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Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency
Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency To determine the effect on aorta-coronary bypass grafts of high-dose aprotinin, a drug known to be effective in reducing bleeding after aU forms of heart operations, a prospective double-blind study was performed. Graft patency was assessed noninvasively 7 to 12 days (median 9 days) postoperatively in 90 patients. In the aprotinin group, 38 of 43 patients had all grafts patent compared with 43 of 47 in the placebo group. In each group, respectively, 126 of 131 grafts versus 134 of 138 grafts were patent. Neither difference was statistically significant (p > 0.05). Blood loss and homologous blood use were significantly reduced in the aprotinin-treated patients. In this study, high-dose aprotinin did not result in early saphenous vein graft occlusion after aorta-coronary bypass operations. This is further evidence that aprotinin reduces hemostatic derangement during cardiopulmonary bypass without creating a "prothrombotic" situation. (J THORAC CARDIOVASC SURG 1993;105:147-53)
Benjamin P. Bidstrup, FRACS, FRCSEda (by invitation), S. Richard Underwood, MRCpb (by invitation), and Ralph N. Sapsford, ChM, FRcsa (by invitation), London, England. Consultant statistician: Elaine M. Streets, MSc* Sponsored by J. C. R. Lincoln, FRCS, London, England
Remarkable reductions in postoperative bleeding and blood use after many forms of operations performed with cardiopulmonary bypass (CPB) have been achieved with high-dose aprotinin.' Since the first descriptions of this novel regimen, double-blind studies have been repeated in centers throughout Europe.v" Each of these studies has shown blood loss reductions of the order of 40% to 50% and reductions in blood use of 40% to 80%. Other studies have examined effects on renal function and other aspects of pathophysiologic disturbances during CPB. 5-8 Few side effects related to the use of aprotinin in these studies have been described. Our own long-term experience and that of vast clinical usage throughout Europe support these observations. Concern has been expressed that hemostatic agents that result in reduced postoperative bleeding might have adverse effects on aorta-coronary bypass graft From Humana Hospital Wellington" and Department of Magnetic Resonance Imaging, Royal Brompton and National Heart Hospitals," London, England. Read at the Seventy-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., April 26-29, 1992. Address for reprints: Ben P. Bidstrup, FRACS, 66 Harley St., London WIN IAE, England. *Bayer pic, Newbury, England.
12/6/41326 0022-5223/93/$1.00/+ 0.10
(ACBG) patency." The long-term success of ACBG operations depends in the main on continued patency of the conduit. Early graft occlusion is believed to be initiated by platelet deposition on areas of endothelial damage, which results in subsequent thrombosis.!" Patency can be modified by the perioperative administration of antiplatelet drugs such as aspirin, dipyridamole, and ticlopidine, 11-13 but the effect of aprotinin, which reduces fibrinolysis after CPB, is not yet known. The aim of this study was to determine whether early (7- to lO-day) saphenous vein graft patency was adversely affected by the use of high-dose aprotinin (Trasylol; Bayer plc, N ewbury, England). Methods Study population. In the period between August 1989 and May 1991, 96 adult male patientswere admitted to a randomized,placebo-controlled double-blind study.During that period a total of 605 patients underwent first-time isolated coronary bypass in this surgical service. All patients were scheduled to receive three or more bypassgrafts. Patients were excluded if they had beenexposed to platelet-active drugs such as aspirinin the 10days beforetheir operation, wereto undergoreoperation or an additional procedure, had previous known exposure to aprotinin,or had had pancreatitis. The protocolwasreviewed by the ethical committee of our hospital, and written informed consent was obtained from all participating patients. Measurements. Blood loss at 6-hour intervalswas carefully 147
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1 4 8 Bidstrup et at.
Table I. Demographic data (all patients) No. Age (yr) Weight (kg) Height (em) Other diseases (%)
Aprotinin
Placebo
47 59.1 (7.4) 80.5 (8.9) 171 (6.6) 38
49 58.8 (8.5) 79.8 (10.3) 171.8 (5.7) 37
There were no significantdifferencesbetween the groups (p > 0.05). All valuesare expressed as mean (standard deviation).
Aprotinin No. No. of SVGs per patient 1 1 2 8 25 3 4 13 Total 144
Placebo %
No.
%
2 17 53 28
1 10 25 13 148
2 20 51 27
There were no significant differences between the treatment groups (P> 0.10).
Table II. Operative details (all patients) Duration of operation (min) Bypass time Crossclamp time Grafts (all) IMA grafts Endarterectomy
Table III. Distribution of saphenous vein grafts (SVGs) per patient (all patients)
Aprotinin
Placebo
135 (120-155) 62 (53-70) 35 (30-45) 3.82 27 9
140 (125-160) 61 (55-67) 36 (31-46) 3.73 25 10
There were no significant differences between treatment groups (p ues are expressed as median (interquartile ranges).
> 0.05). Val-
measured from the time of chest closure until the drains were removed 18 to 24 hours later. The hemoglobin content of this was measured as previously described.' The usage of homologous blood products was carefully controlled according to the hemoglobin level, which was measured as regular intervals. Red cells, either packed cells or, less commonly, whole blood, were administered only if the hemoglobin level fell below 8.5 gm/dl. Measurements were made of prothrombin time, activated partial thromboplastin time, activated clotting time, and fibrinogen levels before, during, and immediately after CPB. Standard hematologic and biochemical variables were measured preoperatively and postoperatively. Graft and bypass techniques. All patients underwent operations by one surgical team. All patients received heparin (300 IU/kg body weight) before cannulation for bypass, after harvesting of the saphenous vein and the internal mammary artery (IMA). At the end of bypass, protamine reversal was in the ratio of 0.7 to 1.0 mg/IOO IU heparin original dose. Activated clotting times (Hemochron; International Technidyne Corporation, Edison, NJ) were measured after aprotinin, at 20to 30-minute intervals during CPB, and after protamine administration. Activated clotting time was maintained at greater than 600 seconds, with additional heparin administered as necessary. Details of grafted vessel size, quality of artery, presence of mural and distal disease, performance of endarterectomy, and type of distal anastomosis were recorded. All distal anastomoses were constructed under a single period of aortic crossclamping, with the proximal anastomoses being made during rewarming with a partial occlusion clamp. Myocardial protection was achieved with cold St. Thomas' Hospital cardioplegic solution and mild systemic hypothermia (29 0 to 30 0 C). Aspirin (75 mg per day) was commenced in all patients after removal of chest drains. The techniques of CPB, anesthesia, and postoperative care were standardized throughout the period ofthe study, in keeping with the safe clinical management of the patient. Otherwise, these were as described in our previous reports.'
