. Using a double-blind design, patients received full-dose aprotinin (n =37) or saline (n =38). Elapsed times between the last dose of clopidogrel and start of the operation were similar between the 2 groups [aprotinin, 58±28 hour (mean± SD); control, 54±27 hour; P=0.86], as were age (aprotinin, 66.4±10 years; control, 68.3±10 years; P=0.51), number of distal anastomoses (aprotinin, 3.6±1.0; control, 3.7±1.0; P=0.79), operative times (aprotinin, 192±48 minutes; control, 200±53 minutes; P=0.55), and lowest intraoperative hemoglobin level (aprotinin, 87±14 g/L; control, 88±14 g/L; P=0.60). Postoperative bleeding was 760±350 mL in aprotinin-treated patients versus 1200±570 mL (P<0.001) in control. During the hospital stay, patients in the aprotinin group received 1.2±1.5 and 0.1±0.4 U of erythrocytes and platelets, respectively, versus 2.8±3.2 (P=0.02) and 0.9±1.4 (P=0.002) units in the control. In the aprotinin group, 53% of patients received transfusions, whereas 79% of controls were exposed to blood products (P=0.02).
Conclusions— Intraoperative aprotinin decreases postoperative bleeding and the number of transfusions in patients undergoing CABG and treated with clopidogrel <5 days before surgery.
Key Words: angina • hemorrhage • inhibitors • platelets • surgery
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Introduction |
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Antiplatelet and antithrombin therapy has been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome (ACS). The combination of clopidogrel and aspirin is superior to aspirin alone for patients hospitalized with non-ST-elevation ACS.1 Moreover, an invasive approach is the preferred strategy in patients with ACS and signs of ischemia on electrocardiography or raised levels of biochemical markers of myocardial damage.2 Patients with ACS often undergo urgent or acute angiography, followed by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). After PCI, long-term clopidogrel therapy significantly reduces the risk of adverse ischemic events.3 Thus, many ACS patients are treated with the platelet inhibitor clopidogrel, in addition to aspirin, and, possibly, low molecular weight heparin (LMWH). However, aggressive antiplatelet and antithrombin therapy has drawbacks, as patients are prone to bleeding, especially if urgent or acute CABG is required. Recent clinical studies have confirmed that clopidogrel, in combination with aspirin before CABG, is associated with higher postoperative bleeding and blood product use.4–6 In one study,6 clopdidogrel induced preoperative platelet dysfunction, measured as ADP aggregometry response <40%, identified all but 1 case of severe coagulopathy requiring multiple transfusions of platelets and packed red blood cells (PRBCs). The potential risks and benefits of early or delayed surgery in patients with ACS on medication with the irreversible platelet inhibitor clopidogrel are debatable. Aprotinin, a serine protease inhibitor, used in cardiac surgery to reduce bleeding and transfusion requirements,7,8 may be of use in patients treated with aggressive antiplatelet therapy who undergo urgent or acute surgery. The aim of this study was to investigate whether or not aprotinin decreases bleeding and transfusion requirements after urgent or acute CABG in patients treated with clopidogrel <5 days before surgery.
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Methods |
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Patient Recruitment
Seventy-five consecutive patients with unstable angina unsuitable for PCI and scheduled for urgent or acute isolated CABG at Karolinska University Hospital were included. All of the patients had been given an oral starting dose of 300 mg clopidogrel followed by a daily intake of 75 mg. Surgery was scheduled for the next available session. Only patients in whom oral clopidogrel treatment had been discontinued <5 days before surgery, were eligible. No patient considered eligible for enrollment declined to participate. Before the start of surgery, patients were randomized to full-dose aprotinin (Trasylol, Bayer AG) IV intraoperatively or an equal volume of saline solution. Random assignment was conducted using unmarked envelopes, each containing a card indicating treatment with aprotinin or placebo. A nurse, assigned to another department in our hospital, was responsible for the preparation of placebo and treatment solutions, which were identical in appearance and packing. Thus, neither patients nor staff were aware of treatment assignment.
