The risks of blood transfusion are well known. Aprotinin

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1 Ultra-Low Dose Arotinin Decreases Transfusion Requirements and Is Cost Effective in Coronary Oerations Rebecca J. Dignan, MD, David W. Law, BSc, Peng W. Seah, MBBS, Con W. Manganas, MBBS, David C. Newman, FRACS, Peter W. Grant, FRACS, and Hugh D. Wolfenden, FRACS Prince of Wales Hosital, Sydney, Australia Background. The recommended dose of arotinin has been shown to reduce blood loss and need for blood transfusions, but the cost recludes its routine use. This study was designed to determine whether a less exensive, ultra-low dose of arotinin is effective when used in coronary artery byass grafting with left internal mammary artery. Methods. Patients (n 202) were randomized to receive either lacebo or arotinin, 0.5 million KIU before incision and 0.5 million KIU during initiation of cardioulmonary byass. Differences in quantity of blood transfused were analyzed. Further grous were analyzed to account for the effect of asirin. Multivariable analysis was erformed to determine risk factors for transfusion. Direct costs of blood roducts and arotinin were tabulated for each grou. Results. There was an imortant reduction in the roortion of atients transfused, and number of blood units transfused when arotinin was given before coronary artery byass grafting. These differences were even more imortant in atients on asirin reoeratively. Indeendent redictors for increased number of transfusions were asirin continued before oeration, smaller body surface area, and the use of lacebo instead of ultra-low dose arotinin. There was no difference in morbidity between treatment grous. There was a reduction in direct costs associated with the use of arotinin. Conclusions. These data suort the routine use of arotinin 1 million KIU in coronary artery byass grafting with left internal mammary artery to reduce cost and transfusion requirements. (Ann Thorac Surg 2001;71:158 64) 2001 by The Society of Thoracic Surgeons The risks of blood transfusion are well known. Arotinin has been found to reduce transfusion requirements in various oerations including rimary coronary artery byass grafting [1], adult reoerations [2], ediatric oerations [3], oerations for endocarditis [4], and valve oerations [5]. Although data are inconsistent [6], atients on asirin undergoing coronary artery byass grafting may be at higher risk for excessive bleeding and requirement of latelet and acked red cell transfusions. One grou of atients on asirin treated with arotinin was shown to have as much as a 75% reduction in bleeding and a marked decrease in allogenic blood transfusions [7]. Arotinin has been shown to be effective in reducing blood roduct usage after oen-heart oerations in a dose-deendent manner [1, 2]. High-dose arotinin, however, is exensive. In attemting to deliver costeffective quality surgical care [3], many institutions are unwilling to use high- or even low-dose arotinin in routine cases. At the study institution, a divided dose of 1 million units of arotinin has been administered routinely for coronary oerations since Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31 Feb 2, Address rerint requests to Dr Dignan, Deartment of Cardiothoracic Surgery, 2986 The Vanderbilt Clinic, Nashville, TN 37232; rebecca.dignan@surgery.mc.vanderbilt.edu. Efficacy of ultra-low dose arotinin, the minimum dose thought to inhibit lasmin [8], has not been comletely defined. The aim of this study was to determine whether 1 million KIU arotinin administered in a divided dose before two stimuli of the inflammatory resonse (skin incision and cardioulmonary byass [CPB]) would be cost effective in reducing transfusion requirements in routine (elective and urgent) coronary artery byass grafting. Material and Methods Aroval for this study rotocol was obtained from the Prince of Wales Hosital/University of New South Wales Research Ethics Committee on October 1, Informed consent was obtained before enrolling any atient. Between October 1997 and January 1999, 202 atients scheduled to undergo first-time coronary artery byass grafting with left internal mammary artery were randomized in a doubleblinded fashion to receive either ultra-low dose arotinin (Bayer Cororation, West Haven, CT; 1 million KIU as a divided dose) or lacebo. The study was conducted at the Prince of Wales Hosital (Sydney, Australia). The atient grou was selected for its similar risk of bleeding: atients undergoing coronary artery byass grafting with left internal mammary artery harvested in combination with conduits other than the right internal mammary artery. Harvest 2001 by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg DIGNAN ET AL 2001;71: ULTRA-LOW DOSE APROTININ IS EFFECTIVE 159 of that conduit would otentially increase bleeding and the risk of receiving a transfusion. Exclusion criteria were refusal of blood transfusions, recent use of antilatelet agents other than asirin, known or susected allergy to arotinin, revious sternotomy, known bleeding disorder, and regnancy. Study Drug Administration The study drug was administered by the anesthesiologist as an infusion in a blinded fashion. The first milliliter was infused slowly as a test