Aprotinin regimen. The patients received aprotinin or placebo (normal saline) from identical bottles supplied by the manufacturer and identifiable only by their random number. Aprotinin, 280 mg contained in 200 ml, was infused intravenously into a central venous catheter, as a loading dose, before the commencement of bypass. An additional 280 mg was added to the prime of the heart-lung machine. A constant infusion of 70 mg/hr was maintained during the procedure until skin closure. Patients in the placebo group received identical volumes of normal saline. Graft patency assessment. Patients underwent noninvasive assessment of graft patency by magnetic resonance imaging (MRI) 7 to 12 days (median 9 days) postoperatively. A series of transverse and sagittal slices 1 em thick, with 0.5 mm interleaving, was done with a Picker machine (Picker International Inc., Mayfield Village, Ohio) operating at 0.5 tesla or a GE Sigma Advantage (LG.E. Ltd., Slough, Berks, U.K.). The area of interest was defined after a pilot scan and extended from the aortic arch to the diaphragmatic surface of the heart. Images were transferred to film and read by two independent observers without knowledge of the treatment group. Graft patency was determined by the presence of a null signal in serial slices in the position of a graft. A null signal is returned by flowing blood indicating graft patency. If a graft was not visualized in consecutive slices, it was deemed to be occluded. Statistical methods. The primary efficacy analysis was the proportion of grafts patency excluding IMA grafts and grafts to endarterectomized vessels and was compared between treatment groups by a test of the standardized normal deviate. The variance was estimated using both the ratio estimate of proportions (nonindependence of grafts) and also assuming the binomial distribution (independence of graftsj.!" The numbers of patients with all grafts patent were compared between groups by means ofax2 test. Exploratory analysis was carried out on outcome for vessels that had endarterectomy, data from blood samples, blood loss, and blood transfusions. Parametric and nonparametric analyses were used as appropriate. For measurements that were repeated during the course of the trial, this included repeated measurements analysis of variance or Friedman's nonparametric two-way analysis of variance. Treatment groups were tested for baseline comparability, with parametric (two-sample t test) or nonparametric (Wilcoxon two-sample test) methods as appropriate for quantitative data with X2 tests for frequency counts. All significance tests were to be two sided with 5% significance level (p :::; 0.05) with the exception of grafts patent. This was to be one sided with 5% significance level (p :::; 0.05) since
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Effect of aprotinin on ACBGs
January 1993
Table IV. Distribution of arteries receiving SVGs
Vessel LAD Diagonal Circumflex RCA
Table V. Patency of saphenous vein grafts (SVGs) on a per graft basis
Placebo
Aprotinin
149
No.
%
No.
%
20 38 56 30
14 26 39 21
23 37 55 33
16 25 37 22
There were no significant differences between treatment groups (p > 0.05). SVG, Saphenous vein graft; LAD, left anterior descending artery; RCA, right coronary artery.
Placebo
Aprotinin
No. of grafts patent No. ofgrafts occluded Total
No.
%
No.
%
126 5
96.2 3.8
134 4 138
97.1 2.9
I3l
There were no significant differences between treatment groups either by ratio estimate or binomial assumption for determination of variance (see text).
Table VI. Patency of grafts on a per patient basis it wasof interestin this study onlyto determineas statistically significant an aprotininoutcomeworsethan with placebo. Thesamplesizecalculation wasbasedon the estimateof90% of grafts being patent at 7 days, and patencyof lessthan 80% withtreatmentbeingunacceptable. With one-sided testingwith 5% significance and 80% power, a minimumtotal of 88 patients receiving three or more grafts was needed. This allowed for the possibility of nonindependence of grafts within patients.
Placebo
Aprotinin
No. of patients with all grafts patent No. of patients with I or more grafts occluded
No.
%
No.
%
38
88.4
43
91.5
5
11.6
4
8.5
There were no significant differences between groups (p
> 0.05)
X2 test.
Results Demography. The groups were similar with respect to age, weight, and height (Table I). The presence of other diseases and the preoperative drug treatments were also similar. Bypass time, operation duration, crossclamp time, and number of grafts placed were again similar (Table 11). The use of the IMA graft and the number of endarterectomies actually performed in all patients are also shown in Table II. Six patients withdrew from the study, four in the aprotinin group and two in the placebo group. Two patients in the aprotinin group died 8 hours and 5 days, respectively, after operation. In one patient the quality of the images was too poor for analysis because of arrhythmia. In one, wound infection had developed, and two patients were unable to complete the scan because of intolerance. Thus a total of 269 venous grafts in 90 patients were suitable for analysis. Number and description of grafts. The distribution of grafts per patient for all patients excluding those with endarterectomized vessels and those receiving IMA grafts is shown in Table III. Table IV shows the distribution of vessels receiving saphenous vein grafts for all patients. All groups were similar. There were no significant differences between quality of the vein used for grafting, quality of the vessel at the site of anastomosis and distally, and size of the arteries grafted. Results of patency analysis. Excluding IMA grafts and endarterectomized vessels, there were 292 grafts performed in 96 patients. In the 6 patients who were excluded for the reasons given, there were 23 grafts, leaving 269 venous grafts in the 90 patients who completed the full study protocol, suitable for primary efficacy analysis.
Table V lists the number of grafts patent in each group. Table VI shows the number of patients with all grafts patent in each group. There were no significant differences between groups either on a per graft basis or on a per patient basis. An exploratory analysis was carried out with endarterectomized vessels included: 288 grafts in 90 patients. In the aprotinin group, 134 grafts (95.7%) were patent compared with 143 grafts (96.6%) in the placebo group. All grafts were patent in 37 patients in the aprotinin group (86.1%) and in 42 patients in the placebo group (89.4%). There were no significant differences (p > 0.05) between treatment groups either on a per graft or a per patient basis. Of 46 IMA grafts for which there was an outcome recorded, all were patent. Blood loss analysis. Total chest drainage after operation was significantly reduced in the aprotinin group compared with the placebo group and hemoglobin loss was reduced by 50% (Fig 1). Use of homologous blood products was significantly decreased in the aprotinin group. Whereas 24 patients in the placebo group received homologous red cells, only 9 in the aprotinin group received transfusions (p = 0.006). Totals of 795 ml (420 to 900) and 450 ml (410 to 500) (median and interquartile ranges) were given to each group, respectively (p = 0.03). Other clinical measurements. Hemoglobin levels before, during, and 24 hours and 5 days after operation did not differ significantly. Platelet counts differed only 10 minutes after protamine was administered, being 91 X 109/L and 121 X 109/L in the aprotinin and place-
150
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Bidstrup et al.
ACT
1400
sees
----
1200
1000
SOO
Aprotinir Placebo
600
400
200
Base
10' CPB
End CPB
10' Prot
Fig. 1. Total chest drainage and hemoglobin loss after operation (median and interquartile range). Differences between groups were significant (p < 0.01) for both measurements.
Fig. 2. Activated clotting times (ACT) preoperatively, 10 minutes on bypass, 40 minutes on bypass, and after reversal of heparin (median and interquartile range).
