Population pharmacokinetic analysis and dosing regimen optimization of aprotinin in neonates and young infants undergoing cardiopulmonary bypass.

The objective of this study was to determine an optimal dosing regimen for maintaining the therapeutic target range of aprotinin in neonates and young infants during cardiopulmonary bypass (CPB). A total of 27 patients scheduled for open heart surgery were enrolled. Aprotinin was administered a 25 000 KIU (kallikrein inhibition unit)/kg bolus before operation, a 35 000 KIU/kg for CPB circuit priming, and a 12 500 KIU/kg/hour continuous infusion intra- and immediate postoperative period. Blood samples were obtained at 12 time points per patient. Population pharmacokinetic modeling and Monte-Carlo simulations were used to optimize the aprotinin dosing regimen. No mortality or aprotinin-related complication was encountered. A CPB adjusted 2-compartment model best fit the data. Clearance was 687 mL/hour during CPB and 350 mL/hour pre- and post-CPB, and corresponding volumes of distribution were 1577 mL and 1352 mL, respectively. The simulations conducted showed that more than twice the dose administered in this study is required to maintain the target concentration of aprotinin. The pharmacokinetics of aprotinin appears to be affected more sensitively by CPB in neonates and young infants than in adults. Therefore, dosage adjustment considering these pharmacokinetic differences and the influence of CPB is needed in neonates and young infants.

ε-Aminocaproic acid and clinical value in cardiac anesthesia.

OBJECTIVE: The primary aim was to compare the "clinical value" of tranexamic acid (TXA) with ε-aminocaproic acid (EACA) when used for blood conservation during high-risk cardiac surgery. DESIGN: Data previously reported by the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study investigators were reanalyzed independently after appropriate statistical adjustment. The authors compared TXA with EACA for important primary and secondary outcomes and applied the "clinical value" equation to this comparison. SETTING: BART, the largest blinded multicenter study on this topic to date, compared all 3 commonly used antifibrinolytics head-to-head in a randomized dose-equivalent fashion during high-risk cardiac surgery. Comparisons of TXA with EACA with application of the clinical value equation was not performed specifically by the BART investigators. PARTICIPANTS: One thousand five hundred fifty patients enrolled in 2 of the 3 arms of the BART study were included in the analysis (TXA, n= 770 and EACA, n = 780, with data reported by the investigators in the New England Journal of Medicine). MAIN RESULTS: The major finding was that there were no significant differences in overall safety and clinically important efficacy between TXA and EACA. CONCLUSIONS: Considering the substantial difference in costs and with the increasing volume of high-risk cardiac surgery, EACA has increased "clinical value" when compared with TXA. EACA should be the antifibrinolytic medication of choice for high-risk cardiac surgery.

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.

Impact of aprotinin on adverse clinical outcomes and mortality up to 12 years in a registry of 3,337 patients.

BACKGROUND: Recent studies have suggested increased renal complications and long-term mortality with aprotinin use in coronary artery bypass grafting (CABG) patients. However, these studies have been criticized for including multiple centers and different dosing strategies. We analyzed prospectively collected registry data from a single center hospital utilizing a full-dose aprotinin regimen to evaluate if aprotinin was associated with increased mortality and adverse outcomes compared with Amicar. METHODS: Data were prospectively collected from 1994 to 2006 at a teaching hospital. Long-term mortality was collected from a Social Security database. To account for differences between aprotinin and Amicar-treated patients, a propensity score was generated and propensity-stratified multivariate model for mortality were performed. RESULTS: Compared with Amicar-treated patients (n = 1,830), aprotinin-treated patients (n = 1,507) were older, more often female, had lower creatinine clearance, and more baseline risk factors. Blood loss was lower in aprotinin-treated patients (median 715 mL vs 918 mL, p < 0.001). Postoperative renal failure was significantly higher in aprotinin patients (6.2% vs 2.7%, p < 0.001). At median 5.4-year follow-up (up to 12.2 years), aprotinin-treated patients had higher mortality versus Amicar-treated patients (Kaplan-Meier failure rates 43.5% vs 23.7% at 8 years, p < 0.0001). In a propensity-stratified model with multivariate adjustment, aprotinin remained associated with increased mortality (hazard ratio 1.62, 95% CI 1.39 to 1.90, p < 0.001). There was a stepwise relationship between weight-based aprotinin dose and mortality (p-trend < 0.001). CONCLUSIONS: Among patients undergoing CABG in this registry, aprotinin use was associated with increased renal failure and higher mortality through 12 years in a propensity-stratified analysis. The increased mortality may be related to higher concentrations of aprotinin received.

