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Ann Thorac Surg 1998;65:674-683
© 1998 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Aprotinin and Dipyridamole for the Safe Reduction of Postoperative Blood Loss

Gideon Cohen, MD, Joan Ivanov, MSc, Richard D. Weisel, MD, Vivek Rao, MD, Molly K. Mohabeer, BSc, Donald A. G. Mickle, MD

Division of Cardiovascular Surgery and the Centre for Cardiovascular Research, The Toronto Hospital and the University of Toronto, Toronto, Ontario, Canada

Accepted for publication September 12, 1997.

Dr Weisel, General Division, The Toronto Hospital, EN 14-215, Toronto, Ontario M5G 2C4 Canada.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 Appendix 1
 References
 
Background. Aprotinin (APR) reduces postoperative blood loss but may induce thrombosis. Dipyridamole (DIP) limits platelet aggregation and may reduce the thrombotic complications associated with APR.

Methods. To evaluate the safety and effectiveness of combined APR and DIP, we undertook a prospective randomized trial in patients undergoing cardiac operations. Patients were stratified according to risk for bleeding (low or high), and received either DIP with placebo (DIP group; n = 59) or DIP with APR (DIP + APR group; n = 56). Blood samples were obtained for the measurement of hematologic and biochemical parameters. Blood loss and transfusion requirements were documented postoperatively.

Results. Postoperative blood loss and transfusion requirements were significantly lower in the DIP + APR group at 6, 12, and 24 hours after bypass (p < 0.01). No significant differences were found between groups in the incidence of perioperative mortality (DIP, 0%; DIP + APR, 3%), myocardial infarction (DIP, 0%; DIP + APR, 3%), stroke (DIP, 1%; DIP + APR, 1%), or potential thrombotic events (death, myocardial infarction, and stroke: DIP, 2%; DIP + APR, 5%). In addition, these rates did not differ from those of nonparticipating matched control patients.

Conclusions. Administration of both drugs simultaneously was more effective than DIP alone in reducing postoperative blood loss. A platelet inhibitor may be required to reduce the thrombotic complications associated with APR. Further studies evaluating graft patency and perioperative ischemia are necessary to confirm the potential benefits of the combination of a platelet inhibitor and APR.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 Appendix 1
 References
 
The contemporary results of cardiac operations are excellent. However, excessive postoperative bleeding remains a serious complication contributing to postoperative morbidity. The growing number of high-risk patients being referred for cardiac procedures has increased the risk of postoperative bleeding [1][2]. Postoperative reexploration for excessive bleeding is required in 3% to 5% of patients, among which only 50% are found to have a surgical source [3]. The remaining patients often exhibit generalized bleeding attributable to an acquired coagulopathy or pathologic fibrinolysis. Administration of blood products exposes patients to the risk of transfusion-related reactions and blood-borne infections. Because more than 200,000 cardiac operations are performed annually in North America, the magnitude of the problem is substantial. Interventions aimed at reducing postoperative blood loss may reduce the morbidity associated with cardiac operations and may decrease the demand for limited supplies of blood products.

Fibrinolysis, resulting from contact activation of various proteases, contributes to bleeding after cardiopulmonary bypass (CPB), as evidenced by elevated levels of fibrin degradation products and plasminogen activators intraoperatively [4]. Among the most potent activators of plasminogen conversion to plasmin is kallikrein, the circulating concentration of which increases significantly during CPB [5].

Aprotinin (APR) is a nonspecific serine proteinase inhibitor that inhibits plasmin and kallikrein. Clinical confirmation of aprotinin’s efficacy in reducing blood loss during and after CPB has resulted in its widespread application in high-risk cardiac operations [6][7]. However, although the blood-sparing effects of APR are well documented, significant concern exists regarding its safety for use in routine cardiac operations. Various studies have suggested that in addition to reducing blood loss, APR induces a hyperthrombotic state due to the inhibition of physiologic fibrinolytic activity [8][9][10].