bo groups, respectively. Activated clotting times were greater in the aprotinin group at all time points during bypass (Fig. 2) (p < 0.001). Adverse events. Adverse events were recorded in 34 patients in total. The most common was atrial fibrillation/flutter, occurring in 10 patients in the aprotinin group and 12 in the placebo group. Three patients in the placebo group were reexplored for bleeding. There was one cerebrovascular accident, from which the patient, in the placebo group, made a good recovery. Two patients died, both in the aprotinin group, and causes of death are discussed in the next paragraph. Two other cardiac events occurred in patients treated with aprotinin. In one patient ventricular fibrillation developed on day 1 postoperatively after right coronary endarterectomy. A new inferior Q wave infarct was seen on postoperative electrocardiograms; one graft supplying the inferior surface was occluded. One patient had refractory supraventricular arrhythmias in the first 3 postoperative days. A probable myocardial infarction was diagnosed, but there were no new Q waves on the postoperative electrocardiogram. His remaining postoperative course was uneventful. All grafts were patent on imaging. One patient died from irreversible ventricular fibrillation some 6 hours after an uneventful operation. At autopsy, an acute, extensive inferior infarction predating operation by 48 hours was found. All four grafts were patent, and there was no evidence of intravascular thrombosis. Acute pulmonary hypertension at the time of protamine administration had developed in the second patient who died. This responded to vasodilators, and the chest was closed. Before the patient left the operating room, systemic hypotension required reinstitution of bypass. The right coronary graft had poor flow and was
redone. Porridge-like atheroma but no thrombus was present in the artery, and this was believed to be occluding the graft distally. All grafts were patent with no evidence of thrombosis when the chest was reexplored later that day for continued low cardiac output. Because neither of these patients completed the protocol, they were not included in patency assessment. Neither event was believed to be related to the treatment. Discussion Patency. This study has indicated that aprotinin therapy, while reducing blood loss and blood use significantly, has not resulted in increased early aorta-coronary bypass graft occlusion. These results support the concept that aprotinin achieves improved hemostasis by allowing hemostatic mechanisms to function normally at the end of bypass, rather than by creating a "hypercoagulable" situation. Many studies have examined the effects of various drug regimens on improving graft patency after operation. There may be an enormous variation in patency according to center and surgeon.P The EPPAC study showed a variation in occlusion rate from 2.8% to 28.6% of anastomoses and 7.1% to 57.1% per patient. This may reflect in part differing experience and factors, such as differing attitudes to grafting small vessels with poor runoff. Any study must take this into account. Therefore we elected to do this as a single-center study. Other studies have shown patency rates varying from 98.4% to 85%.11, 12, 16 The early (median 9 days) patency in this study is in keeping with those studies and with our own earlier recatheterization data (Bidstrup BP. Unpublished data). Timing of early study may determine patency rates because there appears to be a linear decrease in the first
Volume 105 Number 1 January 1993
few months. We elected to perform this assessment as early as practicable to determine the effect of the treatment applied and before other factors that might result in graft occlusion came into play. All patients received lowdose aspirin after chest drain removal. All therefore had been exposed to this drug for 6 to 11 days before patency assessment. Any adverse effect of aprotinin on patency would be seen early and modified equally between groups by aspirin. Early graft closure has been shown in animal models to be due to thrombosis of the conduit."? This is initiated on areas of endothelial damage. Mild degrees of damage result in a monolayer of platelets adhering to the vessel wall, but more extensive degrees of damage result in a greater response with additional activation of the clotting/repair system and laying down of thrombus. This response is carefully regulated in the body, so that it is appropriate for the stimulus. If this were not so, a single stimulus would result in uncontrolled activation of the clotting cascade. In the arterial circulation, platelet adherence occurs via the glycoprotein Ib receptors, which results largely in platelet thrombi. This is the basis for antiplatelet treatment for the improvement of graft patency. Other factors that may determine graft patency include the size and quality of the grafted vessel:Poor flow and distal disease may result in early occlusion. There are technical considerations because the use of magnification for coronary anastomosis is now almost universal. The effect of other treatments that are used frequently (platelet and fresh frozen plasma transfusions) is not known. The exact mechanism by which aprotinin achieves its hemostatic effects is still the subject of much debate. What is certain is that fibrinolysis, initially not thought to be a major contributor to bleeding after bypass.l'' is inhibited by aprotinin.' This may have effects on platelets. They are known to have the distribution of their glycoprotein Ib receptors altered by plasmin.!?: 20 Hypothermia is also known to adversely affect platelet function.P In these higher doses, aprotinin is also believed to inhibit kallikrein. The contribution of the kallikrein/factor XII loop to coagulation activation is probably unimportant? Much of the activation seen during CPB (and indeed in all operations) arises from the tissue factor pathway. Kallikrein is another pathway by which plasminogen may be activated under the conditions of extracorporeal circulation, however.P That platelet function is improved by aprotinin has been demonstrated by us and others. I, 24, 25 After reversal of heparin, the release of the platelet granule substance, {3-thromboglobulin, is increased, showing that platelets are better able to respond to the physiologic stimulus of thrombin (Bidstrup BP. Unpublished data). Serine protease inhibitors (of which aprotinin is one) are
Effect of aprotinin on ACBGs
15 1
controllers of coagulation, not initiators. Lack of these inhibitors (such as antithrombin III) results in increased thrombosis. It is likely then that the combination of poor platelet function (the initiator of hemostasis in high shear situations) and increased fibrinolysis (destroying formed hemostatic clots) after CPB causes bleeding. The addition of aprotinin returns the situation to nearly normal in the first hours after CPB. Normal repair and remodeling can occur because aprotinin does not inhibit physiologic fibrinolysis, being effective only against free plasmin. Graft thrombosis may occur, but it is not increased by aprotinin and can be controlled by aspirin. As has been shown previously, activated clotting times were increased by aprotinin. This does not support the concept, however, that aprotinin is a heparin-sparing agent. In this study, care was taken to monitor activated clotting time and maintain it at a level greater than has been recommended in the past. The blood loss data in this study are similar to those we have reported in the past. Blood use was reduced in both groups compared with our previous study. We attribute this to an increased awareness of the potential risks of transfusion and a more aggressive approach to reducing transfusions. Previous studies have used graft angiography to determine patency. We elected to use a noninvasive method because our original approaches to patients resulted in a refusal to have a formal catheterization before discharge. It was also believed important that the examination be carried out early for the reasons that we have detailed. This method has been reported by several centers previously.26-28 Improvements in technique early in the study enabled us to determine patency of IMA grafts as well. Alternative noninvasive methods, such as high-speed cine-eomputed tomography, were not available. We believe that MRI is a suitable method for use early after operation. One patient was unable to complete the study because of claustrophobia, which is a problem with the current range of machines in use. The two deaths are explained in detail previously. Neither was believed to be related to treatment, and in both patients all grafts were patent. Other indicators of increased coagulation activity, such as stroke, were not seen in either group. The one patient who had a cerebrovascular accident was able to complete the study protocol without difficulty. There is now a large body of experience with high-dose aprotinin, both in the controlled environment of the clinical study and in routine clinical use. Reports of side effects have been remarkably few. In particular, patients who have received the drug in both primary coronary sit-
I 52
Bidstrup et al.
uations and during reoperation have not exhibited signs of early graft failure. Aprotinin is an adjunct to safer cardiac operations, both for the patient (less exposure to blood) and the surgeon (easier operating conditions). The risk-benefit profile for its use is very favorable. Special thanks are due to the members of the staff of the magnetic resonance units at the Royal Brompton and National Heart Hospital and S1. Mary's Hospital for performing the scans.
REFERENCES 1. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin (Trasylol). J THORAC CARDIOVASC SURG 1989;97:364-72. 2. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotinin-preliminary results. Thorac Cardiovasc Surg 1989; 37:89-91. 3. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26. 4. Harder MP, Eijsman L, Roozendaal KJ, van Oeveren W, Wildevuur CRH. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991;51:936-41. 5. Blauhut B, Gross C, Necek S, Doran JE, Spath P, Lundsgaardhansen P. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1991;101:958-67. 6. Elliot MJ, Allen A. Aprotinin in paediatric cardiac surgery. Perfusion 1990;5:73-6. 7. Girard C, Vedrinne C, Bouvier H, et al. High dose aprotinin or intraoperative autotransfusion: effects on blood loss and blood transfusion after cardiopulmonary bypass. J Cardiothorac Anesth 1990;4:44. 8. Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J THORAC CARDIOVASC SURG 1991;101:968-72. 9. Salzman E, Weinstein M, Weintraub R, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 1986;314:1402-6. 10. Bulkley BH, Hutchins GM. Pathology of coronary artery bypass graft surgery. Arch Pathol Lab Med 1978;102:27380. II. Goldman S, Copeland J, Moritz T, et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988; 77:1324-32.