dose and the atient observed for hyersensitivity or other untoward reaction. The initial dose was comleted before skin incision and the second dose during the initiation of CPB. The atients in the arotinin arm of the study received 0.5 million KIU arotinin before skin incision and 0.5 million KIU during initiation of CPB. Patients in the lacebo arm received the same volume of saline. Surgical, Anticoagulation, and Transfusion Protocols The conduct of the oeration was erformed according to the technique of several anesthetists and surgeons (ie, anesthetic technique, oxygenator tye, degree of hyothermia, blood cardiolegia technique, and use of ostoerative asirin). One surgeon used a membrane oxygenator and cardiotomy return suction in every atient (cases distributed equally between the two treatment grous). Two surgeons used bubble oxygenators without cardiotomy return suction. Hearin-bonded tubing was not used. Bovine hearin was administered as a loading dose (300 IU/kg) and 10,000 IU was added to the um rime. Activated clotting time was maintained at more than 400 seconds as measured by the kaolin-activated system before and after hearinization. Cell-saver suction and ostoerative autotransfusion were not used. Homologous red blood cells were transfused during CPB if the atient s hemoglobin was less than 7.0 g/dl and ostoeratively if less than 8.0 g/dl or if the atient s conditioned warranted (ie, excessive mediastinal bleeding). Platelets and fresh frozen lasma were transfused as judged necessary by the investigators or the articiating surgeons (ie, coaguloathy and excessive mediastinal bleeding). Cryoreciitate was available but never used in these atients. Crossover to arotinin use for the lacebo grou and use of additional arotinin ostoeratively in the arotinin grou was allowed by the articiating surgeon or investigator if mediastinal hemorrhage occurred, identifying the treatment grou to which the atient belonged in only 1 atient. Data Collection and Criteria for Evaluation of Efficacy and Morbidity Demograhic data, body surface area, hearin doses, activated clotting times, untoward reactions, blood roducts transfused intraoeratively and ostoeratively, and mediastinal tube drainage at 4 and 12 hours were recorded on a study rotocol data sheet for each atient. Changes between reoerative and ostoerative electrocardiograms (erformed on day 1, and as indicated thereafter by clinical changes), hemodynamic instability, neurologic events, and any other comlications were noted on the data sheet. Preand ostoerative hemoglobin, creatine kinase and myocardial isoenzymes (measured twice ostoeratively), troonin (which became available at the study institution in June 1998), re- and ostoerative creatinine, and liver function tests were also recorded. Evaluation of efficacy included the quantity of mediastinal tube drainage at 4 and 12 hours, incidence of reexloration for diffuse nonsurgical bleeding, roortion of atients requiring transfusion, and comarison of the total number of the blood units and of each tye of blood roduct (acked red blood cells, fresh frozen lasma, and latelets) transfused. Analysis of morbidity was based on surgeons and investigators clinical diagnosis of myocardial infarction, neurologic evaluation, and increase in creatinine level measured reoeratively and ostoeratively (highest of day 1, 2, and 4 or 5) of more than 0.05 mg/dl. Diagnosis of clinically significant myocardial infarction was made before unblinding and based on the surgeons and investigators evaluation of electrocardiograhic changes, hemodynamic instability, and increase in cardiac isoenzymes or troronin. Direct costs of arotinin (US $74 er 1 million units), cross match (US $66), and blood roducts (US $66 er unit) were calculated and comared between lacebo and arotinintreated grous. These were calculated using study institution-secific costs converted from Australian to US dollars. Indirect costs were not available at the study institution because costing is not itemized (ie, cost of blood roduct administration, oerating room costs, intensive care bed costs, and hosital bed costs). To translate cost efficacy to an institution in the US, cost and charges er atient were calculated for the corresonding author s institution based on the number of units transfused in the two study grous. Costs were calculated using arotinin cost ($146 er 1 million units), blood rocessing fees contracted (er unit) with the American Red Cross (red cells, $119.50; fresh frozen lasma, $46; latelets, $200), latelet ooling fee ($18 er unit), blood administration cost ($4.36 er unit), and cross match ($21.33 er unit) at the corresonding author s institution. Charges were calculated using arotinin cost lus harmacy administrative fee ($ er 1 million units), the blood roduct rocessing fee contracted (er unit) with the American Red Cross lus blood bank administrative fee (red cells, $216; fresh frozen lasma, $150; latelets er 4 U ack, $344) and latelet ooling fee ($18), blood administration cost ($4.36 er unit), and charge for cross match ($124) at the corresonding author s institution. Arotinin was considered cost effective if the cost er atient was less than or equal to the cost er atient in the lacebo grou. Data collection was erformed in a blinded fashion; the investigators were unblinded as to treatment after the atient s discharge so that the medical record could be marked aroriately. Data Analysis Data were tabulated using the database Summit (Minnetonka, MN). Patients requiring mediastinal reex-