Dipyridamole (DIP), a pyrido-pyrimidine compound, limits platelet activation, aggregation, and granular release. In combination with aspirin, DIP has been shown to improve early vein graft patency in patients undergoing coronary artery bypass grafting [11][12]. However, unlike aspirin, DIP does not increase bleeding due to its preservative effects on platelet number and membrane function [13].

The combination of DIP and APR may reduce the incidence of thrombotic complications associated with APR use alone. The inhibition of platelet aggregation may counteract the tendency toward thrombosis in injured vessels of the cardiac, cerebral, or renal vasculature. Moreover, the two drugs may act together to reduce blood loss in patients undergoing cardiac operations.

A prospective, randomized, placebo-controlled trial was designed to study the potential benefits of the combination of APR and DIP therapy for the reduction of postoperative blood loss.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 Appendix 1
 References
 
Patient Selection
One hundred fifteen patients undergoing cardiac operation for valve replacement or myocardial revascularization, or a combined procedure, between January 1991 and March 1992 were randomized in this double-blind, placebo-controlled trial. The study protocol was approved by the Committee for Research on Human Subjects at the Toronto Hospital. Eligible patients provided written informed consent before enrollment. Patients were excluded from enrollment if they had impaired renal function (serum creatinine level >150 mmol/L), biochemical evidence of hepatic dysfunction, a known allergy to APR, known previous exposure to APR, or previous history of acute pancreatitis. Participants were stratified into two groups according to low- and high-risk of postoperative bleeding. The low-risk group included patients undergoing myocardial revascularization or single valve replacement, and the high-risk group included patients undergoing repeat valve replacement, multiple valve replacement, valve replacement with myocardial revascularization, or repeat myocardial revascularization.

Drug Administration
All patients received DIP and were randomized to receive either APR or placebo. Dipyridamole was administered orally (100 mg four times daily, as described by Chesebro and colleagues [11]) for three or more doses preoperatively, and intravenously at a rate of 0.24 mg · kg-1 · h-1 beginning before anesthetic induction and continuing for 1 hour postoperatively [13]. The intravenous regimen was based on previous work at our institution, which demonstrated the effectiveness of this dose in preserving platelets and reducing postoperative bleeding compared with placebo. In view of our previous studies documenting the safety and effectiveness of DIP, a control group that received neither DIP nor APR was not studied.

Aprotinin was supplied by Bayer Canada Inc. After satisfactory administration of the 280-mg (200 mL) APR loading dose, an additional 280-mg dose was added to the pump prime. In addition, APR was administered intravenously before and after bypass at a rate of 70 mg (50 mL) per hour intraoperatively and for 1 hour postoperatively. Patients were randomized by the hospital pharmacy after stratification and blocking in groups of six. The pharmacy supplied bags that contained DIP and APR or a saline placebo.

Heparinization
The whole blood activated clotting time was used to monitor the adequacy of heparinization during CPB. Aprotinin, due to its inhibition of kallikrein, prolongs clotting tests such as activated clotting time independent of the effects of heparin. Thus, to ensure therapeutic heparin concentrations, the activated clotting time was not permitted to drift below 450 seconds.

Operative Technique
Anesthetic induction and operative techniques were performed as previously described by our group [2]. Before institution of CPB, intravenous heparin was administered at a dose of 300 U/kg, and as necessary to maintain an activated clotting time of no less than 450 seconds. Systemic hypothermia (28°C) was maintained during the cross-clamp period. Blood was transfused during CPB if the hematocrit remained below 18% despite attempts to induce a diuresis. After discontinuation of bypass, heparin was reversed by the administration of protamine sulfate (1 mg/100 units of heparin).

Postoperative Management
Postoperative management was directed by the surgeon and the intensive care unit physician, both of whom followed established guidelines for volume replacement and transfusions. Autologous blood shed into sterile cardiotomy reservoirs from chest drains was autotransfused to the patient when drainage exceeded 150 mL during the first 4 hours postoperatively.