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12. Chesebro J, Clements I, Fuster V, et al. A platelet inhibitor drug trial in coronary artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative graft patency. N Engl J Med 1982;307:73-8. 13. Limet R, David J-L, Magotteaux P, Larock M-P, Rigo P. Prevention of aorta-coronary bypass graft occlusion: beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass grafts-a double-blind study. J THORAC CARDIOVASC SURG 1987;94:773-83. 14. Henderson W, Moritz T, Goldman S, et al. The statistical analysis of graft patency data in a clinical trial of antiplatelet agents following coronary artery bypass grafts. Controlled Clin Trials 1988;9:189-205. 15. Ollivier JP, EPPAC group. Patency of aorto-coronary bypass grafts at 6 months: a French multi-centre study. Arch Mal Coeur 1991;84:537-42. 16. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary bypass surgery. Circulation 1991;83:152633. 17. Josa M, Lie J, Bianco R, Kaye M. Reduction of thrombosis in canine coronary bypass vein grafts with dipyridamole and aspirin. Am J Cardiol 1981;47:1248-54. 18. Harker L. Bleeding after cardiopulmonary bypass. N Engl J Med 1986;314:1446-8. 19. Lu H, Soria C, Commin PL, et al. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991;66:633-7. 20. Lu H, Cramer EM, Soria JM, et al. Temperature dependence of plasmin-induced activation or inhibition of human platelets. Blood 1991;77:996-1005. 21. Valeri C, Cassidy G, Khuri S, Feingold H, Ragno G, Altschule M. Hypothermia induced reversible platelet dysfunction. Ann Surg 1987;205:175-81. 22. Furie B, Furie Be. Seminars in medicine of the Beth Israel Hospital: molecular and cellular biology of blood coagulation. N Engl J Med 1992;326:800-6. 23. Kluft C. Pathomechanisms of defective hemostasis during and after extracorporeal circulation: contact phase activation. In: Friedel N, Hetzer R, Royston D, ed. Blood use in cardiac surgery. Darmstadt: Steinkopff, 1991:10-5. 24. Nagaoka H, Innami R, Murayama F, et al. Effects of aprotinin on prostaglandin metabolism and platelet function in open heart surgery. J Cardiovasc Surg 1991;32: 31-7. 25. van Oeveren W, Eijsman L, Roozendal KJ, Wildevuur CR. On the mechanism of platelet preservation during cardiopulmonary bypass by aprotinin. Lancet 1988;1:644. 26. Jenkins JPR, Love HG, Foster CJ, Isherwood I, Rowlands DJ. Detection of coronary bypass graft patency as assessed by magnetic resonance imaging. Br J Radiol 1988;61:2-4. 27. Gomes AS, Lois JF, Drinkwater DC, Corday SR. Coronary artery bypass grafts: visualization with MR imaging. Radiology 1987;162:175-9. 28. White RD, Caputo GR, Mark AS, Modin GW, Higgins CB. Coronary artery bypass graft patency: noninvasive evaluation with MR imaging. Radiology 1987;164:681-6.
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Discussion Dr. Safuh Attar (Baltimore, Md.). Dr. Bidstrup and colleagues' study is a well-conducted, timely study that demonstrates the effectiveness of the prophylactic use of aprotinin in reducing bleeding after coronary artery bypass without affecting the patency of the saphenous vein grafts. Nevertheless, graft occlusionat an unusually increased rate has been reported by the Cleveland Clinic group recently. Changes in renal function and histology have also been reported, and, more ominously, two cases of cardiac arrest after the use of aprotinin have been reported recently. It is important to clarify the effects of aprotinin on the other systems before recommending its widespread prophylactic use in heart operations. What were the fibrinolytic studies that were done during this investigation, including fibrinogen, plasminogen activator activity, fibrinogen degradation products, plasmin, and others? Was there hyperplasminemia or increased plasminogen activator activity? Would bleeding resulting from plasminogen activation be treated better with s-aminocaproic acid than with aprotinin? What were the renal functions in these patients; was there increased creatinine in the aprotinin-treated group? Were there other unreported additional changes? And what was the role of aspirin in maintaining the patency of these grafts? I think aprotinin is a useful drug, but we should determine its full effects, delineate the specificindications supported by specific laboratory monitoring data before recommending its general use. Dr. Victor Jebara (Paris, Fraru:e). The blood-saving effects of aprotinin are now well established, as Dr. Bidstrup has pointed out. Certain reluctance remains to routine use of this drug, however, mainly because of potential complications, as noted by Dr. Attar, and because of the high cost of this treatment. At Hopital Broussais in Paris we have conducted a prospective, randomized, double-blind study to explore the benefits and effects of low-dose aprotinin. Three groups of 30 patients each undergoing cardiac operations were individualized. In group I were patients who received high-dose aprotinin, which corresponded to the dose classically recommended in the literature and by Dr. Bidstrup. Group II included patients who received low-doseaprotinin corresponding to one fifth of the dose classically recommended. Group III was the control group of patients who did not receive aprotinin. Results showed that patients receiving aprotinin, that is to say, groups I and II, had a statistically significant decrease in blood loss of about 45% when compared with the patients who did not receive aprotinin, whereas no statistical significance could be shown between high-dose aprotinin, group I, and lowdose aprotinin, group II. These results were reported in detail at the last American Society of Anesthesiology meeting in San Francisco. This study demonstrates that a significantly lower dose of aprotinin can be used, thus decreasing the cost of this treatment and perhaps decreasing the prevalence of potential complications, which were never encountered in our extensive experience with this drug.
Effect of aprotinin on ACBGs
1 53
I have two questions, Dr. Bidstrup. Do you have any experience with low-dose aprotinin, and in your experience have you encountered any complications due to the use of aprotinin? Dr. Bidstrup. Ithank both Dr. Attar and Dr. Jebara for their kind comments. Dr. Attar, this study had one aim in mind, and that was to determine ACBG patency and the effects of aprotinin on that, and we carried out very few other hematologic investigations during this study. We certainly looked at fibrinogen levels,and they were unchanged between either group, but we did not look in detail at other parts of the fibrinolytic pathway. We are presently carrying out such investigations in a different group of patients. As far as the use of s-aminocaproic acid versus aprotinin for bleeding after operations, one of the difficulties that we have in theory with the use of e-aminocaproic acid, or Amicar, is that it is a competitive inhibitor of plasmin. The mode of action compared with aprotinin, which forms a sroichiometric complex plasmin, is totally different. There have been, in the past, a number of reports of increased thrombotic cerebrovascular events and, anecdotally, graft thromboses with the use of s-aminocaproic acid. With regard to your point on renal function, we have seen no changes that have been described by others. In a number of our studies where we have looked at serum creatinine levels and the changes during the course of the study, we have seen that the creatinine level tends to fall to within the normal range in patients who start off with a higher level. Some of the changes result in a slight increase in serum creatinine, which usually remains within the normal range for our laboratory. Regarding the use of aspirin, I think it is well established that nearly every patient who undergoes an aortacoronary bypass operation receivesaspirin or some other platelet-inhibiting agent postoperatively. We elected to use aspirin in this study because that is our normal practice. The idea of the early graft patency assessment was to try to determine whether aprotinin, per se, made any difference when compared with our normal practice. To answer Dr. Jebara's questions, we have had no experience formally with use of low-dose aprotinin. I know there are a number of other studies that have been published showing that there is a reduction in postoperative blood loss with lower doses. I would point out that the dosage regimen that we have described is a theoretic regimen. It was designed to achieve levels of aprotinin in the circulation during CPB that would inhibit kallikrein. For those of you who were present yesterday and heard Dr. Wachtfogel's report in a closed loop system, we certainly do achieve the inhibition of kallikrein with the doses that we are using. We have seen no other complications that we would attribute directly to the use of aprotinin. To answer Dr. Attar's point about the two cases of cardiac arrest that have been reported, these were patients who had, I believe, allergic phenomena probably related to previous exposure to the drug. This is a foreign protein and there is that real risk.