3 160 DIGNAN ET AL Ann Thorac Surg ULTRA-LOW DOSE APROTININ IS EFFECTIVE 2001;71: loration were excluded only if a documented site amenable to surgical reair was located. Comarisons of demograhics and mediastinal drainage were made using an indeendent t test or Wilcoxon test of rank sums. Analysis of the roortion of atients transfused in each grou and comarison of ostoerative comlication rates (neurologic events, renal insufficiency, and myocardial infarction) were made using 2 analysis. Comarisons of median units of blood roducts transfused for all atients and also for only those who were transfused were made using analysis of rank sums (Wilcoxon test for nonarametric data). The reand ostoerative cardiac enzymes for all atients, atients with a clinical diagnosis of myocardial infarction, and atients without myocardial infarction were tested for differences in medians between treatment grous using Wilcoxon test for nonarametric data. Although not stratified from the outset, grous were analyzed to determine the effect of asirin on the roortion of atients transfused and units of blood roducts transfused in each treatment grou. The asirin grou was defined as those atients who received asirin on days 1 through 6 before oeration. The no asirin grou included those atients who did not receive asirin or received asirin on day 7 or more before oeration. Multiariable linear regression analyses were erformed to determine indeendent redictors of greater number of transfusions and logistic regression to determine risk factors for transfusion (yes/no transfusion). A two-stage logistic regression analysis was erformed, with the covariates entered on the first ste and the treatment (lacebo versus arotinin) offered in a stewise method on the second ste, adjusting for the covariates to redict transfusion risk. The first ste of the multile linear regression analysis was erformed by forcing variables into the model in a ste-wise fashion. In the second ste of the analysis, the treatment grou was added to the model after adjusting for the other variables. Statistical tests were erformed using the software ackage JMP (Altura Software, SAS Institute, Inc, Cary, NC) and SPSS v9.0 (SPSS, Inc, Chicago, IL) and were considered significant if value was 0.05 or less. Results Two hundred two atients were randomized and two hundred were included in the analysis. Two of those atients in the arotinin grou, who were reexlored and found to have surgical bleeding (one from a branch of a sahenous vein graft and one an arterial branch on the ericardium), were excluded from the analysis before unblinding of the investigators. Aroximately one-half of each treatment grou was on asirin reoeratively. Table 1 shows the results of the demograhic analysis. Treatment grous were similar for age, body surface area, gender distribution, and rate of urgent cases er grou. There was no difference between grous in number of units of blood given on CPB, oerative activated clotting time, time on CPB, or reoerative and discharge hemoglobin levels. Mediastinal tube drainage (Table 2) at 4 hours ostoeratively was significantly less in the arotinin-treated Table 1. Demograhic and Other Variables Variables Arotinin (n 101) Placebo (n 99) Age (mean with 62.8 (35 80) 65.2 (40 81) 0.10 range) Gender (% female) 26% 22% 0.56 BSA (m 2 ) a a 0.39 % Urgent cases ACT on CPB 582 b 556 b 0.10 (seconds) PRBCs on CPB (U) a a 0.71 Time on CPB a a 0.30 (minutes) Preoerative Hgb a a 0.99 (g/dl) Postoerative Hgb (g/dl) a a 0.39 a Mean standard error. b Median (Wilcoxon test of rank sums). ACT activated clotting time; BSA body surface area; CPB cardioulmonary byass; Hgb hemoglobin; PRBCs acked red blood cells. grou for the total oulation and significantly less in the asirin and nonasirin grous as well. These differences in drainage remained significant at 12 hours. Table 3 shows the mean number of units transfused (total units and acked red blood cells, fresh frozen lasma, and latelets considered searately) and roortion of atients transfused were significantly less in the arotinin-treated grou when comared to the lacebo grou. The same was true of the asirin and no asirin grous when the arotinin-treated atients were comared with the lacebotreated atients. Although the median number of units of acked red blood cells and total number of units transfused were comared between treatment grous using the Wilcoxon test (Aendix 1) and were significantly less in the arotinin-treated grous, the means are reorted as these are clinically more significant. The roortion of atients receiving latelets and fresh frozen lasma were too small to have meaningful medians and, therefore, are reorted in Table 2. Mediastinal Drainage a Drainage Arotinin Placebo 4-hour drainage (ml) Total grou (n) (101) (99) Asirin grou (n) (49) (53) No asirin grou (n) (52) (46) 12-hour drainage (ml) Total grou (n) (99) (99) Asirin grou (n) (48) (53) No asirin grou (n) (51) (46) a Mean standard error.

