Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery.

OBJECTIVE: Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. METHODS: This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. RESULTS: Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. CONCLUSIONS: Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Aprotinin in pediatric neuromuscular scoliosis surgery.

Reduction of blood transfusions in patients with neuromuscular scoliosis can decrease potential complications such as immune suppression, infection, hemolytic reaction and viral transmission. Aprotinin (Trasylol), Bayer), an antifibrinolytic, has proven to be effective in reducing blood loss in cardiac and liver surgery, but little data exists in patients undergoing spinal fusion for neuromuscular scoliosis. The purpose of this study was to evaluate the safety and efficacy of aprotinin in pediatric neuromuscular scoliosis patients undergoing spinal fusion. The medical records of all patients undergoing initial spinal fusions for neuromuscular scoliosis between January 1999 and March 2003 were reviewed to determine demographic data, perioperative data, wound drainage and number of transfusion required. Cases were compared to a matched group of historical controls. We had 14 patients in the aprotinin group and 17 in the control group. Total blood loss in the aprotinin group was significantly lower compared to the control group (715 vs. 2,110 ml; P = 0.007). Significantly less blood loss occurred in the aprotinin group when blood loss per kilogram was evaluated as well (23 vs. 60 ml/kg, respectively; P = 0.002). Intra-operative packed red blood cell (PRBC) transfusions were also significantly lower in the aprotinin group (1.25 vs. 3.16 units; P = 0.001). No clinical evidence of anaphylaxis, deep vein thrombosis (DVT) or renal failure was observed in the aprotinin group. After considering the price of drug therapy, operating room time, and the cost of blood products, the use of aprotinin saved an average of $8,577 per patient. In our series, the use of aprotinin resulted in decreased blood loss and a decreased rate of transfusions in children with neuromuscular scoliosis undergoing extensive spinal fusion. At out institution, the use of aprotinin is safe and cost effective for patients with neuromuscular scoliosis.

Randomized study of aprotinin effect on transfusions and blood loss in primary THA.

A projected increase in total hip arthroplasties, shortfalls in blood availability, and awareness of complications of transfusion make blood management in orthopaedic surgery important. In a multicenter, randomized, double-blind, placebo-controlled study, we hypothesized use of aprotinin would reduce blood transfusions (any and allogeneic) and blood loss in total hip arthroplasty. Using an intent-to-treat approach, we recruited 393 patients stratified by preoperative autologous blood donation or none and then randomized them to receive aprotinin (176 patients receiving a 10,000 kallikrein inhibitor units [KIU] test dose, 2 million KIU load, 0.5 million KIU per hour) or placebo (177 patients). We assessed patients at baseline; postoperative days 1, 2, 3, and 7 (or discharge); and 6 +/- 2 weeks. Primary efficacy was percentage of patients having blood transfusion through day 7 or discharge. We based safety on reported adverse events. Aprotinin reduced transfusions by 46% (30 of 176 versus 56 of 177 patients). Aprotinin reduced the total number of any blood units and the number of allogeneic blood units transfused relative to placebo (48 versus 109 units and 30 versus 72 units, respectively). Serious complications were similar in the two groups (placebo, 11%; aprotinin, 10%). Our data suggest full-dose aprotinin is safe and effective in decreasing blood transfusion in total hip arthroplasty.

Acute plateletpheresis and aprotinin reduces the need for blood transfusion following Ross operation.

The effect of acute intraoperative plateletpheresis (25% platelet yield) in combination with intraoperative low-dose aprotinin (2 million units) on blood conservation was investigated in 18 young adult patients undergoing elective Ross operation. The results were compared with a group of 19 similar patients without plateletpheresis (control group). The hematological and coagulation parameters at admission and discharge were statistically similar in both groups. The total blood product transfusion requirements were significantly reduced in the plateletpheresis group compared with the control group (3.2 units and 5.1 units, respectively, P=0.036). The total blood donor exposure was also reduced significantly in the plateletpheresis group compared with the control group (3.2 and 6.9 donors/patient, respectively, P<0.001). The direct costs for the hospital for the plateletpheresis procedure, including costs for all blood products, were similar to those for blood products alone in the control group. In summary, acute plateletpheresis in combination with low-dose aprotinin significantly reduces the blood product transfusions and blood donor exposures following the Ross operation; the treatment is cost-effective.