Benjamin P. Bidstrup, FRACS, FRCSEda (by invitation), S. Richard Underwood, MRCpb (by invitation), and Ralph N. Sapsford, ChM, FRcsa (by invitation), London, England. Consultant statistician: Elaine M. Streets, MSc* Sponsored by J. C. R. Lincoln, FRCS, London, England
Remarkable reductions in postoperative bleeding and blood use after many forms of operations performed with cardiopulmonary bypass (CPB) have been achieved with high-dose aprotinin.' Since the first descriptions of this novel regimen, double-blind studies have been repeated in centers throughout Europe.v" Each of these studies has shown blood loss reductions of the order of 40% to 50% and reductions in blood use of 40% to 80%. Other studies have examined effects on renal function and other aspects of pathophysiologic disturbances during CPB. 5-8 Few side effects related to the use of aprotinin in these studies have been described. Our own long-term experience and that of vast clinical usage throughout Europe support these observations. Concern has been expressed that hemostatic agents that result in reduced postoperative bleeding might have adverse effects on aorta-coronary bypass graft From Humana Hospital Wellington" and Department of Magnetic Resonance Imaging, Royal Brompton and National Heart Hospitals," London, England. Read at the Seventy-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., April 26-29, 1992. Address for reprints: Ben P. Bidstrup, FRACS, 66 Harley St., London WIN IAE, England. *Bayer pic, Newbury, England.
12/6/41326 0022-5223/93/$1.00/+ 0.10
(ACBG) patency." The long-term success of ACBG operations depends in the main on continued patency of the conduit. Early graft occlusion is believed to be initiated by platelet deposition on areas of endothelial damage, which results in subsequent thrombosis.!" Patency can be modified by the perioperative administration of antiplatelet drugs such as aspirin, dipyridamole, and ticlopidine, 11-13 but the effect of aprotinin, which reduces fibrinolysis after CPB, is not yet known. The aim of this study was to determine whether early (7- to lO-day) saphenous vein graft patency was adversely affected by the use of high-dose aprotinin (Trasylol; Bayer plc, N ewbury, England). Methods Study population. In the period between August 1989 and May 1991, 96 adult male patientswere admitted to a randomized,placebo-controlled double-blind study.During that period a total of 605 patients underwent first-time isolated coronary bypass in this surgical service. All patients were scheduled to receive three or more bypassgrafts. Patients were excluded if they had beenexposed to platelet-active drugs such as aspirinin the 10days beforetheir operation, wereto undergoreoperation or an additional procedure, had previous known exposure to aprotinin,or had had pancreatitis. The protocolwasreviewed by the ethical committee of our hospital, and written informed consent was obtained from all participating patients. Measurements. Blood loss at 6-hour intervalswas carefully 147
The Journal of Thoracic and Cardiovascular Surgery
1 4 8 Bidstrup et at.
Table I. Demographic data (all patients) No. Age (yr) Weight (kg) Height (em) Other diseases (%)
Aprotinin
Placebo
47 59.1 (7.4) 80.5 (8.9) 171 (6.6) 38
49 58.8 (8.5) 79.8 (10.3) 171.8 (5.7) 37
There were no significantdifferencesbetween the groups (p > 0.05). All valuesare expressed as mean (standard deviation).
Aprotinin No. No. of SVGs per patient 1 1 2 8 25 3 4 13 Total 144
Placebo %
No.
%
2 17 53 28
1 10 25 13 148
2 20 51 27
There were no significant differences between the treatment groups (P> 0.10).
Table II. Operative details (all patients) Duration of operation (min) Bypass time Crossclamp time Grafts (all) IMA grafts Endarterectomy
Table III. Distribution of saphenous vein grafts (SVGs) per patient (all patients)
Aprotinin
Placebo
135 (120-155) 62 (53-70) 35 (30-45) 3.82 27 9
140 (125-160) 61 (55-67) 36 (31-46) 3.73 25 10
There were no significant differences between treatment groups (p ues are expressed as median (interquartile ranges).
> 0.05). Val-
measured from the time of chest closure until the drains were removed 18 to 24 hours later. The hemoglobin content of this was measured as previously described.' The usage of homologous blood products was carefully controlled according to the hemoglobin level, which was measured as regular intervals. Red cells, either packed cells or, less commonly, whole blood, were administered only if the hemoglobin level fell below 8.5 gm/dl. Measurements were made of prothrombin time, activated partial thromboplastin time, activated clotting time, and fibrinogen levels before, during, and immediately after CPB. Standard hematologic and biochemical variables were measured preoperatively and postoperatively. Graft and bypass techniques. All patients underwent operations by one surgical team. All patients received heparin (300 IU/kg body weight) before cannulation for bypass, after harvesting of the saphenous vein and the internal mammary artery (IMA). At the end of bypass, protamine reversal was in the ratio of 0.7 to 1.0 mg/IOO IU heparin original dose. Activated clotting times (Hemochron; International Technidyne Corporation, Edison, NJ) were measured after aprotinin, at 20to 30-minute intervals during CPB, and after protamine administration. Activated clotting time was maintained at greater than 600 seconds, with additional heparin administered as necessary. Details of grafted vessel size, quality of artery, presence of mural and distal disease, performance of endarterectomy, and type of distal anastomosis were recorded. All distal anastomoses were constructed under a single period of aortic crossclamping, with the proximal anastomoses being made during rewarming with a partial occlusion clamp. Myocardial protection was achieved with cold St. Thomas' Hospital cardioplegic solution and mild systemic hypothermia (29 0 to 30 0 C). Aspirin (75 mg per day) was commenced in all patients after removal of chest drains. The techniques of CPB, anesthesia, and postoperative care were standardized throughout the period ofthe study, in keeping with the safe clinical management of the patient. Otherwise, these were as described in our previous reports.'
Aprotinin regimen. The patients received aprotinin or placebo (normal saline) from identical bottles supplied by the manufacturer and identifiable only by their random number. Aprotinin, 280 mg contained in 200 ml, was infused intravenously into a central venous catheter, as a loading dose, before the commencement of bypass. An additional 280 mg was added to the prime of the heart-lung machine. A constant infusion of 70 mg/hr was maintained during the procedure until skin closure. Patients in the placebo group received identical volumes of normal saline. Graft patency assessment. Patients underwent noninvasive assessment of graft patency by magnetic resonance imaging (MRI) 7 to 12 days (median 9 days) postoperatively. A series of transverse and sagittal slices 1 em thick, with 0.5 mm interleaving, was done with a Picker machine (Picker International Inc., Mayfield Village, Ohio) operating at 0.5 tesla or a GE Sigma Advantage (LG.E. Ltd., Slough, Berks, U.K.). The area of interest was defined after a pilot scan and extended from the aortic arch to the diaphragmatic surface of the heart. Images were transferred to film and read by two independent observers without knowledge of the treatment group. Graft patency was determined by the presence of a null signal in serial slices in the position of a graft. A null signal is returned by flowing blood indicating graft patency. If a graft was not visualized in consecutive slices, it was deemed to be occluded. Statistical methods. The primary efficacy analysis was the proportion of grafts patency excluding IMA grafts and grafts to endarterectomized vessels and was compared between treatment groups by a test of the standardized normal deviate. The variance was estimated using both the ratio estimate of proportions (nonindependence of grafts) and also assuming the binomial distribution (independence of graftsj.!" The numbers of patients with all grafts patent were compared between groups by means ofax2 test. Exploratory analysis was carried out on outcome for vessels that had endarterectomy, data from blood samples, blood loss, and blood transfusions. Parametric and nonparametric analyses were used as appropriate. For measurements that were repeated during the course of the trial, this included repeated measurements analysis of variance or Friedman's nonparametric two-way analysis of variance. Treatment groups were tested for baseline comparability, with parametric (two-sample t test) or nonparametric (Wilcoxon two-sample test) methods as appropriate for quantitative data with X2 tests for frequency counts. All significance tests were to be two sided with 5% significance level (p :::; 0.05) with the exception of grafts patent. This was to be one sided with 5% significance level (p :::; 0.05) since
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Effect of aprotinin on ACBGs
January 1993
Table IV. Distribution of arteries receiving SVGs
Vessel LAD Diagonal Circumflex RCA
Table V. Patency of saphenous vein grafts (SVGs) on a per graft basis
Placebo
Aprotinin
149
No.