4 Ann Thorac Surg DIGNAN ET AL 2001;71: ULTRA-LOW DOSE APROTININ IS EFFECTIVE 161 Table 3. Transfusion Requirements After CABG With LIMA Variables Arotinin (n) Placebo (n) Total transfusions (U) Total grou a (101) (99) d Asirin grou b (49) (53) d No asirin grou c (52) (46) d PRBCs (U) Total grou a (101) (99) d Asirin grou b (49) (53) 0.03 d No asirin grou c (52) (46) d FFP (U) Total grou a (101) (99) d Asirin grou b (49) (53) d No asirin grou c (52) (46) d Platelets (U) Total grou a (101) (99) d Asirin grou b (49) (53) d No asirin grou c (46) d Transfusion rate e Total grou a 37% 62% f Asirin grou b 49% 70% f No asirin grou c 25% 54% f a All atients included in analyses. b Patients who received asirin within 6 days before oeration. c Patients who did not receive asirin within 6 days before oeration. d Analysis using Wilcoxon rank-sums test. e Percent of atients requiring transfusions. f Analysis using 2. CABG coronary artery byass grafting; FFP fresh frozen lasma; LIMA left internal mammary artery; PRBCs acked red blood cells. Aendix 2 as roortion of atients transfused and are also significantly less in all arotinin-treated grous. Of those atients transfused (excluding atients from the analysis who received no transfusions), the arotinintreated grou had significantly fewer transfusions than the lacebo-treated grou ( vs ). Again, the mean is reorted because the median number of units transfused was 2.0 for both grous (significantly different, by Wilcoxon test). Indeendent redictors for both risk of transfusion (Table 4) and greater number of transfusions (Table 5) were Table 4. Results of Logistic Regression Analysis of Factors Associated With Risk of Postoerative Transfusion Variables a Ex (B) b 95% Confidence Limits Lower Uer Hemoglobin Cardiotomy return c Age 65 years BSA 1.9 m Asirin d No arotinin a Continuous values were recorded as below or above the median. b Log odds ratio. c Same surgeon used cardiotomy return and membrane oxygenator. d Asirin administered within 6 days of oeration reoeratively. BSA body surface area. Table 5. Results of Linear Regression Analysis of Variables Associated With Risk of Greater Number of Transfusions Variable B a 95% Confidence Limits Lower Uer Low reo Hgb b Cardiotomy return c Older age Lower BSA Days off asirin d No arotinin a B is the regression coefficient; negative value indicates inverse relationshi with number of transfusions; standard error. b Low reoerative hemoglobin. c Same surgeon used cardiotomy return and membrane oxygenator. d Days of asirin reoeratively. BSA body surface area; Hgb hemoglobin. smaller body surface area and asirin administered reoeratively within 6 days of surgery. Preoerative hemoglobin below 14.3 g/dl and age more than 65 years redicted transfusion but not a greater number of transfusions. Use of cardiotomy return suction and membrane oxygenator was not a risk factor for either. Treatment without arotinin was found to be a statistically significant redictor of transfusion and greater number of transfusions indeendent of the covariates. Patients treated without arotinin had an increase in the odds of transfusion by a factor of Treatment with arotinin had a significant, indeendent effect of reducing transfusion requirements and decreasing risk of transfusion (yes/no). Morbidity was similar for each grou and there were no deaths. The rate of reentry for mediastinal hemorrhage (2% for both grous), temorary (arotinin 1% versus lacebo 0%) and ermanent cerebrovascular accident (1% for both), myocardial infarction (arotinin 3% versus lacebo 5%), and the rate of increased creatinine level of more than 0.05 mg/dl (arotinin 2% versus lacebo 3%) ostoeratively was not different between grous. Acute renal failure did not occur. Cardiac enzymes, isoenzymes, relative index, and troonin were no different between treatment grous when comared for all atients and atients with or without myocardial infarction (medians comared for each grou). As mentioned, accounting was not erformed by individual deartments in the study institution as to actual cost of oerating room time, length of hosital stay, blood Table 6. Cost of Arotinin and Transfusions a Variable Arotinin Placebo Drug (grou cost) $5,840 0 Blood roducts (grou cost) $6,336 $16,500 Postoerative arotinin (grou cost) $43 $147 Cross-match $5,214 $4,884 Cost/atient a $220 $290 Cost/atient b $343 $463 Charge/atient c $826 $940 a Cost at study institution in US dollars. b Cost in US dollars using cost at corresonding author s institution; January c Charge in US dollars using cost lus administrative fees at corresonding author s institution; January 2000.

