Asian Cardiovasc Thorac Ann 2008;16:483-487
© 2008 Asia Publishing EXchange Ltd
Aprotinin for Patients Exposed to Clopidogrel Before Off-Pump Coronary Bypass
Feza Nurözler, MD,
Tolga Kutlu, MD,
Güngör Küçük, MD
Division of Cardiovascular Surgery Central Hospital Izmir, Turkey
For reprint information contact: Feza Nurözler, MD Tel: 90 533 332 3088 Fax: 90 232 345 3456 Email: fnurozler{at}yahoo.com, Central Hospital, 1644 sok 2/2, Bayrakli, Izmir, Turkey.
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ABSTRACT
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To verify whether low-dose aprotinin reduces blood loss and blood product usage in patients with clopidogrel exposure within 5 days before off-pump coronary artery bypass, 51 patients with clopidogrel exposure were randomized in a double-blind fashion to receive low-dose aprotinin (25 patients), or placebo (26 patients). The baseline characteristics and number of distal anastomoses in the patients in each group were comparable. Time between the last dose of clopidogrel and start of the operation was similar in both groups, as was mean left ventricular ejection fraction. Chest tube drainage, blood product usage, and reoperation rate were significantly higher in the placebo group. In patients with unstable angina and recent clopidogrel exposure who are undergoing off-pump coronary artery bypass, intraoperative administration of low-dose aprotinin is recommended to reduce blood loss and transfusion requirements.
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INTRODUCTION
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Clopidogrel is an irreversible and potent inhibitor of platelet aggregation, used mainly to prevent clotting complications immediately before and after intracoronary stenting. In patients with acute coronary syndrome, carotid and peripheral vascular disease, or aspirin intolerance, cardiologists are increasingly favoring clopidogrel.1,2 As a result, more patients are undergoing urgent or emergency coronary artery bypass grafting (CABG) under the influence of clopidogrel. Its beneficial effect in preventing clot formation may become a hazardous effect on hemostasis in those who need urgent or emergency CABG.3,4 Generally, antiplatelet agents are discontinued at the appropriate time before surgery, but in some patients, delaying surgery may not be possible due to ongoing ischemia. Unfortunately, they have usually received a more potent antiplatelet agent such as clopidogrel. Avoiding cardiopulmonary bypass (CPB) and additional insults to already dysfunctional platelets, off-pump coronary artery bypass (OPCAB) has recently gained interest for use in patients with recent exposure to clopidogrel. Randomized trials, matched cohort and retrospective studies consistently demonstrate reductions in blood loss, reoperation for bleeding, and requirements for allogenic blood products in OPCAB compared to CABG on CPB.5 Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when used prophylactically at high-, low-, or even mini-doses in cardiac surgical patients.6 Aprotinin significantly reduced postoperative blood loss without reducing the transfusion rate after OPCAB, and decreased both postoperative bleeding and the number of transfusions in patients treated with clopidogrel before on-pump CABG.7,8 The objective of our study was to verify the various benefits of low-dose aprotinin in patients with clopidogrel exposure within 5 days before multivessel OPCAB.