%
No.
%
20 38 56 30
14 26 39 21
23 37 55 33
16 25 37 22
There were no significant differences between treatment groups (p > 0.05). SVG, Saphenous vein graft; LAD, left anterior descending artery; RCA, right coronary artery.
Placebo
Aprotinin
No. of grafts patent No. ofgrafts occluded Total
No.
%
No.
%
126 5
96.2 3.8
134 4 138
97.1 2.9
I3l
There were no significant differences between treatment groups either by ratio estimate or binomial assumption for determination of variance (see text).
Table VI. Patency of grafts on a per patient basis it wasof interestin this study onlyto determineas statistically significant an aprotininoutcomeworsethan with placebo. Thesamplesizecalculation wasbasedon the estimateof90% of grafts being patent at 7 days, and patencyof lessthan 80% withtreatmentbeingunacceptable. With one-sided testingwith 5% significance and 80% power, a minimumtotal of 88 patients receiving three or more grafts was needed. This allowed for the possibility of nonindependence of grafts within patients.
Placebo
Aprotinin
No. of patients with all grafts patent No. of patients with I or more grafts occluded
No.
%
No.
%
38
88.4
43
91.5
5
11.6
4
8.5
There were no significant differences between groups (p
> 0.05)
X2 test.
Results Demography. The groups were similar with respect to age, weight, and height (Table I). The presence of other diseases and the preoperative drug treatments were also similar. Bypass time, operation duration, crossclamp time, and number of grafts placed were again similar (Table 11). The use of the IMA graft and the number of endarterectomies actually performed in all patients are also shown in Table II. Six patients withdrew from the study, four in the aprotinin group and two in the placebo group. Two patients in the aprotinin group died 8 hours and 5 days, respectively, after operation. In one patient the quality of the images was too poor for analysis because of arrhythmia. In one, wound infection had developed, and two patients were unable to complete the scan because of intolerance. Thus a total of 269 venous grafts in 90 patients were suitable for analysis. Number and description of grafts. The distribution of grafts per patient for all patients excluding those with endarterectomized vessels and those receiving IMA grafts is shown in Table III. Table IV shows the distribution of vessels receiving saphenous vein grafts for all patients. All groups were similar. There were no significant differences between quality of the vein used for grafting, quality of the vessel at the site of anastomosis and distally, and size of the arteries grafted. Results of patency analysis. Excluding IMA grafts and endarterectomized vessels, there were 292 grafts performed in 96 patients. In the 6 patients who were excluded for the reasons given, there were 23 grafts, leaving 269 venous grafts in the 90 patients who completed the full study protocol, suitable for primary efficacy analysis.
Table V lists the number of grafts patent in each group. Table VI shows the number of patients with all grafts patent in each group. There were no significant differences between groups either on a per graft basis or on a per patient basis. An exploratory analysis was carried out with endarterectomized vessels included: 288 grafts in 90 patients. In the aprotinin group, 134 grafts (95.7%) were patent compared with 143 grafts (96.6%) in the placebo group. All grafts were patent in 37 patients in the aprotinin group (86.1%) and in 42 patients in the placebo group (89.4%). There were no significant differences (p > 0.05) between treatment groups either on a per graft or a per patient basis. Of 46 IMA grafts for which there was an outcome recorded, all were patent. Blood loss analysis. Total chest drainage after operation was significantly reduced in the aprotinin group compared with the placebo group and hemoglobin loss was reduced by 50% (Fig 1). Use of homologous blood products was significantly decreased in the aprotinin group. Whereas 24 patients in the placebo group received homologous red cells, only 9 in the aprotinin group received transfusions (p = 0.006). Totals of 795 ml (420 to 900) and 450 ml (410 to 500) (median and interquartile ranges) were given to each group, respectively (p = 0.03). Other clinical measurements. Hemoglobin levels before, during, and 24 hours and 5 days after operation did not differ significantly. Platelet counts differed only 10 minutes after protamine was administered, being 91 X 109/L and 121 X 109/L in the aprotinin and place-
150
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Bidstrup et al.
ACT
1400
sees
----
1200
1000
SOO
Aprotinir Placebo
600
400
200
Base
10' CPB
End CPB
10' Prot
Fig. 1. Total chest drainage and hemoglobin loss after operation (median and interquartile range). Differences between groups were significant (p < 0.01) for both measurements.
Fig. 2. Activated clotting times (ACT) preoperatively, 10 minutes on bypass, 40 minutes on bypass, and after reversal of heparin (median and interquartile range).