Transfusion of any blood product followed strict guidelines. Packed red cells were administered to high-risk patients with hemoglobin levels below 85 g/L, or to low-risk patients with hemoglobin levels below 80 g/L. Clinically significant coagulation defects were treated by infusion of fresh frozen plasma or cryoprecipitate in patients who had excessive bleeding. Platelet concentrates were given to patients with excessive bleeding and platelet counts of less than 20 x 109/L. Platelets were administered to patients with counts greater than 20 x 109/L when inadequate hemostasis was found after prolonged bypass (>120 minutes). Reoperation was performed for suspected surgically correctable bleeding or cardiac tamponade.

Postoperative blood loss was recorded in sterile cardiotomy reservoirs from the time of bypass termination. Blood loss was documented at 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours after bypass, and thereafter until removal of all chest drains. Excessive bleeding was defined as blood loss (by volume) in excess of the 50th percentile (950 mL). Clinical outcomes were recorded for each patient and were reported as morbidity or mortality. Definitions for various outcome variables are provided in Appendix 1.

Blood Sampling
Blood samples for hematologic, biochemical, and coagulation parameters were drawn preoperatively, during bypass, at the termination of bypass, and at 2, 4, 8, 12, and 24 hours after bypass.

Laboratory Assessments
Blood samples for platelet, leukocyte, and erythrocyte counts were collected in tubes containing ethylene diaminetetraacetic acid and analyzed with a TOA electronic blood cell counter (Baxter Industries, Toronto, Ontario, Canada). The bleeding time was measured with the Template II bleeding time device (Organon Teknika; Akzo, Pharma Group, Scarborough, Ontario, Canada). Bleeding times of more than 9 minutes were considered abnormal. Activated clotting time was measured with the Hemochron device (International Technidyne Corp, Edison, NJ) using Celite as the activator. Prothrombin and activated partial thromboplastin times were determined with standard commercial reagents (Thromborel-S; Hoechst-Roussel, Montreal, Quebec, Canada) in an automatic coagulation device (ACL; Coulter Electronics Canada, Burlington, Ontario, Canada). Plasmin activity was determined by means of a chromogenic substrate specific for plasmin-like activity (Kabi-Pharmacia Laboratories, Toronto, Ontario, Canada). Fibrinogen levels were determined by the Clauss method [14]. Plasminogen antigen levels were measured using the radial immunodiffusion method (Intermedico Inc).

To overcome the limitations inherent in routine screening for hemostatic abnormalities, thromboelastography was undertaken using a commercially available thromboelastograph. Blood samples obtained at the aforementioned intervals were assayed for reaction time, clot formation time, maximum plot amplitude, and the {alpha} angle.

Statistical Analysis
Statistical analyses were performed with the SAS statistical program (SAS Institute Inc, Cary, NC). Results are presented as mean and standard deviation or as percent incidence where indicated. Statistical significance was assumed for a p value of less than 0.05. Categoric data were analyzed using a {chi}2 test or Fisher’s exact test where appropriate. Continuous data were analyzed by two tailed t tests. Serial measures were compared with repeated measures analysis of variance using the general linear model procedure, and Duncan’s multiple range tests were used to specify differences when the F ratio of the analysis of variance was significant. Logistic models were constructed for each outcome variable. Possible prognostic variables were carefully evaluated using appropriate univariate analyses. Variables were selected for inclusion in a multivariable model if their univariate p value was less than 0.25 or if the variable was of known clinical importance. The ability of each model to describe the outcome variable (model precision) was determined using the Hosmer-Lemeshow goodness of fit statistic [15]. Differences between observed data and estimated values for each covariate pattern were calculated accordingly. In addition, the receiver operator characteristic curve was obtained for each model and the area under the receiver operator characteristic curve was calculated to determine overall model accuracy.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 Appendix 1
 References
 
A total of 124 patients were randomized initially to receive either APR + DIP (treatment group) or DIP alone (placebo group). Nine patients were subsequently excluded from the trial: three due to procedure cancellation, five due to protocol violation (previously unrecognized contraindications to APR therapy, 2; unstable before APR administration, 2; failure to obtain proper consent, 1), and 1 patient due to an adverse reaction with administration of the APR test dose. Among the remaining 115 patients, 56 received DIP with APR (DIP + APR group), and 59 received DIP alone (DIP group). Among the 59 patients who received DIP alone, 33 (56%) were in the low-risk group and 26 (44%) were in the high-risk group. Among the 56 patients who received DIP and APR, 31 (55%) were low risk and 25 (45%) were high risk.