5 162 DIGNAN ET AL Ann Thorac Surg ULTRA-LOW DOSE APROTININ IS EFFECTIVE 2001;71: roducts or administration of transfusions by nursing staff. The Sydney Red Cross Blood Service estimated the cost to acquire and rocess each unit of blood roduct to be A$ 100 (equal to aroximately US $66). The difference in cost at the study institution (Table 6) between the two grous reresents a 24% reduction in cost for the arotinin grou. The difference in cost at the corresonding author s institution reresents a 26% reduction er atient in the arotinin grou. The difference in charges at the corresonding author s institution reresents a 12% reduction er atient in the atinin grou. Comment Although the mediastinal tube drainage was significantly reduced in arotinin-treated atients, the imortant reduction in roortion of atients transfused and number of units transfused is a more sensitive indicator of the effect of arotinin. These data suort the routine use of ultra-low dose arotinin before skin incision and during initiation of CPB as an effective measure to reduce transfusion requirements. This would be esecially true in atients on asirin within 6 days before oeration, more than 65 years of age, and body surface area less than 1.9 m 2. Although safety is difficult to rove, arotinin at this dose did not have a higher morbidity rate and was cost effective. The effectiveness of this dose has a hysiologic basis. The antifibrinolytic effect of arotinin is thought to result from the direct inhibition of lasmin, whereas inhibition of kallikrein is involved to a lesser extent [9, 10], or ossibly absent at this dose. Although arotinin lasma concentrations of 200 KIU/mL or greater are needed to inhibit kallikrein, lasma concentrations of 50 KIU/mL are required to inhibit lasmin. This level can be achieved with a loading dose of 1,000,000 KIU [11], the dose used in this study. Hayashida and colleagues [12] showed that when minimal dose arotinin (1 million units in the um rime) was used, increased levels of 2-lasmin inhibitor, lasminogen activator-1, and decreased levels of D-dimer were measured after CPB as comared to controls, thus suorting an antifibrinolytic effect [12]. This reduction in transfusion requirements was true whether or not the atient was on asirin. The benefit of ultra-low dose arotinin, however, was more marked in atients who had received recent asirin. This has been confirmed in another study but at a higher dose of arotinin [1]. The number of transfusions was also reduced in those atients who received arotinin and were at reduced risk for bleeding (ie, those atients off asirin for 7 or more days reoeratively) comared to those who received lacebo. In addition, no atient treated with arotinin and not on asirin received a latelet transfusion. The similarity in rate of transient ischemic attack, stroke, myocardial infarction, increase in creatinine level, and acute renal failure between grous, although not roved, suort the safety of this arotinin dose. Other studies have shown high-dose but not low-dose arotinin to reduce the risk of stroke [13]. The risk of myocardial infarction and graft thrombosis is still controversial. Recent studies, after the imortance of adequate hearinization has been acknowledged, have shown no difference in graft atency [4, 14] between atients treated with arotinin or lacebo. Some investigators have suggested that arotinin is safe and effective only at the full-dose regimen [15]. The large number of study atients required to show the small difference in morbidity and mortality between a