After induction of anesthesia, patients received a 1-mL test dose of aprotinin or placebo. If no adverse reaction occurred, either aprotinin [2x106 kallikrein inhibiting units (KIU) bolus before start of surgery, 2x106 KIU in cardiopulmonary bypass (CPB) prime, and 0.5x106 KIU/h during surgery] or an equal volume of placebo was administered. The Hospital Ethical Committee approved the study, and written informed consent was obtained from all of the patients. Investigational procedures were in accordance with institutional guidelines.
Operative Procedure
Anesthetic and surgical management were standardized for all of the patients. Operations were performed through a standard complete median sternotomy with a CPB flow rate of 
2.4 L/m2 and mild hypothermia (34°C). CPB was instituted with a standard kit, a hollow fiber membrane oxygenator (Dideco Simplex D708, Dideco), and a roller pump perfusion system (Stöckert Instrumente GmbH). The CPB circuit was primed with Ringer’s acetate, 300 mL of mannitol 10%, and 200 mL of aprotinin or placebo and carefully deaired. The distal ascending aorta was cannulated, and a 2-stage venous cannula was inserted into the right atrium and inferior vena cava. Myocardial preservation consisted of intermittent antegrade and retrograde cold blood cardioplegia. Cardiotomy suction, 1.5 L/min, was used intermittently throughout CPB. Cell salvage was not used in any patient. An off-pump procedure was preferred, if intraoperative epiaortic ultrasound of the ascending aorta, performed on a routine basis before arterial and venous cannulation, showed severe athersclerosis. Two 32-Fr chest tubes (Argyle, Sherwood Medical) were inserted through separate skin incisions and placed in the left pleura and mediastinum, and a negative pressure of 15 cm of H2O was applied.
Anticoagulation was achieved with sodium heparin (ie, porcine, 400 IU/kg) IV and 7500 IU in the CPB prime and monitored with serial measurements of the activated clotting time (ACT) performed with a kaolin-activated Hemotec device (Medtronic Hemotec Inc). The ACT was maintained above 400 s during CPB and when anastomoses were performed during off-pump surgery. At completion of CPB and anastomoses during off-pump surgery, respectively, heparin was reversed with protamine sulfate given in a 1:1.3 ratio. After this dose, an additional dose of 100 mg of protamine sulfate was given if the ACT remained above 140 s. Tranexamic acid (range, 0 to 6 g IV) was given at the discretion of the anesthetist, if excessive drainage without clots was observed after the reversal of heparin with protamine sulfate and transfusion of platelets.
Measurements
Mediastinal drainage was measured at hourly intervals in the intensive care unit, and mediastinal drains were removed when blood loss was <100 mL over 4 hours. Mediastinal shed blood was autotransfused hourly during the first 4 hours in the intensive care unit if the bleeding was >100 mL per hour.
All of the patients had an ECG the day before surgery, the first day after surgery, before discharge, and additionally at the discretion of the attending physician. Serum levels of troponin-T were followed preoperatively, including the day before surgery and postoperatively on day 1.
Preoperative use of aspirin and LMWH within 24 hours before surgery, as well as the number of hours elapsing between the last intake of clopidogrel and start of surgery, were recorded. Also, transfusions of any blood products were recorded during the operation, postoperatively until the next morning, and every postoperative day until discharge. PRBC was given at an arterial hemoglobin of <70 g/L during CPB and <85 g/L after CPB, except in patients with major ongoing hemorrhage; plasma was given if >2 U of PRBC was given; and platelets were given if bleeding was excessive and clots were missing after the reversal of heparin with protamine.
Statistics
Data were analyzed with the SPSS version 11.0 statistical program. Data were tested for normality with the Kolmogorov-Smirnov test, and some data were found to be not normally distributed. Conventional nonparametric tests were applied for all of the data. Differences were considered significant at P<0.05.