Specified outcomes were compared with those of nonparticipating control patients at our institution who underwent the same cardiac surgical procedures during the same time period. Patients in the control groups received neither APR nor DIP perioperatively. Preoperative profiles and cardiac risk factors were not different between treatment groups and were similar to those of nonparticipating control patients (Table 1). Similarly, when stratified according to risk of perioperative bleeding, no significant differences in preoperative variables were found between groups. Intraoperative characteristics including cross-clamp and CPB times were also similar between groups regardless of risk stratification.


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  		Preoperative Patient Demographics and Characteristics by Randomization Group1

 
Bleeding
Blood loss for both groups during the first 12 hours after CPB is presented in Fig 1. When compared with patients in the DIP group, patients in the DIP + APR group had significantly less cumulative blood loss at 6 hours (DIP, 579 ± 108 mL; DIP + APR, 198 ± 65 mL; p < 0.001), 12 hours (DIP, 795 ± 130 mL; DIP + APR, 326 ± 115 mL; p < 0.01), 24 hours after CPB (DIP, 1153 ± 320 mL; DIP + APR, 560 ± 182 mL; p < 0.001), and the total blood loss after CPB (DIP, 1,497 ± 360 mL; DIP + APR, 780 ± 262 mL; p < 0.001). Aprotinin administration resulted in a 66% reduction in blood loss from 0 to 6 hours after CPB, a 40% reduction in blood loss from 6 to 12 hours after CPB, a 35% reduction in blood loss from 12 to 24 hours, and a total reduction in blood loss of 48% (p < 0.01). Blood loss at all time periods was not significantly different between high- and low-risk patients within each randomization group.



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  		Patients in the dipyridamole group (DIP) had significantly more blood loss 12 hours postoperatively and were more likely to bleed excessively and receive a transfusion than patients in the dipyridamole and aprotinin group (DIP + APR).

 
The number of patients who bled excessively (>950 mL) during the postoperative period is presented in Fig 1. A total of 57 patients experienced excessive bleeding, 71% of which were in the DIP group, and 27% of which were in the APR group (p < 0.0001). Randomization group was the only significant predictor of excessive bleeding.

One patient in the DIP group required reoperation for excessive bleeding, at which time no surgical cause was found.

Transfusions
The number of patients requiring packed red blood cell transfusions in the two groups is shown in Fig 1. The majority of transfusions (78%) were administered early postoperatively in the intensive care unit. Among those who required transfusions, significantly less blood was transfused in patients receiving DIP and APR compared with patients receiving DIP alone (64% reduction; p < 0.001). Transfusion requirements were not significantly different between high- and low-risk patients within each randomization group. Significantly less blood was autotransfused from the sterile drainage reservoirs in the DIP + APR group (227 ± 152 mL) in comparison to the DIP group (533 ± 377 mL; p < 0.01). Although less packed red blood cell transfusions were required intraoperatively, the differences were not significant (DIP, 126 ± 112 mL; DIP + APR, 106 ± 81 mL; p = not significant). Fig 2 illustrates the effects of sex on postoperative blood loss and transfusion requirements. Although 19 (79%) female patients required packed red blood cell transfusions compared with only 34 (37%) male patients (p < 0.001), no differences were found in the incidence of excessive postoperative blood loss between sex groups (Fig 2).



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  		Women had lower preoperative hemoglobin values than men, and despite a similar incidence of excessive bleeding had a greater incidence of transfusions. (PRE-OP = preoperative.)