Cost reduction of perioperative coagulation management in cardiac surgery: value of "bedside" thrombelastography (ROTEM).

OBJECTIVE: Demographic changes and aggressive platelet inhibition have resulted in a marked increase in blood- and coagulation product expenditure and costs in cardiac surgery. We analyzed "bedside" coagulation test (ROTEM) in order to verify clot forming quality for the purpose of finding a cost-effective treatment path. METHODS: Annual treatment costs of all cardiosurgical patients were analyzed before (729 patients) and after (693 patients) implementation of "bedside" ROTEM. Cumulative numbers and costs of platelet concentrates (PltC), fresh frozen plasma (FFP), red blood cell units (RBC), and coagulation factors: pooled coagulation concentrates (PCC), recombinant factor VIIa (rFVIIa), factor XIII (FXIII), and fibrinogen were assessed. Average monthly numbers and costs were compared. Number of resternotomies and early mortality was assessed and compared in both periods. RESULTS: After ROTEM implementation cumulative RBC expenditure showed 25% decrease while PltC exhibited 50% decrease. FFP expenditure remained unchanged. PCC, FXIII were markedly reduced (-80%) while rFVIIa were entirely omitted. Fibrinogen, however, increased two-fold. Cumulative average monthly costs of all blood products decreased from 66,000 euro to 45,000 euro (-32%). Coagulation factor average monthly costs decreased from 60,000 euro to 30,000 euro (-50%) yielding combined savings of 44%. In contrast, average monthly costs for ROTEM were 1.580 euro. Total number of resternotomies decreased from 6.6% to 5.5% while early mortality (5.9%; 6.0%) remained stable. CONCLUSION: Cumulative costs for treatment of perioperative coagulation disorders can be reduced by "bedside" ROTEM analysis to achieve a selective substitution management. Saved costs for blood- and coagulation products clearly outweighed the expenses of ROTEM. Adequate differential coagulation management can therefore be cost-effective.

Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

OBJECTIVES: To compare patient outcomes, resource use and costs to the NHS and NHS Blood Transfusion Authority (BTA) associated with cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion. DATA SOURCES: Electronic databases covering the period 1996-2004 for systematic reviews and 1994-2004 for economic evidence. REVIEW METHODS: Existing systematic reviews were updated with data from selected randomised controlled trials (RCTs) that involved adults scheduled for elective non-urgent surgery. Any resource use or cost data were extracted for potential use in populating an economic model. Relative risks or weighted mean difference of each outcome for each intervention were assessed, taking into account the number of RCTs included in each outcome and intervention and the presence of any heterogeneity. This allowed indirect comparison of the relative effectiveness of each intervention when the intervention is compared with allogeneic blood transfusion. A decision analytic model synthesised clinical and economic data from several sources, to estimate the relative cost-effectiveness of cell salvage for people undergoing elective surgery with moderate to major expected blood loss. The perspective of the NHS and patients and a time horizon of 1 month were used. The economic model was developed from reviews of effectiveness and cost-effectiveness and clinical experts. Secondary analysis explored the robustness of the results to changes in the timing and costs of cell salvage equipment, surgical procedure, use of transfusion protocols and time horizon of analysis. RESULTS: Overall, 668 studies were identified electronically for the update of the two systematic reviews. This included five RCTs, of which two were cell salvage and three preoperative autologous donation (PAD). Five published systematic reviews were identified for antifibrinolytics, fibrin sealants and restrictive transfusion triggers, PAD plus erythropoietin, erythropoietin alone and acute normovolaemic haemodilution (ANH). Twelve published studies reported full economic evaluations. All but two of the transfusion strategies significantly reduced exposure to allogeneic blood. The relative risk of exposure to allogeneic blood was 0.59 for the pooled trials of cell salvage (95% confidence interval: 0.48 to 0.73). This varied by the type and timing of cell salvage and type of surgical procedure. For cell salvage, the relative risk of allogeneic blood transfusion was higher in cardiac surgery than in orthopaedic surgery. Cell salvage had lower costs and slightly higher quality-adjusted life years compared with all of the alternative transfusion strategies except ANH. The likelihood that cell salvage is cost-effective compared with strategies other than ANH is over 50%. Most of the secondary analyses indicated similar results to the primary analysis. However, the primary and secondary analyses indicated that ANH may be more cost-effective than cell salvage. CONCLUSIONS: The available evidence indicates that cell salvage may be a cost-effective method to reduce exposure to allogeneic blood transfusion. However, ANH may be more cost-effective than cell salvage. The results of this analysis are subject to the low quality and reliability of the data used and the use of indirect comparisons. This may affect the reliability and robustness of the clinical and economic results. There is a need for further research that includes adequately powered high-quality RCTs to compare directly various blood transfusion strategies. These should include measures of health status, health-related quality of life and patient preferences for alternative transfusion strategies. Observational and tracking studies are needed to estimate reliably the incidence of adverse events and infections transmitted during blood transfusion and to identify the lifetime consequences of the serious hazards of transfusion on mortality, health status and health-related quality of life.

Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials.

BACKGROUND: Aprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery. The lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are cheaper, but it is not known if they are as effective as aprotinin. METHODS: Studies were identified by searching electronic databases and bibliographies of published articles. Data from head-to-head trials were pooled using a conventional (Cochrane) meta-analytic approach and a Bayesian approach which estimated the posterior probability of TXA and EACA being equivalent to aprotinin; we used as a non-inferiority boundary a 20% increase in the rates of transfusion or re-operation because of bleeding. RESULTS: Peri-operative blood loss was significantly greater with TXA and EACA than with aprotinin: weighted mean differences were 106 mls (95% CI 37 to 227 mls) and 185 mls (95% CI 134 to 235 mls) respectively. The pooled relative risks (RR) of receiving an allogeneic red blood cell (RBC) transfusion with TXA and EACA, compared with aprotinin, were 1.08 (95% CI 0.88 to 1.32) and 1.14 (95% CI 0.84 to 1.55) respectively. The equivalent Bayesian posterior mean relative risks were 1.15 (95% Bayesian Credible Interval [BCI] 0.90 to 1.68) and 1.21 (95% BCI 0.79 to 1.82) respectively. For transfusion, using a 20% non-inferiority boundary, the posterior probabilities of TXA and EACA being non-inferior to aprotinin were 0.82 and 0.76 respectively. For re-operation the Cochrane RR for TXA vs. aprotinin was 0.98 (95% CI 0.51 to 1.88), compared with a posterior mean Bayesian RR of 0.63 (95% BCI 0.16 to 1.46). The posterior probability of TXA being non-inferior to aprotinin was 0.92, but this was sensitive to the inclusion of one small trial. CONCLUSION: The available data are conflicting regarding the equivalence of lysine analogues and aprotinin in reducing peri-operative bleeding, transfusion and the need for re-operation. Decisions are sensitive to the choice of clinical outcome and non-inferiority boundary. The data are an uncertain basis for replacing aprotinin with the cheaper lysine analogues in clinical practice. Progress has been hampered by small trials and failure to study clinically relevant outcomes.

What is the evidence for using hemostatic agents in surgery?