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Results |
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Baseline characteristics and operative data are listed in Table 1. Thirty-eight patients were administered saline, and 37 were administered aprotinin. All of the patients were first-time cardiac surgery patients and were treated with clopidogrel <5 days before surgery. The last oral dose of clopidogrel was taken 54.4±27 and 58.0±28 hours before start of surgery in the control and treatment groups, respectively (P=0.86). Corresponding medians were 51 hours (25/75 percentiles, 31/75; ranges, 5 to 120) and 50 hours (25/75 percentiles, 30/82; ranges, 25 to 102), respectively (P=0.86). Almost all of the patients also received aspirin and LMWH within 24 hours of surgery with no significant differences between the groups. Three patients in each group underwent off-pump CABG because of severe arteriosclerosis of the ascending aorta. Routine intraoperative transesophageal echocardiography identified 1 patient with a preoperatively unknown significant mitral regurgitation in the aprotinin group, and this patient underwent concomitant mitral valve repair.
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No significant differences between the groups were observed regarding preoperative, intraoperative, and postoperative hemoglobin levels (Table 2). Total postoperative bleeding was 1200±570 mL in the placebo versus 760±350 mL in the aprotinin group (P<0.001; Figure 1), a 37% reduction compared with placebo. Control subjects received significantly more units of PRBC and platelets during the first 24 postoperative hours, as well as the total hospital stay (Table 2). Thus, more than twice as many units of blood products were given to control patients (4.8±5.7) as compared with aprotinin-treated patients (1.8±2.3, P=0.02). Seventy-nine percent of patients in the placebo group received blood transfusions during the hospital stay versus 53% in the aprotinin group (P=0.02). Fifty-five percent (55%) of patients treated with saline received 1.8±1.8 g of tranexamic acid, as compared with 25% of aprotinin-treated patients (P=0.008) receiving 0.5±0.9 g (P=0.001).
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Clinical outcomes are depicted in Table 3. One patient in the control group died on postoperative day 25 primarily because of postoperative mediastinitis. Three deaths occurred in the treatment group. One patient experienced atrial fibrillation, a stroke on postoperative day 2, and died on postoperative day 8. A second patient experienced a postoperative stroke and died on postoperative day 13. The third patient had a myocardial infarction in the operating room and died. This patient was excluded from the postoperative analysis. None of the patients who died received tranexamic acid. The aprotinin group had significantly higher preoperative troponin-T values than the control group (P=0.02) but did not experience a rise in values on postoperative day 1 (P=0.47). In contrast, troponin-T levels in the control group increased significantly on postoperative day 1 (P<0.001). Thus, the change in troponin-T differed significantly between the groups (P=0.003).
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Discussion |
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The major findings of this randomized, double-blind, placebo-controlled trial are that intraoperative aprotinin decreases postoperative bleeding and transfusion requirements in patients undergoing CABG and treated with clopidogrel, in addition to aspirin and LMWH, <5 days before surgery.
Several recent nonrandomized studies have demonstrated that clopidogrel within 4 days of CABG is associated with increased blood loss, reoperation rates for bleeding, and increased use of blood products, including PRBC and platelets.4–6 These findings raise concern about the routine adminstration of clopidogrel before anticipated but undecided PCI. Increasingly, centers use an early interventional strategy for ACS similar to that described in Fast Revascularization During Instability in Coronary Disease Trial II.2 In addition, clopidogrel, together with aspirin, is superior to aspirin alone for patients hospitalized with non-ST-elevation ACS.1 The current American College of Cardiology/American Heart Association Practice Guidelines state as a class I recommendation, "If clinical circumstances permit, clopidogrel should be withheld for five days before performance of CABG surgery. (Level of Evidence: B)."9 However, Fox et al10 reported that in patients with non-ST-elevation ACS treated with the combination of clopidogrel and aspirin, benefits and risks of early and long-term clopidogrel therapy (freedom from cardiovascular death, MI, stroke, or life-threatening bleeding) are similar, independent of revascularization (CABG or PCI). Overall, the benefits of starting clopidogrel on admission appeared to outweigh the risks, even among those who proceeded to CABG during the initial hospitalization. For patients undergoing CABG and continuing clopidogrel within 5 days before CABG, a nonsignificant trend of 
1 additional patient per 100 experienced life-threatening bleeding, and an additional 2 patients per 100 experienced a major bleed.10 The contribution of aspirin to bleeding was uncertain, because the timing of aspirin discontinuation was not recorded.10