 
Among patients who bled excessively, 32 (56%) received packed red blood cell transfusions. Thirty-seven (63%) patients in the DIP group required packed red blood cell transfusions, compared with only 17 (30%) patients in the DIP + APR group (p < 0.01). Administration of other blood products including plasma, platelets, and cryoprecipitate was not significantly different between groups. In the DIP group, 3 (5%) patients received fresh frozen plasma (1 patient received 1 unit and 2 patients received 2 units each), 2 (3%) patients received platelet transfusions (1 patient: 6 units), and 2 (3%) patients received cryoprecipitate. In the DIP + APR group, 1 (2%) patient received fresh frozen plasma (2 units), and 2 (4%) patients received platelets (1 patient: 6 units; 1 patient: 25 units).

Laboratory Values and Coagulation Parameters
Preoperative hematologic and coagulation parameters did not differ significantly between groups (Table 2). Two-way analysis of variance revealed a significant effect of sample timing on bleeding time, platelet count, hemoglobin, prothrombin time, and activated partial thromboplastin time (p < 0.001), and a significant interactive effect between timing and randomization group for hemoglobin. Platelet count, hemoglobin, fibrinogen antigen, and plasminogen antigen decreased after initiation of CPB, while bleeding time, prothrombin time, and activated partial thromboplastin time increased. All values began returning toward normal levels at 2 hours after bypass.


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  		Laboratory Values by Sample Timing and Randomization Group

 
At 2 hours after bypass, patients in the DIP + APR group had significantly higher hemoglobin levels (p < 0.01) and activated partial thromboplastin times (p < 0.001) in comparison with patients in the DIP group. Platelet numbers were higher in the DIP + APR group at 2, 12, and 24 hours after CPB; however, these differences only approached statistical significance at 12 hours (p = 0.06). Leukocyte counts and prothrombin times were similar between groups at all sample times.

Plasmin activity (normal reference range, 0.80 to 1.2 U/mL) began decreasing below normal levels in the DIP + APR group before the initiation of bypass, and, in comparison to the DIP group, was significantly lower after sternotomy (p < 0.001), at the start of CPB (p < 0.001), and 2 hours after bypass (p < 0.01) (Fig 3). Plasmin activity decreased below normal levels in both groups after initiation of CPB. Conversely, plasminogen antigen (normal reference range, 0.06 to 0.25 g/L) and fibrinogen antigen levels (normal reference range, 2.0 to 4.5 g/L) remained within normal limits and were not significantly different between groups, although both tended to be higher in the APR group.



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  		Plasmin activity was lower in the dipyridamole and aprotinin group (DIP + APR) than in the dipyridamole group (DIP) at all times postoperatively. (PRE-OP = preoperative; POST-STERN = poststernotomy; END-CPB = termination of cardiopulmonary bypass after rewarming; 2 HRS POST-CPB = 2 hours after termination of cardiopulmonary bypass.

 
Linear regression analysis was used to determine the factors predictive of postoperative bleeding and transfusion requirements. A weak but statistically significant inverse relation was found between platelet counts at 2 hours after bypass and blood loss at 12 hours after bypass (r2 = 0.05; p < 0.05; slope = -0.020). The lower platelet counts 2 hours postoperatively could have contributed to or may have resulted from greater postoperative bleeding. The bleeding time 2 hours postoperatively correlated directly with 12-hour blood loss in the DIP + APR group (r2 = 0.20; p < 0.01; slope = 0.01) (Fig 4). Bleeding time did not correlate with blood loss in the DIP group suggesting that an effect of factors other than platelet-related variables contributed to blood loss. Blood loss at 12 hours correlated directly with 2-hour plasminogen antigen levels in the DIP group (r2 = 0.19; p < 0.001) implying greater blood loss in patients who were able to generate more plasmin. Multiple regression analysis revealed that postoperative blood loss (at 12 hours) was predicted by randomization group and plasminogen (antigen) levels at 2 hours (model r2 = 0.32; p < 0.01).