The pharmacological methods used to achieve systemic hemostasis have generated much discussion due to concerns of serious adverse effects (e.g., thromboembolic complications) and costs of therapy in addition to efficacy considerations. There are a limited number of well-controlled trials involving pharmacological hemostasis for spine surgery. In the largest double-blinded randomized controlled trial to date involving spine surgery, there was a trend toward reduced homologous transfusion in patients receiving aprotinin, but the only statistically significant result ( p<0.001) was a reduction in autologous red cell donations. The findings of this trial are important, since the investigators used a number of restrictive transfusion strategies (e.g., autologous donation, low hematocrit trigger for transfusion, blood-salvaging procedures with the exception of no cell saver) that were not always employed in earlier trials involving hemostatic agents. Smaller studies involving antifibrinolytic agents other than aprotinin have demonstrated reductions in blood loss and transfusion requirements in patients undergoing spine surgery, although the results were not always statistically significant. A very large randomized trial would be required to address comparative medication- and transfusion-related adverse events; such a trial involving patients undergoing cardiac surgery is currently being performed. Additionally, cost-effectiveness analyses are needed to help define the role of these agents based on the data that is available.

Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials.

BACKGROUND: The full kallikrein-inhibiting dose of aprotinin has been shown to reduce blood loss, transfusion requirements, and the systemic inflammatory response associated with cardiopulmonary bypass graft surgery (CABG). A half-dose regimen, although having a reduced delivery cost, inhibits plasmin and fibrinolysis without substantially effecting kallikrein-mediated inflammation associated with bypass surgery. The differing pharmacologic effects of the two regimens impact the decision-making process. The current study assessed the medical cost offset of full-dose and half-dose aprotinin from short- and long-term perspectives to provide a rational decision-making framework for clinicians. METHODS: To estimate CABG admission costs, resource utilization and clinical data from aprotinin clinical trials were combined with unit costs estimated from a Duke University-based cost model. Lifetime medical costs of stroke and acute myocardial infarction were based on previous research. RESULTS: Relative to placebo, the differences in total perioperative cost for primary CABG patients receiving full-dose or half-dose aprotinin were not significant. When lifetime medical costs of complications were considered, total costs in full-dose and half-dose aprotinin-treated patients were not different relative to that of placebo. Total perioperative cost was significantly lower for repeat CABG patients treated with aprotinin, with savings of $2,058 for full-dose and $2,122 for half-dose patients when compared with placebo. Taking lifetime costs of stroke and acute myocardial infarction into consideration, the cost savings estimates were $6,044 for full-dose patients and $4,483 for half-dose patients, due to substantially higher lifetime stroke costs incurred by the placebo patients. CONCLUSIONS: Using this cost model, use of full-dose and half-dose aprotinin in primary CABG patients was cost neutral during hospital admission, whereas both dosing regimens were significantly cost saving in reoperative CABG patients. Additional lifetime cost savings were realized relative to placebo due to reduced complication costs, particularly with the full-dose regimen. As the full kallikrein-inhibiting dose of aprotinin has been shown to be safe and effective, the current results support its use in both primary and repeat CABG surgery. No demonstrable economic advantage was observed with the half-dose aprotinin regimen.

A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit.