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PATIENTS AND METHODS
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The study population consisted of 51 consecutive patients with unstable angina and clopidogrel exposure within 5 days before OPCAB performed between January 2003 and July 2005. All patients were advised of the procedures and their associated risks, in accordance with institutional guidelines, and gave consent. There were 37 men and 14 women, their mean age was 63.8 ± 8.4 years (range, 43–72 years). Patients were randomized in a double-blind fashion, according to a list of random treatment codes generated by a biostatistician using a block design. Thus, 25 patients were assigned to receive low-dose aprotinin (group A) and 26 had a placebo (group P). The blinding of intensive care unit (ICU) staff to the treatment protocol was conducted in an appropriate way. Patients in group A received a bolus of 1 x 106 KIU aprotinin over 30 min, followed by continuous infusion of 0.5 x 106 KIU·h–1 until the end of surgery. Mean aprotinin dose was 2.1 x 106 KIU in a mean volume of 210 mL. Patients in group P received 100 mL saline over 30 min, followed by continuous infusion of saline at 100 mL·h–1; mean placebo volume was 280 mL. Exclusion criteria included on-pump CABG, reoperation, endstage renal failure, liver dysfunction, preexisting bleeding disorders, warfarin usage, and exposure to glycoprotein IIb/IIIa inhibitors. Packed red blood cells were transfused if the hematocrit was < 25%. The clinical criterion for platelet and fresh frozen plasma transfusion in the ICU was chest tube drainage > 250 mL·h–1 after the 1st hour, despite a normalized activated clotting time (ACT). Perioperative infusion of platelets was also based on coagulation parameters (platelets < 80,000/mL, pathologic bleeding time > 10 min). Surgical reexploration was indicated when bleeding exceeded 400 mL during the 1st hour, or > 300 mL·h–1 during the next 3 hours, despite normalized ACT and global coagulation status (ACT < 110% of baseline, normalized thrombin time and/or bleeding time). Perioperative myocardial infarction (MI) was defined as new electrocardiographic or echocardiographic changes with creatine kinase MB (CK-MB) > 100 mg·dL–1 or CK-MB/total CK ratio > 10%.9 CK-MB and total CK levels were assessed within 12 hours after surgery. In patients who did not develop perioperative MI, CK-MB and total CK levels were not assessed thereafter. Preoperative demographics and other variables are given in Table 1
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Similar anesthetic and surgical procedures were carried out in all patients, according to the Central Hospital protocol. Anesthesia was induced with flunitrazepam 0.02 mg·kg–1 and fentanyl 10–20 µg·kg–1. Pancuronium bromide 0.1 mg·kg–1 was used for muscle relaxation. Anesthesia was maintained with successive doses of fentanyl isoflurane (0.5%–1%) added to the ventilation system when needed. Complete revascularization was aimed for in all patients. The same surgeon performed all procedures using a standardized technique for coronary revascularization through a full sternotomy incision. Stabilization and exposure of the coronary vessels have been described previously.9 The left internal mammary artery was prepared in 49 patients (96%). Anticoagulation was achieved with heparin (150 U·kg–1); the targeted ACT was 200 sec throughout the operation. No patient received additional heparin, tranexamic acid, or desmopressin. Exposure to aspirin within a week before surgery was similar in both groups (6 patients in group A, 8 in group P). Heparin was not given to any patient before surgery. At the end of the procedure, heparin was neutralized with protamine sulfate (1.5 mg/100 U heparin).
Continuous data are presented as mean ± standard deviation. Dichotomous variables are shown as percentages. Mean differences between the groups were analyzed using the Student t test. Proportional differences were compared by Fisher’s exact chi-squared analysis using SPSS software (SPSS, Inc., Chicago, IL, USA). Differences were considered significant when probability values were 
0.05. The sample size for both groups was calculated based on the following assumptions: type I error as 0.05, type II error as 0.20 (power 80%), and the minimum significant difference in mean drainage between groups was taken as 126.26 mL (the expected standard deviation of mean drainage was taken as 180 mL). The minimum significant difference between groups in mean creatinine clearance (as a safety outcome variable) was taken as 14.2 mL (the expected standard deviation of mean creatinine clearance was taken as 20 mL).
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RESULTS
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The mean number of grafts per patient in the whole study population was 3.2 ± 1.0. The number of distal anastomosis was comparable between groups (3.1 ± 1.0 in group A, 3.2 ± 1.0 in group P; p = 0.81). The time between the last dose of clopidogrel and the start of the operation was similar in both groups (39 ± 23 hours in group A, 42 ± 27 hours in group P; p = 0.36). Postoperative variables are listed in Table 2. Total chest tube drainage and need for transfusion with blood and blood products were significantly higher in group P. Reexploration for mediastinal bleeding was required in 2 patients in group P; the bleeding was secondary to coagulopathy as no specific sources could be identified.
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DISCUSSION
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The thienopyridine derivative, clopidogrel, inhibits platelet aggregation induced by adenosine diphosphate, thereby reducing ischemic events. Clopidogrel has a rapid onset of activity, making it the drug of choice for acute ischemic events. It was found to significantly reduce the risk of the composite outcome of death from cardiovascular causes, nonfatal MI, and stroke, as well as a range of related ischemic events.1,2 However, it may increase the risk of major nonsurgical bleeding in patients who need urgent or emergency CABG.3,4 Withholding clopidogrel preoperatively is adequate in elective cases, although the optimal period is still unclear. The manufacturer recommends that clopidogrel be discontinued 7 days prior to elective coronary surgery. In the CURE trial, patients who stopped clopidogrel treatment within 5 days prior to CABG trended to have more bleeding than those in the control group.10 Thus the management of patients on clopidogrel who need urgent or emergency CABG presents a dilemma.