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  		Platelet count correlated inversely with bleeding time 2 hours postoperatively (r2 = 0.08; p < 0.01). The bleeding time tended to be lower in the dipyridamole and aprotinin group (DIP + APR) than in the dipyridamole group (DIP) at any given platelet count (top). Postoperative blood loss (at 12 hours) correlated directly with bleeding time at 2 hours postoperatively in the dipyridamole group (r2 = 0.20; p < 0.01), but not in the dipyridamole and aprotinin group (bottom).

 
Fig 4 illustrates the inverse correlation between the bleeding time and the platelet count at 2 hours postoperatively (r2 = 0.08; p < 0.01; slope = -3.52). The inverse relation was stronger in the DIP + APR group (r2 = 0.15; p < 0.01; slope = -0.03) in comparison to the DIP group (r2 = 0.03; p = 0.27; slope = -0.02). In addition, bleeding time tended to be lower at any given platelet count in the APR group.

After evaluation by linear logistic regression analysis, two factors were found to be predictive of the need for packed red blood cell transfusion: preoperative hemoglobin (regression coefficient, -0.90; odds ratio, 0.91; 95% confidence interval, 0.87 to 0.96) and randomization group (regression coefficient, 1.75; odds ratio, 5.73; 95% confidence interval, 2.12 to 15.5). The model provided excellent prediction of the need for transfusion as evidenced by a Hosmer-Lemeshow goodness of fit p value of 0.88 (where unity is the best fit). Similarly, the area under the receiver operating curve (0.79) suggested an excellent combination of sensitivity and specificity for the model.

Preoperative hemoglobin correlated inversely with the amount of packed red blood cells transfused (r2 = 0.07; p < 0.01; slope = -0.01). The negative slope was greater in the DIP + APR group in comparison to the DIP group. Postoperative (12 hour) blood loss correlated directly with the volume of packed red blood cells transfused (r2 = 0.37; p = 0.0001; slope = 0.25).

Although thromboelastographic parameters were analyzed for all time periods, no significant differences were noted between groups, and these parameters were not predictive of postoperative bleeding or transfusion requirements.

Clinical Outcomes
Aortic cross-clamp (DIP, 64 ± 20 minutes; DIP + APR, 68 ± 21 minutes) and CPB (DIP, 91 ± 29 minutes; DIP + APR, 97 ± 30 minutes) times did not differ between groups. Similarly, the number of postoperative days in the intensive care unit (DIP, 2.2 ± 0.9 days; DIP + APR, 2.7 ± 2.7 days) and in the hospital (DIP, 9.9 ± 4.8 days; DIP + APR, 10.9 ± 7.2 days) were similar between groups. The percentage of patients requiring prolonged intensive care unit (>3 days) or hospital admission (>14 days) was also similar between groups. These values were not different from those of nonparticipating control patients undergoing the same procedures during the same time period.

The adverse outcomes are presented according to randomization group in Table 3 and are stratified according to procedure in Table 4Table 5. The highest incidence of perioperative ischemic complications was found in patients undergoing primary or reoperative coronary artery bypass grafting. When procedures with similar risk of morbidity were compared, no differences were found in adverse outcomes between groups, and the incidence of morbidity closely resembled that of nonparticipating controls. Two patients in the aprotinin group died postoperatively; however, mortality was not significantly different between groups, and was similar to that of nonparticipating controls. Myocardial ischemic outcomes including the incidence of patients with a myocardial infarction, ischemic electrocardiographic changes, and elevated creatine kinase MB fraction and percentage of MB values were not significantly different between groups. Similarly, rates of low output syndrome (the requirement for postoperative intraaortic balloon pump augmentation or inotropic support, as defined in the Appendix 1) and intraaortic balloon pump assistance were not different between groups. The incidence of stroke (2%) was similar between groups and was the same as that of nonparticipating hospital controls. The incidence of postoperative renal dysfunction (DIP, 1 [2%]; DIP + APR, 2 [4%]) was not significantly different between groups. When patients were stratified according to operative procedure, no significant differences in rates of adverse events were found between groups.