If urgent surgery is preferred, excessive bleeding induced by clopidogrel remains an issue. Blood transfusions during cardiac surgery are associated with increased in hospital morbidity (infectious complications11–13) and mortality.14 In this context, aprotinin may be of interest, because it reduces overall bleeding and transfusion requirements in patients exposed to aspirin.15 In animals, aprotinin has been shown to reduce bleeding time prolongation from clopidogrel.16 However, we are not aware of any earlier published randomized trial evaluating the effect of aprotinin on bleeding and the need for transfusions in patients receiving clopidogrel undergoing CABG. Clopidogrel selectively acts to inhibit platelet aggregation by reducing activation in response to ADP, whereas aprotinin positively affects platelet aggregation and adhesion in CPB patients through multiple mechanisms mediated by its effects on kallikrein, thrombin, and plasmin, including inhibition of undesirable platelet activation and aggregation by thrombin at PAR-117,18 and allowing epinephrine and collagen to stimulate appropriate clot formation at wound sites.19 These multiple mechanisms likely contribute to the clinical effects achieved in our current study. Our study shows that aprotinin can be used to reduce bleeding and transfusion requirements in patients on clopidogrel medication. Patients in the treatment group bled 37% less postoperatively and received fewer units of PRBC, platelets, and total number of blood products. Controls received an average total of 4.8 U of blood products as compared with 1.8 U in aprotinin-treated patients.
The hemostatic effect of aprotinin in patients with ACS undergoing CABG may have clinical disadvantages. Although uncommon, severe and fatal adverse events associated with extensive venous and arterial thromboses have been reported after CABG, both with the full-dose regimen and variations of the recommended dose.
At present, data are available from only 1 randomized multicenter trial8 that used postoperative coronary angiographic assessment and the recommended full dose in CABG patients. It showed that the incidence of saphenous vein graft thrombosis in the aprotinin group was not significantly higher than that observed in placebo when adjusted for risk factors associated with vein graft occlusion (aprotinin versus placebo risk ratio 1.05; 90% CI, 0.6 to 1.8). A recent meta-analysis of 35 randomized, controlled trials, including a total of 3879 patients, showed no increased risk in mortality, myocardial infarction, or renal failure in patients undergoing CABG who received aprotinin.20 Interestingly, a reduced risk of stroke was associated with patients who received aprotinin. We did not find any difference in stroke rate or mortality between the groups, although our study lacked the power to evaluate infrequent clinical outcomes. To study such end points, far more patients would have been needed. For example, a type II error may explain the nonsignificant tendency toward more reoperations because of bleeding in the control. In our study, aprotinin therapy was associated with a reduction in the postoperative elevation of troponin-T, in accordance with data reported by Taggart et al.21 These findings may be explained by the antithrombotic and antinflammatory mechanisms of action of aprotinin.17
A recent editorial in Circulation22 has highlighted the problem of clopidogrel resistance and therapy failure, because 5% to 15% of treated patients appear to be nonresponders. Several new methods for platelet function analysis are available to evaluate the response to clopidogrel medication.23 Thus, future studies may help to individualize antiplatelet treatment and identify patients requiring urgent surgery who may benefit the most from the use of intraoperative aprotinin.
One limitation of this study is that tranexamic acid was given at the discretion of the anesthetist if excessive drainage without clots was observed after the reversal of heparin with protamine sulfate and transfusion of platelets. However, tranexamic acid possesses similar antifibrinolytic properties as aprotinin, but without the reported platelet benefit, indicating that the effects of aprotinin in this study must logically be attributed to platelet effects rather than antifibrinolytic properties. This view is supported by our observation that in this double-blind study, tranexamic acid was administered to fewer patients in the aprotinin group and at lower doses than in the control.
In conclusion, full-dose aprotinin decreases bleeding and transfusion requirements after urgent or acute CABG in patients treated with clopidogrel <5 days before surgery.
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Acknowledgments |
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This study was supported by research grants from Bayer and Sanofi-BMS.
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Footnotes |
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Presented at the 77th Annual Scientific Sessions of the American Heart Association, New Orleans, La, November 7–10, 2004.
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