grou treated with and without arotinin at half or lower doses of arotinin is rohibitive. The benefit of arotinin-induced reduction in transfusion requirements, and transfusionassociated morbidity and mortality calculated over time, far outweigh the extremely low risk of mortality or morbidity associated with arotinin administration. Although satisfactory determination of detailed and actual hosital costs was not available in this ublic hosital, this study showed a reduction in direct cost when ultra-low dose arotinin was used. In a retrosective study, low-dose arotinin was shown to be effective in redo coronary oerations in reducing cost [16]. In another rosective, nonblinded study comaring high-dose, low-dose, and no arotinin used in atients undergoing oen heart oeration, costs were significantly reduced when low-dose but not high-dose arotinin was used [3]. Many variables can be considered when cost analysis is undertaken and may vary between countries and institutions. The costs of blood roducts as well as arotinin may vary widely between hositals. In one study, the cost of a ack of latelets was listed as US $545 [17]. At the study institution, the cost of a ack of latelets was estimated to be the same as any other unit of blood roduct desite the scarcity of latelets. The effect of arotinin in reducing cost in this study would only increase if the higher estimated cost of latelets were used in the analysis. Deending on the cost of each unit of blood roduct, esecially latelets, ultra-low dose arotinin (aroximately US $80 to US $180) [17] would be effective in reducing cost in most institutions if even one unit less was required in arotinin-treated atients comared to nontreated atients. Comarison of charges between institutions and harmacies is unreliable because frequently harmacy costs are added to the total charges for a articular drug. In another trial, which included atients taking asirin within 48 hours of rimary coronary oeration, another low-dose arotinin regimen (28 mg or 200,000 KIU then 28 mg/h) was comared to tranexamic acid (10 mg/kg then 1mg kg 1 h 1 ), and aminocaroic acid (5 g then 1 g/h). All significantly reduced both blood loss and the use of blood roducts comared with no treatment [18]. Studies have comared high-dose arotinin to aminocaroic acid and have shown arotinin to be suerior in reducing transfusion requirements [17, 19]. Comarison of the effect of ultra-low dose arotinin versus aminocaroic acid treatment in reducing transfusion requirements and cost should now be undertaken in a double-blinded, randomized fashion. Many thanks are due to the cardiac anesthetists at The Prince of Wales Hosital for their art in carrying out this study. We also thank the cardiac surgery intensive care nurses and anesthetic technicians for their dedicated assistance. We acknowledge the advice of Julia Potter, BMed Sc. MBBS Ph.D., FRCPA, Director of Chemical Pathology, The Prince Charles Hosital, Brisbane, Queensland, on the role of cardiac enzymes in the diagnosis of myocardial infarction, and Peta Dennington, Staff Secialist, Sydney Red Cross Blood Services on the cost of blood roducts in Sydney, Australia. Thanks are also due to Pat Tanley, Senior Associate in Pathology, Vanderbilt University Medical Center, Blood Bank Manager and Philli Johnston, PharmD, Vanderbilt University Medical Center Pharmacy for their hel in cost analysis. We are grateful also to Daniel W. Byrne, Director of Biostatistics at Vanderbilt University, for statistical advice and assistance esecially in multivariable analysis.