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  		Adverse Outcomes by Randomization Group

 

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  		Outcomes in Low-Risk Patients

 

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  		Outcomes in High-Risk Patients

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 Appendix 1
 References
 
Excessive postoperative bleeding after coronary artery bypass grafting results from excessive fibrinolysis and an acquired platelet defect. Platelet numbers are diminished by hemodilution, deposition, and aggregation [13]. In addition, the systemic inflammatory reaction associated with CPB may impair platelet function and prolong bleeding times [16][17][18][19]. Platelets activated by damaged endothelium or foreign surfaces undergo a conformational change resulting in exposure of membrane glycoprotein receptors. Serine proteases are believed to cleave exposed platelet receptors, thus diminishing their ability to adhere to bleeding sites [20][21][22].

Fibrinolysis represents an additional mechanism of excessive postoperative bleeding after CPB. Contact activation of kallikrein and plasmin by the foreign surfaces of the oxygenator system increases clotting factor consumption and induces excessive thrombolysis postoperatively [23].

Aprotinin is a serine antiproteinase that is a potent inhibitor of human trypsin, plasmin, and kallikrein. Numerous studies have documented the significant blood-sparing effects of APR administered before and during CPB [8][24]. By inhibiting kallikrein-mediated plasminogen conversion to plasmin, APR may protect platelet receptors while preventing fibrinolysis [21][24].

Our results reaffirm the benefits of APR for the reduction of postoperative blood loss after CPB. Aprotinin administration resulted in a 50% reduction in postoperative bleeding. Similarly, both exogenous and autotransfusion requirements were significantly reduced in the APR patients. Aprotinin reduced postoperative bleeding by inhibiting fibrinolysis and may have augmented the previously demonstrated protective effects of DIP on platelet function. Plasmin activity (indicative of plasmin availability) began decreasing in the APR group before the initiation of CPB. Thereafter, values decreased below normal baseline levels in both groups due to hemodilution, along with the slow conversion of plasminogen to plasmin and the rapid reaction of {alpha}2-antiplasmin with plasmin during CPB [25]. Plasmin activity was significantly lower in the DIP + APR group at all time periods. This finding, in association with normal intraoperative and postoperative plasminogen antigen levels in both groups, suggests a type II defect of plasmin activity (a dysfunction rather than a deficiency), which may have been precipitated by aprotinin’s strong binding capacity to plasmin. Fibrinogen levels, although not significantly different, were consistently higher in the APR group, possibly indicating a reduction in fibrinolysis, and thus, a decrease in fibrinogen conversion to fibrin.

Aprotinin did not significantly increase platelet numbers or bleeding times postoperatively. However, as shown in Fig 4, APR tended to reduce the bleeding time at any given platelet count, suggesting a possible beneficial effect on platelet function. Multivariable analysis revealed both variables to be predictive of blood loss.

Changes in the values of other hematologic parameters were secondary to hemodilution and consumption. The significant differences in activated partial thromboplastin time between groups may have been reflective of reduced antithrombin III consumption in the APR group due to the inhibition of the early phase of intrinsic clotting.

Multivariable linear logistic analysis demonstrated that both preoperative hemoglobin values and APR administration predicted the requirement for transfusions. The higher incidence of transfusions in female patients was likely attributable to lower preoperative hemoglobin values.

Although DIP may have contributed to the reduction in blood loss and transfusion requirement, our study was not designed to evaluate this effect as all patients received DIP. Nonetheless, in a previous placebo-controlled, randomized trial, we demonstrated that intravenous DIP safely reduced blood loss and transfusion requirements [13].