bo groups, respectively. Activated clotting times were greater in the aprotinin group at all time points during bypass (Fig. 2) (p < 0.001). Adverse events. Adverse events were recorded in 34 patients in total. The most common was atrial fibrillation/flutter, occurring in 10 patients in the aprotinin group and 12 in the placebo group. Three patients in the placebo group were reexplored for bleeding. There was one cerebrovascular accident, from which the patient, in the placebo group, made a good recovery. Two patients died, both in the aprotinin group, and causes of death are discussed in the next paragraph. Two other cardiac events occurred in patients treated with aprotinin. In one patient ventricular fibrillation developed on day 1 postoperatively after right coronary endarterectomy. A new inferior Q wave infarct was seen on postoperative electrocardiograms; one graft supplying the inferior surface was occluded. One patient had refractory supraventricular arrhythmias in the first 3 postoperative days. A probable myocardial infarction was diagnosed, but there were no new Q waves on the postoperative electrocardiogram. His remaining postoperative course was uneventful. All grafts were patent on imaging. One patient died from irreversible ventricular fibrillation some 6 hours after an uneventful operation. At autopsy, an acute, extensive inferior infarction predating operation by 48 hours was found. All four grafts were patent, and there was no evidence of intravascular thrombosis. Acute pulmonary hypertension at the time of protamine administration had developed in the second patient who died. This responded to vasodilators, and the chest was closed. Before the patient left the operating room, systemic hypotension required reinstitution of bypass. The right coronary graft had poor flow and was
redone. Porridge-like atheroma but no thrombus was present in the artery, and this was believed to be occluding the graft distally. All grafts were patent with no evidence of thrombosis when the chest was reexplored later that day for continued low cardiac output. Because neither of these patients completed the protocol, they were not included in patency assessment. Neither event was believed to be related to the treatment. Discussion Patency. This study has indicated that aprotinin therapy, while reducing blood loss and blood use significantly, has not resulted in increased early aorta-coronary bypass graft occlusion. These results support the concept that aprotinin achieves improved hemostasis by allowing hemostatic mechanisms to function normally at the end of bypass, rather than by creating a "hypercoagulable" situation. Many studies have examined the effects of various drug regimens on improving graft patency after operation. There may be an enormous variation in patency according to center and surgeon.P The EPPAC study showed a variation in occlusion rate from 2.8% to 28.6% of anastomoses and 7.1% to 57.1% per patient. This may reflect in part differing experience and factors, such as differing attitudes to grafting small vessels with poor runoff. Any study must take this into account. Therefore we elected to do this as a single-center study. Other studies have shown patency rates varying from 98.4% to 85%.11, 12, 16 The early (median 9 days) patency in this study is in keeping with those studies and with our own earlier recatheterization data (Bidstrup BP. Unpublished data). Timing of early study may determine patency rates because there appears to be a linear decrease in the first
Volume 105 Number 1 January 1993
few months. We elected to perform this assessment as early as practicable to determine the effect of the treatment applied and before other factors that might result in graft occlusion came into play. All patients received lowdose aspirin after chest drain removal. All therefore had been exposed to this drug for 6 to 11 days before patency assessment. Any adverse effect of aprotinin on patency would be seen early and modified equally between groups by aspirin. Early graft closure has been shown in animal models to be due to thrombosis of the conduit."? This is initiated on areas of endothelial damage. Mild degrees of damage result in a monolayer of platelets adhering to the vessel wall, but more extensive degrees of damage result in a greater response with additional activation of the clotting/repair system and laying down of thrombus. This response is carefully regulated in the body, so that it is appropriate for the stimulus. If this were not so, a single stimulus would result in uncontrolled activation of the clotting cascade. In the arterial circulation, platelet adherence occurs via the glycoprotein Ib receptors, which results largely in platelet thrombi. This is the basis for antiplatelet treatment for the improvement of graft patency. Other factors that may determine graft patency include the size and quality of the grafted vessel:Poor flow and distal disease may result in early occlusion. There are technical considerations because the use of magnification for coronary anastomosis is now almost universal. The effect of other treatments that are used frequently (platelet and fresh frozen plasma transfusions) is not known. The exact mechanism by which aprotinin achieves its hemostatic effects is still the subject of much debate. What is certain is that fibrinolysis, initially not thought to be a major contributor to bleeding after bypass.l'' is inhibited by aprotinin.' This may have effects on platelets. They are known to have the distribution of their glycoprotein Ib receptors altered by plasmin.!?: 20 Hypothermia is also known to adversely affect platelet function.P In these higher doses, aprotinin is also believed to inhibit kallikrein. The contribution of the kallikrein/factor XII loop to coagulation activation is probably unimportant? Much of the activation seen during CPB (and indeed in all operations) arises from the tissue factor pathway. Kallikrein is another pathway by which plasminogen may be activated under the conditions of extracorporeal circulation, however.P That platelet function is improved by aprotinin has been demonstrated by us and others. I, 24, 25 After reversal of heparin, the release of the platelet granule substance, {3-thromboglobulin, is increased, showing that platelets are better able to respond to the physiologic stimulus of thrombin (Bidstrup BP. Unpublished data). Serine protease inhibitors (of which aprotinin is one) are
Effect of aprotinin on ACBGs
15 1
controllers of coagulation, not initiators. Lack of these inhibitors (such as antithrombin III) results in increased thrombosis. It is likely then that the combination of poor platelet function (the initiator of hemostasis in high shear situations) and increased fibrinolysis (destroying formed hemostatic clots) after CPB causes bleeding. The addition of aprotinin returns the situation to nearly normal in the first hours after CPB. Normal repair and remodeling can occur because aprotinin does not inhibit physiologic fibrinolysis, being effective only against free plasmin. Graft thrombosis may occur, but it is not increased by aprotinin and can be controlled by aspirin. As has been shown previously, activated clotting times were increased by aprotinin. This does not support the concept, however, that aprotinin is a heparin-sparing agent. In this study, care was taken to monitor activated clotting time and maintain it at a level greater than has been recommended in the past. The blood loss data in this study are similar to those we have reported in the past. Blood use was reduced in both groups compared with our previous study. We attribute this to an increased awareness of the potential risks of transfusion and a more aggressive approach to reducing transfusions. Previous studies have used graft angiography to determine patency. We elected to use a noninvasive method because our original approaches to patients resulted in a refusal to have a formal catheterization before discharge. It was also believed important that the examination be carried out early for the reasons that we have detailed. This method has been reported by several centers previously.26-28 Improvements in technique early in the study enabled us to determine patency of IMA grafts as well. Alternative noninvasive methods, such as high-speed cine-eomputed tomography, were not available. We believe that MRI is a suitable method for use early after operation. One patient was unable to complete the study because of claustrophobia, which is a problem with the current range of machines in use. The two deaths are explained in detail previously. Neither was believed to be related to treatment, and in both patients all grafts were patent. Other indicators of increased coagulation activity, such as stroke, were not seen in either group. The one patient who had a cerebrovascular accident was able to complete the study protocol without difficulty. There is now a large body of experience with high-dose aprotinin, both in the controlled environment of the clinical study and in routine clinical use. Reports of side effects have been remarkably few. In particular, patients who have received the drug in both primary coronary sit-
I 52
Bidstrup et al.
uations and during reoperation have not exhibited signs of early graft failure. Aprotinin is an adjunct to safer cardiac operations, both for the patient (less exposure to blood) and the surgeon (easier operating conditions). The risk-benefit profile for its use is very favorable. Special thanks are due to the members of the staff of the magnetic resonance units at the Royal Brompton and National Heart Hospital and S1. Mary's Hospital for performing the scans.
REFERENCES 1. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin (Trasylol). J THORAC CARDIOVASC SURG 1989;97:364-72. 2. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotinin-preliminary results. Thorac Cardiovasc Surg 1989; 37:89-91. 3. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26. 4. Harder MP, Eijsman L, Roozendaal KJ, van Oeveren W, Wildevuur CRH. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991;51:936-41. 5. Blauhut B, Gross C, Necek S, Doran JE, Spath P, Lundsgaardhansen P. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1991;101:958-67. 6. Elliot MJ, Allen A. Aprotinin in paediatric cardiac surgery. Perfusion 1990;5:73-6. 7. Girard C, Vedrinne C, Bouvier H, et al. High dose aprotinin or intraoperative autotransfusion: effects on blood loss and blood transfusion after cardiopulmonary bypass. J Cardiothorac Anesth 1990;4:44. 8. Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J THORAC CARDIOVASC SURG 1991;101:968-72. 9. Salzman E, Weinstein M, Weintraub R, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 1986;314:1402-6. 10. Bulkley BH, Hutchins GM. Pathology of coronary artery bypass graft surgery. Arch Pathol Lab Med 1978;102:27380. II. Goldman S, Copeland J, Moritz T, et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988; 77:1324-32.