BACKGROUND: Cardiac patients sometimes bleed postoperatively and consequently require rethoracotomy, necessitating a longer stay in the intensive care unit (ICU) of the cardiothoracic unit (CTU). When ICU capacity is limited, rethoracotomy necessitates postponing treatment of the next patient. Aprotinin, a bovine lung-derived proteinase inhibitor, has been shown to reduce the frequency of rethoracotomies in cardiac patients. OBJECTIVE: This study was undertaken to quantify the reduction of potentially avoidable cost to the CTU of postoperative bleeding, both directly and indirectly, by administering aprotinin before and during coronary artery bypass graft (CABG). METHODS: A novel, validated operational research model was developed, featuring the principal CABG-related health care resource parameters believed to influence waiting lists and times. Factors and costs were derived from both local data from a CTU and relevant recent literature. RESULTS: According to the model, aprotinin therapy reduced the waiting list by approximately 3% by reducing the number of rethoracotomies. Using data from the literature, for an annual throughput of 431 patients who would receive aprotinin costing 97,333 pounds per year, the annual net savings to the CTU would be 46,586 pounds, which comprised direct savings on blood products of 35,036 pounds and indirect marginal savings of 11,550 pounds derived from 3.2% fewer rethoracotomies (each at a marginal cost of 837 pounds). By reason, then, reinvesting savings in increasing CTU capacity would yield further waiting-list reductions and improve patient morbidity. These results had 2 major limitations. First, it was assumed that all operations would have the same duration and all surgeons would perform operations in the same manner. Second, nonurgent patients were assumed to have been treated in order of strict referral sequence, which may not be done in real-world practice. CONCLUSIONS: Aprotinin reduced costs in CABG directly by reducing the use of blood products and indirectly by reducing waiting lists, as well as by reducing morbidity and mortality associated with waiting time.

Antifibrinolytic agents and desmopressin as hemostatic agents in cardiac surgery.

OBJECTIVE: To review the use of systemic hemostatic medications for reducing bleeding and transfusion requirements with cardiac surgery. DATA SOURCES: Articles were obtained through computerized searches involving MEDLINE (from 1966 to September 2000). Additionally, several textbooks containing information on the diagnosis and management of bleeding associated with cardiac surgery were reviewed. The bibliographies of retrieved publications and textbooks were reviewed for additional references. STUDY SELECTION: Due to the large number of randomized investigations involving systemic hemostatic medications for reducing bleeding associated with cardiac surgery, the article selection process focused on recent randomized controlled trials, metaanalyses and pharmacoeconomic evaluations. DATA EXTRACTION: The primary outcomes extracted from the literature were blood loss and associated transfusion requirements, although other outcome measures such as mortality were extracted when available. DATA SYNTHESIS: Although the majority of investigations for reducing cardiac bleeding and transfusion requirements have involved aprotinin, evidence from recent meta-analyses and randomized trials indicates that the synthetic antifibrinolytic agents, aminocaproic acid and tranexamic acid, have similar clinical efficacy. Additionally, aminocaproic acid (and to a lesser extent tranexamic acid) is much less costly. More comparative information of hemostatic agents is needed retative to other outcomes (eg., reoperation rates, myocardial infarction, stroke). There is insufficient evidence to recommend the use of desmopressin for reducing bleeding and transfusion requirements in cardiac surgery, although certain subsets of patients may benefit from its use. CONCLUSIONS: Of the medications that have been used to reduce bleeding and transfusion requirements with cardiac surgery, the antifibrinolytic agents have the best evidence supporting their use. Aminocaproic acid is the least costly therapy based on medication costs and transfusion requirements.

Leukodepletion and aprotinin improve clinical outcome after extracorporeal circulation.

Most cardiac operations involve the use of extracorporeal circulation with its attendant systemic inflammatory response syndrome. Many anti-inflammatory strategies hold promise for reducing the associated morbidity of cardiopulmonary bypass. The application of pharmacological and mechanical strategies to control this inflammatory response now has demonstrable clinical benefit. The additional costs of these successful strategies are offset by the economic savings and improved quality of care.

Ultra-low dose aprotinin decreases transfusion requirements and is cost effective in coronary operations.