To assess the safety and possible antithrombotic benefits of the combination of DIP + APR, we compared the outcomes of patients undergoing procedures with similar risk of postoperative complications. Although no significant differences were found in perioperative mortality or morbidity between groups, our study was not designed and had insufficient power to critically evaluate either mortality or graft patency. However, as there was no statistically significant difference between the two randomization groups in the incidence of perioperative thrombotic events, and as the incidence in the APR group was less than that in the control population from which the study patients were derived, we conclude with modest confidence that the combination of APR and DIP was not worse than DIP alone. This combination appears to be safe, but further studies of graft patency will be required to determine whether the combination is effective in reducing the thrombotic tendency of APR.

With the doses used in this study, the cost of APR was $1,100.00 (Canadian) per patient. We did not find a difference in length of postoperative intensive care unit or hospital stay between groups, and therefore, we could not justify the expense of APR. However, the reduction in blood product utilization may reduce the risks of blood-borne infections, thus justifying the cost. A more complete cost–benefit analysis will be required before the routine use of APR can be recommended.

In conclusion, the combination of APR and DIP reduced blood loss and decreased transfusion requirements after CPB. No significant increase in thrombotic complications was found in patients receiving DIP + APR in comparison to those receiving DIP alone. Further studies of graft patency are necessary to assess the efficacy of APR when combined with DIP.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
Appendix 1
 References
 
We recognize the generous support of Bayer Canada Inc along with its representatives, Dr JoAnn Lux and Dr Jayanti Mukherjee. We also acknowledge Charlene Weisel, RN, Rebecca Yu, RN, and Lynda White, RN, for their invaluable assistance in patient recruitment, hematologic analyses, and data recording. Finally, we thank the cardiovascular surgeons and perfusionists of the Division of Cardiovascular Surgery at the Toronto Hospital for their continued support. Doctor Cohen is a Fellow of the Heart and Stroke Foundation of Canada, Dr Weisel is a Career Investigator of the Heart and Stroke Foundation of Ontario, and Dr Rao is a Fellow of the Heart and Stroke Foundation of Canada.


   Appendix 1
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 Appendix 1
References
 
Definitions of Perioperative Variables

Diabetes: Patients with a preoperative diagnosis of diabetes mellitus treated with insulin, oral hypoglycemic agents, or diet.
Elderly: Patients over the age of 70 years.
Hypertension: Preoperative systemic hypertension requiring medical treatment.
Ischemic electrocardiographic changes: Appearance of a new Q-wave, ST elevation or depression, T wave inversion, or a bundle branch block.
Left main disease: Greater than 50% stenosis of the left main coronary artery.
Low output syndrome: The requirement in the intensive care unit for postoperative intraaortic balloon pump augmentation or inotropic support for >30 minutes to maintain a systolic blood pressure of >90 mm Hg and a cardiac index >2.2 L · min-1 · m-2.
Left ventricular grade: Ejection fraction more than 0.60 (grade 1), between 0.40 and 0.60 (grade 2), between 0.20 and 0.40 (grade 3), less than 0.20 (grade 4), as assessed by a single plane contrast ventriculogram or by echocardiography or nuclear ventriculography if a contrast ventriculogram was not performed.
Morbidity: Death, myocardial infarction, stroke, low output syndrome, or renal failure.
Myocardial infarction: Appearance of a new Q wave or new ST- and T-wave changes with an elevation of cardiac enzymes (creatine kinase fraction >50 and percentage of MB >5%).
Peripheral vascular disease: Patients with known carotid, aortoiliac, or femoropopliteal disease or patients with a previous carotid endarterectomy or peripheral vascular operation.
Redo operation: Previous cardiac operation including aortocoronary bypass, aortic valve replacement, or mitral valve replacement.
Renal failure: Serum creatinine level >150 mmol/L on the sixth postoperative day.
Thrombotic event: Death, myocardial infarction, or stroke.
Timing: Elective, semiurgent (same hospitalization), or urgent (within 72 hours of an event). An event represents either cardiac catheterization or an ischemic episode after cardiac catheterization.
Triple-vessel coronary disease: Significant lesions (>50% luminal narrowing) affecting the territories supplied by the right, left anterior descending, and left circumflex coronary arteries.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 Appendix 1
 References
 

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