6 Ann Thorac Surg DIGNAN ET AL 2001;71: ULTRA-LOW DOSE APROTININ IS EFFECTIVE 163 References 1. Lemmer JH, Dilling EW, Morton JR, et al. Arotinin for rimary coronary artery byass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1196;62: Royston D, Bidstru BP, Taylor KM, Sasford RN. Effect of arotinin on need for blood transfusion after reeat oen heart surgery. Lancet 1987;2: Lazzara RR. Kidwell FE, Kraemer MF, Wood JA, Starr A. Reduction in costs, blood roducts, and oerating time in atients undergoing oen heart surgery. Arch Surg 1997;132: Bidstru BP, Royston D, Taylor KM, Sasford RN. Effect of arotinin on need for blood transfusion in atients with setic endocarditis having oen-heart surgery. Lancet 1988;1: Ray JM, Marsh NA. Arotinin reduces blood loss after cardioulmonary byass by direct inhibition of lasmin. Thromb Haemost 1997;78: Belisle S, Hardy JF. Hemorrhage and the use of blood roducts after adult cardiac oerations: myths and realities. Ann Thorac Surg 1996; Murkin JM, Lux J, Shannon NA, et al. Arotinin significantly decreases bleeding and transfusion requirements in atients receiving asirin and undergoing cardiac oerations. J Thorac Cardiovasc Surg 1994;107: Matroroberto P, Chello M, Zofrea S, et al. Suressed fibrinolysis after administration of low-dose arotinin: reduced level of lasmin-alha(2)-lasmin inhibitor comlexes and ost-oerative blood loss. Eur J Cardiothorac Surg 1995;9: Davis R, Whittington R. Arotinin: a review of its harmacology and theraeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995;49: Peters DC, Noble S. Arotinin: an udate of its harmacology and theraeutic use in oen heart surgery and coronary artery byass surgery. Drugs 1999;57: Levy JH, Balley JM, Salmenera M. Pharmacokinetics of arotinin in reoerative cardiac surgical atients. Anesthesiology 1994;80: Hayashida N, Isomura T, Sato T, et al. Effects of minimaldose arotinin on coronary artery byass grafting. J Thorac Cardiovasc Surg 1997;114: Levy JH, Ramsay JG, Murkin J. Arotinin reduces the incidence of stokes following cardiac surgery [abstract]. Circulation 1996;94(Sul 1): Lass M, Simic O, Ostermeyer J. Re-graft atency and clinical efficacy of arotinin in elective byass surgery. Cardiovasc Surg 1997;5: Smith PK, Muhlbaier LH. Arotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996;62: Able ME, Tilly DA. The effect on costs of the use of half-dose arotinin for first time reoerative coronary artery byass atients. Clin Ther 1998;20: Bennett-Guerrero E, Shoran JG, Gurevich ML, et al. Costbenefit, and efficacy of arotinin comared with aminocaroic acid in atients having reeated cardiac oerations. A randomized, blinded clinical trial. Anesthesiology 1997;87: Landymore RW, Murhy JT, Lummis H, et al. The use of low-dose arotinin, -aminocaroic acid or tranexamic acid for revention of mediastinal bleeding in atients receiving asirin before coronary artery byass oerations. Eur J Cardiothorac Surg 1997;11: Eberle B, Mayer E, Hafner G, et al. High-dose aminocaroic acid versus arotinin. antifibrinolytics efficacy in first-time coronary oerations. Ann Thorac Surg 1998;65: Aendix 1. Transfusion Requirements After CABG With LIMA (Medians) Variable Arotinin Placebo d Total transfusions (U) Total grou a Asirin grou b No asirin grou c PRBCs e (U) Total grou a Asirin grou b No asirin grou c a All atients included in analysis. b Patients who received asirin within 6 days before oeration. c Patients who did not receive asirin within 6 days before oeration. d Analysis using 2. e Medians for fresh frozen lasma and latelet transfusion not included because frequency of transfusion was low. CABG coronary artery byass grafting; LIMA left internal mammary artery; PRBCs acked red blood cells. Aendix 2. Transfusion Rate After CABG With LIMA Variable Arotinin Placebo d Total transfusions Total grou a 37% 62% Asirin grou b 49% 70% No asirin grou c 25% 54% PRBCs Total grou a 37% 59% Asirin grou b 49% 68% No asirin grou c 25% 48% FFP Total grou a 5% 25% Asirin grou b 8% 34% No asirin grou c 2% 15% Platelets Total grou a 5% 23% Asirin grou b 10% 36% No asirin grou c 0% 9% a All atients included in analysis. b Patients who received asirin within 6 days before oeration. c Patients who did not receive asirin within 6 days before oeration. d Analysis using 2. CABG coronary artery byass grafting; FFP fresh frozen lasma; LIMA left internal mammary artery; PRBCs acked red blood cells. DISCUSSION KENNETH M. TAYLOR (London, UK): Dr Matloff, Dr Murray, members, and guests. I am grateful to Dr Dignan for roviding me with a full manuscrit of her resentation well in advance of this meeting. I commend her and her colleagues from Sydney for a very well-conducted study and a very clear, well-written aer. I do find the results very interesting and largely consistent with our own thoughts on the issue of arotinin dosage. When we consider the original Hammersmith, or high-dose regime in arotinin, it should not be forgotten that this dose regime (a test dose, a loading dose of 2 million KIU, a um rime dose of 2 million KIU, and a constant infusion of 0.5 million KIU during the eriod of the oeration) was not calculated on the hyothesis that it would be hemostatic, rather that it would be kallikrein inhibiting throughout the eriod of the