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12. Chesebro J, Clements I, Fuster V, et al. A platelet inhibitor drug trial in coronary artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative graft patency. N Engl J Med 1982;307:73-8. 13. Limet R, David J-L, Magotteaux P, Larock M-P, Rigo P. Prevention of aorta-coronary bypass graft occlusion: beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass grafts-a double-blind study. J THORAC CARDIOVASC SURG 1987;94:773-83. 14. Henderson W, Moritz T, Goldman S, et al. The statistical analysis of graft patency data in a clinical trial of antiplatelet agents following coronary artery bypass grafts. Controlled Clin Trials 1988;9:189-205. 15. Ollivier JP, EPPAC group. Patency of aorto-coronary bypass grafts at 6 months: a French multi-centre study. Arch Mal Coeur 1991;84:537-42. 16. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary bypass surgery. Circulation 1991;83:152633. 17. Josa M, Lie J, Bianco R, Kaye M. Reduction of thrombosis in canine coronary bypass vein grafts with dipyridamole and aspirin. Am J Cardiol 1981;47:1248-54. 18. Harker L. Bleeding after cardiopulmonary bypass. N Engl J Med 1986;314:1446-8. 19. Lu H, Soria C, Commin PL, et al. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991;66:633-7. 20. Lu H, Cramer EM, Soria JM, et al. Temperature dependence of plasmin-induced activation or inhibition of human platelets. Blood 1991;77:996-1005. 21. Valeri C, Cassidy G, Khuri S, Feingold H, Ragno G, Altschule M. Hypothermia induced reversible platelet dysfunction. Ann Surg 1987;205:175-81. 22. Furie B, Furie Be. Seminars in medicine of the Beth Israel Hospital: molecular and cellular biology of blood coagulation. N Engl J Med 1992;326:800-6. 23. Kluft C. Pathomechanisms of defective hemostasis during and after extracorporeal circulation: contact phase activation. In: Friedel N, Hetzer R, Royston D, ed. Blood use in cardiac surgery. Darmstadt: Steinkopff, 1991:10-5. 24. Nagaoka H, Innami R, Murayama F, et al. Effects of aprotinin on prostaglandin metabolism and platelet function in open heart surgery. J Cardiovasc Surg 1991;32: 31-7. 25. van Oeveren W, Eijsman L, Roozendal KJ, Wildevuur CR. On the mechanism of platelet preservation during cardiopulmonary bypass by aprotinin. Lancet 1988;1:644. 26. Jenkins JPR, Love HG, Foster CJ, Isherwood I, Rowlands DJ. Detection of coronary bypass graft patency as assessed by magnetic resonance imaging. Br J Radiol 1988;61:2-4. 27. Gomes AS, Lois JF, Drinkwater DC, Corday SR. Coronary artery bypass grafts: visualization with MR imaging. Radiology 1987;162:175-9. 28. White RD, Caputo GR, Mark AS, Modin GW, Higgins CB. Coronary artery bypass graft patency: noninvasive evaluation with MR imaging. Radiology 1987;164:681-6.
Volume 105 Number 1 January 1993
Discussion Dr. Safuh Attar (Baltimore, Md.). Dr. Bidstrup and colleagues' study is a well-conducted, timely study that demonstrates the effectiveness of the prophylactic use of aprotinin in reducing bleeding after coronary artery bypass without affecting the patency of the saphenous vein grafts. Nevertheless, graft occlusionat an unusually increased rate has been reported by the Cleveland Clinic group recently. Changes in renal function and histology have also been reported, and, more ominously, two cases of cardiac arrest after the use of aprotinin have been reported recently. It is important to clarify the effects of aprotinin on the other systems before recommending its widespread prophylactic use in heart operations. What were the fibrinolytic studies that were done during this investigation, including fibrinogen, plasminogen activator activity, fibrinogen degradation products, plasmin, and others? Was there hyperplasminemia or increased plasminogen activator activity? Would bleeding resulting from plasminogen activation be treated better with s-aminocaproic acid than with aprotinin? What were the renal functions in these patients; was there increased creatinine in the aprotinin-treated group? Were there other unreported additional changes? And what was the role of aspirin in maintaining the patency of these grafts? I think aprotinin is a useful drug, but we should determine its full effects, delineate the specificindications supported by specific laboratory monitoring data before recommending its general use. Dr. Victor Jebara (Paris, Fraru:e). The blood-saving effects of aprotinin are now well established, as Dr. Bidstrup has pointed out. Certain reluctance remains to routine use of this drug, however, mainly because of potential complications, as noted by Dr. Attar, and because of the high cost of this treatment. At Hopital Broussais in Paris we have conducted a prospective, randomized, double-blind study to explore the benefits and effects of low-dose aprotinin. Three groups of 30 patients each undergoing cardiac operations were individualized. In group I were patients who received high-dose aprotinin, which corresponded to the dose classically recommended in the literature and by Dr. Bidstrup. Group II included patients who received low-doseaprotinin corresponding to one fifth of the dose classically recommended. Group III was the control group of patients who did not receive aprotinin. Results showed that patients receiving aprotinin, that is to say, groups I and II, had a statistically significant decrease in blood loss of about 45% when compared with the patients who did not receive aprotinin, whereas no statistical significance could be shown between high-dose aprotinin, group I, and lowdose aprotinin, group II. These results were reported in detail at the last American Society of Anesthesiology meeting in San Francisco. This study demonstrates that a significantly lower dose of aprotinin can be used, thus decreasing the cost of this treatment and perhaps decreasing the prevalence of potential complications, which were never encountered in our extensive experience with this drug.
Effect of aprotinin on ACBGs
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I have two questions, Dr. Bidstrup. Do you have any experience with low-dose aprotinin, and in your experience have you encountered any complications due to the use of aprotinin? Dr. Bidstrup. Ithank both Dr. Attar and Dr. Jebara for their kind comments. Dr. Attar, this study had one aim in mind, and that was to determine ACBG patency and the effects of aprotinin on that, and we carried out very few other hematologic investigations during this study. We certainly looked at fibrinogen levels,and they were unchanged between either group, but we did not look in detail at other parts of the fibrinolytic pathway. We are presently carrying out such investigations in a different group of patients. As far as the use of s-aminocaproic acid versus aprotinin for bleeding after operations, one of the difficulties that we have in theory with the use of e-aminocaproic acid, or Amicar, is that it is a competitive inhibitor of plasmin. The mode of action compared with aprotinin, which forms a sroichiometric complex plasmin, is totally different. There have been, in the past, a number of reports of increased thrombotic cerebrovascular events and, anecdotally, graft thromboses with the use of s-aminocaproic acid. With regard to your point on renal function, we have seen no changes that have been described by others. In a number of our studies where we have looked at serum creatinine levels and the changes during the course of the study, we have seen that the creatinine level tends to fall to within the normal range in patients who start off with a higher level. Some of the changes result in a slight increase in serum creatinine, which usually remains within the normal range for our laboratory. Regarding the use of aspirin, I think it is well established that nearly every patient who undergoes an aortacoronary bypass operation receivesaspirin or some other platelet-inhibiting agent postoperatively. We elected to use aspirin in this study because that is our normal practice. The idea of the early graft patency assessment was to try to determine whether aprotinin, per se, made any difference when compared with our normal practice. To answer Dr. Jebara's questions, we have had no experience formally with use of low-dose aprotinin. I know there are a number of other studies that have been published showing that there is a reduction in postoperative blood loss with lower doses. I would point out that the dosage regimen that we have described is a theoretic regimen. It was designed to achieve levels of aprotinin in the circulation during CPB that would inhibit kallikrein. For those of you who were present yesterday and heard Dr. Wachtfogel's report in a closed loop system, we certainly do achieve the inhibition of kallikrein with the doses that we are using. We have seen no other complications that we would attribute directly to the use of aprotinin. To answer Dr. Attar's point about the two cases of cardiac arrest that have been reported, these were patients who had, I believe, allergic phenomena probably related to previous exposure to the drug. This is a foreign protein and there is that real risk.