BACKGROUND: The recommended dose of aprotinin has been shown to reduce blood loss and need for blood transfusions, but the cost precludes its routine use. This study was designed to determine whether a less expensive, ultra-low dose of aprotinin is effective when used in coronary artery bypass grafting with left internal mammary artery. METHODS: Patients (n = 202) were randomized to receive either placebo or aprotinin, 0.5 million KIU before incision and 0.5 million KIU during initiation of cardiopulmonary bypass. Differences in quantity of blood transfused were analyzed. Further groups were analyzed to account for the effect of aspirin. Multivariable analysis was performed to determine risk factors for transfusion. Direct costs of blood products and aprotinin were tabulated for each group. RESULTS: There was an important reduction in the proportion of patients transfused, and number of blood units transfused when aprotinin was given before coronary artery bypass grafting. These differences were even more important in patients on aspirin preoperatively. Independent predictors for increased number of transfusions were aspirin continued before operation, smaller body surface area, and the use of placebo instead of ultra-low dose aprotinin. There was no difference in morbidity between treatment groups. There was a reduction in direct costs associated with the use of aprotinin. CONCLUSIONS: These data support the routine use of aprotinin 1 million KIU in coronary artery bypass grafting with left internal mammary artery to reduce cost and transfusion requirements.

Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding.

BACKGROUND: Aprotinin and tranexamic acid are routinely used to reduce bleeding in cardiac surgery. There is a large difference in agent price and perhaps in efficacy. METHODS: In a prospective, randomized, partially blinded study, 168 cardiac surgery patients at high risk for bleeding received either a full-dose aprotinin infusion, tranexamic acid (10-mg/kg load, 1-mg x kg(-1) x h(-1) infusion), tranexamic acid with pre-cardiopulmonary bypass autologous whole-blood collection (12.5% blood volume) and reinfusion after cardiopulmonary bypass (combined therapy), or saline infusion (placebo group). RESULTS: There were complete data in 160 patients. The aprotinin (n = 40) and combined therapy (n = 32) groups (data are median [range]) had similar reductions in blood loss in the first 4 h in the intensive care unit (225 [40-761] and 163 [25-760] ml, respectively; P = 0.014), erythrocyte transfusion requirements in the first 24 h in the intensive care unit (0 [0-3] and 0 [0-3] U, respectively; P = 0.004), and durations of time from end of cardiopulmonary bypass to discharge from the operating room (92 [57-215] and 94 [37, 186] min, respectively; P = 0.01) compared with the placebo group (n = 43). Ten patients in the combined therapy group (30.3%) required transfusion of the autologous blood during cardiopulmonary bypass for anemia. CONCLUSIONS: The combination therapy of tranexamic acid and intraoperative autologous blood collection provided similar reduction in blood loss and transfusion requirements as aprotinin. Cost analyses revealed that combined therapy and tranexamic acid therapy were the least costly therapies.

Role of aprotinin in the management of patients during and after cardiac surgery.

Management of patients undergoing cardiac surgery has evolved in recent years as more is understood about the physiological changes and responses that occur during and after cardiopulmonary bypass (CPB). In particular, our understanding of the mechanisms involved in haemostasis and in the inflammatory response to bypass surgery, has allowed significant refinements in patient management. Improvements in the pharmacological conservation of blood loss have been striking, particularly with the development of the serine protease inhibitor, aprotinin (Trasylol, Bayer). Aprotinin represents a significant improvement, especially for patients at high risk, since it reduces the need for allogeneic and (sometimes scarce) blood products. However, in view of its cost, making an appropriate selection of patients most at risk of serious blood loss is a major consideration in the use of aprotinin. While its mechanisms of action are not well understood, the use of aprotinin also appears to reduce inflammatory response to CPB.

Cost-offset analysis of aprotinin in high-risk coronary artery bypass.

Aprotinin, a naturally occurring protease inhibitor derived from bovine lung, is used prophylactically to minimize the amount of perioperative blood loss in patients undergoing coronary artery bypass graft surgery who are at high risk for excessive bleeding. A retrospective multicenter evaluation of aprotinin use was performed in high-risk coronary artery bypass graft patients treated either with aprotinin or according to usual-care to assess (1) differences in demographic and medical history characteristics, and (2) clinical and economic outcomes associated with their care. This study suggests that in many cases, the cost of aprotinin is offset by reductions in overall cost. Additional study is required to better understand this potential. In other cases, however, a more conservative approach to aprotinin use appears to be warranted.