The adverse effect of CPB on hemostasis is well known. Although there are multiple changes in the hemostatic mechanism during CPB, activation of fibrinolytic components and temporary loss of platelet function are the most common and clinically relevant. There is an increase in fibrinogen degradation products and plasminogen activators, with a concomitant decrease in plasminogen and 
2-antiplasmin in plasma, and reduced clot lysis time.11 However, it is still unclear whether this enhanced fibrinolysis is a major contributor to post-surgical bleeding in a substantial number of patients. The role of platelet dysfunction and inflammatory mediators of the complement system and cytokine network has also been considered. CPB adversely affects both platelet count and function. Hemodilution causes platelet counts to decrease rapidly to approximately 50% of preoperative levels soon after starting CPB.12 Of greater significance is the progressive loss of platelet function. Within minutes after starting CPB, bleeding time is prolonged considerably. This transient platelet dysfunction occurs in all patients undergoing CPB; however, it only causes excessive bleeding in a small percentage, particularly those treated with a potent antiplatelet agent such as clopidogrel. Thus, interest in OPCAB for patients with recent exposure to clopidogrel has increased. Randomized trials, matched cohort and retrospective studies consistently demonstrate reductions in blood loss, reoperation for bleeding, and requirements for allogenic blood products in OPCAB compared to on-pump CABG.5
Although concerns about the association between aprotinin and serious end-organ damage have been reported, many centers continue to use aprotinin in selected patients.13 It inactivates human serine proteinases such as trypsin, plasmin, kallikrein, and activated protein C. Because the fibrinolytic components of the hemostatic system are activated during CPB, the hemostatic mechanism of aprotinin was mainly attributed to inhibition of hyperfibrinolysis in earlier studies.14,15 Recently, results have indicated a possible protective action of aprotinin on platelets via inhibition of protease-dependent platelet aggregation and thrombosis.16–18 The protease-activated receptor (PAR) family is widely expressed on platelets and cells of the vasculature. PAR1 is the principal thrombin receptor in humans, mediating thrombi-induced aggregation of platelets and proinflammatory responses.19 Aprotinin selectively inhibited PAR1-dependent platelet activation in in-vitro and in-vivo randomized placebo-controlled trials in patients having CABG on CPB.16,17 Interestingly, blockade of platelet PAR1 by aprotinin does not exacerbate bleeding because platelets maintain their ability to be activated by other stimuli such as collagen and ADP.16 Thus, aprotinin minimizes the participation of thrombin-activated platelets in the coagulation cascade, thereby exerting a net antithrombotic effect, whereas the hemostatic capacity of platelets in surgical wounds is maintained. All things considered, the hemostatic mechanism of aprotinin seems to be related to inhibition of activation of the clotting system and hyperfibrinolysis. During OPCAB, activation of coagulation and fibrinolysis has also been shown, and both hemostatic and antithrombotic effects of aprotinin have been demonstrated.7,19 The results of this study agree with previous findings that aprotinin significantly reduced postoperative bleeding and transfusion requirements in patients undergoing on-pump and off-pump CABG within 5 days of clopidogrel treamment.6–8,20
This is the first randomized placebo-controlled study on the effectiveness of low-dose aprotinin on blood loss and transfusion requirements after OPCAB in patients taking clopidogrel within 5 days before surgery. Intraoperative administration of low-dose aprotinin resulted in significant decreases in blood loss and number of transfusions. The limitations of this study include the small group size that may preclude comprehensive assessment of efficacy and safety, the fact that the typical regimen for low-dose aprotinin (1 million units) was not used, and data on the specific dose and timing of clopidogrel for each patient could not be provided because clopidogrel doses were not recorded. Nevertheless, this clinical investigation provides important preliminary data that may facilitate the design of a comprehensive safety/efficacy randomized controlled clinical trial with adequate numbers of patients to address this important question.
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ABSTRACT
INTRODUCTION