7 164 DIGNAN ET AL Ann Thorac Surg ULTRA-LOW DOSE APROTININ IS EFFECTIVE 2001;71: oeration. The hyothesis being, at that time, that kallikrein inhibition might reduce the inflammatory resonse in the lungs. The issue then of the aroriate dose for hemostasis with arotinin has continued to the resent day. I agree with Dr Dignan and her colleagues that lower doses are effective in atients at lower risk of excessive bleeding. Before this meeting, I ulled that data from around 500 of my ast atients. I use arotinin in aroximately 40% of my surgical ractice. I continue to use full Hammersmith dose for all redos and setic atients. This accounts for around 20%. In a further 20%, I use a 2 million KIU regime, for the most art, in atients who have unstable angina who have been maintained on asirin theray right until their oeration. However, I believe that the hemostatic resonse to arotinin is in fact dose deendent, as roosed by David Royston and colleagues. And that although lower doses may be aroriate and adequate in a low-risk oulation, increased dose gives increased efficacy in those atients at a much higher risk of excessive bleeding. I have three questions and one final comment. Did the 2% reexloration rate include or exclude the two identified atients in the arotinin grou? And was the reentry rate actually 4% for arotinin atients? Second, what do you believe is the aroriate dosage for reoerations and other high-risk bleeding rocedures? And third, do you agree that as far as we know at resent, and this may change with increased understanding, the antiinflammatory effects of arotinin are only seen at higher dosage levels? My final comment relates to the cost issue. I checked with our harmacist at the Hammersmith in London to obtain accurate costs to British hositals for the full Hammersmith, 2 million, and the roosed 1 million KIU dosage regimes. They are roughly one-third of the costs incurred here in the United States. One might be temted to say that there may have been an economic downside to the Declaration of Indeendence after all. I thank the Society for the rivilege of discussing this very interesting aer. DR SALIM RATNANI (Charleston, WV): I want to ask two questions. First question is how many of your atients were setuagenarian and octogenarian diabetic atients where the arteries are usually small and diffusely diseased and, as a result, even with the low dose or ultra low dose of arotinin in these atients, we are seeing some ST changes and ischemic changes on the electrocardiogram? Because those are the arteries where the flows are low and the arteries are small, those are the atients that are more rone for myocardial infarction with even this ultra dose of arotinin. And the second question is how many of your atients have received even ultra dose, low continuous infusion ostoeratively? DR JEFFREY E. GEORGE (Huntington, WV): My question has two arts. Could you comment on your having an extremely high incidence of transfusion, u to 70% to 80% for your atients, and could you discuss your rotocol for transfusion. DR DIGNAN: Thank you, Professor Taylor, for those interesting comments and questions, and for the other questions. As to the reexloration rate, the 2% reexloration rate did not include those two atients that were excluded. The two that were excluded, however, did have surgical bleeding. One was a branch of the sahenous vein and one was a branch on the ericardium. The dose for reoeration I think could ossibly be lower than the full Hammersmith dose; even a half dose would seem to work as well as the full dose in my brief exerience. I believe that the antiinflammatory effects are more ronounced with the high dose as comared to half dose, and ossibly this should be used with endocarditis atients. I agree that the antiinflammatory effects are robably not seen when ultra low dose arotinin is used. As to the question of how many of these atients were octogenarians and diabetics, the mean age of the grou was similar, about 66. We did not have very many octogenarians in the grou. The incidence of diabetes was not analyzed. However, we did analyze cardiac enzymes and the rate of myocardial infarction and they were not different between grous. In fact, the arotinin grou had only a 3% as oosed to 5% rate of myocardial infarction in the lacebo grou. We did not run arotinin infusions ostoeratively. However, 3 atients in the lacebo grou had ostoerative arotinin and that was only a one time dose of 500,000 U. Only 1 atient in the arotinin grou received ostoerative arotinin. The transfusion rate is fairly significant in the lacebo grou but significantly lower in the arotinin grou. This is fairly consistent, however, with transfusion rates in the literature. Protocol for transfusion: if the hemoglobin was less than 8, blood could be given. It was at the discretion of the investigator or the surgeon to administer blood if the atient had mediastinal hemorrhage.