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.

Use of aprotinin in extrapleural pneumonectomy: effect on hemostasis and incidence of complications.

BACKGROUND: The purpose of this study was to examine the effect of aprotinin on blood loss in extrapleural pneumonectomy and to identify potential treatment-related complications. METHODS: Between March 1, 1999, and July 1, 2004, 27 (52%) of 52 patients who underwent extrapleural pneumonectomy received half-dose aprotinin (1 million kallikrein inhibition units load; 250,000 kallikrein inhibition units per hour infusion). A retrospective data review and analysis were performed. RESULTS: The mean age was 59.8 +/- 11 years, and 45 of 52 patients (87%) were male. Indications for extrapleural pneumonectomy were malignant pleural mesothelioma (n = 50) and pleural-based sarcoma (n = 2). The administration of aprotinin had no significant effect on intraoperative blood loss (1,010 +/- 599 versus 1,182 +/- 688 mL; p = 0.34) or units of packed red blood cells transfused intraoperatively (2.0 +/- 1.7 versus 1.9 +/- 1.7 units; p = 0.86). None of the patients who received aprotinin required the use of non-packed red blood cells blood products, but 4 patients (16%) who did not receive aprotinin required such transfusion (p < 0.05). Postoperative chest tube output at 12 and 24 hours was lower in the aprotinin group (381 +/- 195 and 867 +/- 313 mL, respectively) compared with the control group (725 +/- 527 and 1,221 +/- 442 mL, respectively; p < 0.03). There was no significant difference in incidence of postoperative thromboembolic events between the aprotinin and the control group (5 versus 4 patients; p = 1.0), and 2 patients in each group experienced renal insufficiency (p = 1.0). CONCLUSIONS: Half-dose aprotinin did not decrease intraoperative blood loss or packed red blood cells transfusion in extrapleural pneumonectomy. However, use of aprotinin was associated with decreased use of non-packed red blood cells blood products and lower postoperative chest tube output. Aprotinin administration was not associated with an increase in incidence of postoperative complications.

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.

Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass.

BACKGROUND: Aprotinin therapy is now widely used during cardiac surgery. This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo. METHODS: In a double blind, randomized study, three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient (AUS$ = Australian dollars), low-dose aprotinin costing AUS$220 per patient or placebo. Resource use influenced by aprotinin therapy was measured. RESULTS: Both doses were effective in reducing chest drainage and postoperative transfusion requirements, high-dose being more effective than low-dose. Both doses reduced the rate of reoperations for hemostasis. A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient, respectively. If the demonstrated less significant reductions in operating room and ward stay are included, these savings become AUS$463 and AUS$715, respectively. Alternately, if cross-matches are replaced by group-and-hold and cell savers are not used, the savings per patient would be AUS$196 and AUS$467, respectively. CONCLUSIONS: While high-dose aprotinin is clinically more effective than low-dose aprotinin, low-dose therapy demonstrates greater cost savings.

The efficacy and safety of aprotinin use in cardiac surgery.

BACKGROUND: The serine protease inhibitor aprotinin has received much attention in cardiac surgical practice as a pharmacologic intervention to improve the hemostatic derangement associated with cardiopulmonary bypass. This review highlights the major studies undertaken to investigate the efficacy and safety of aprotinin use in both primary and repeat coronary artery bypass graft surgical procedures. METHODS: There have been at least 45 controlled studies in more than 7,000 patients in a variety of patient populations. These have ranged from primary coronary artery bypass graft and valve operations to complex reoperation procedures, including aortic arch reconstructions and thoracic organ transplantation. The recently completed International Multicenter Graft Patency Experience trial, the largest study to date, involved 870 patients at 13 international sites. The study examined the effects of aprotinin on graft patency, incidence of myocardial infarction, and blood loss in patients undergoing primary coronary artery bypass graft operations with cardiopulmonary bypass. RESULTS: Twenty-one studies in approximately 5,000 patients undergoing primary coronary artery bypass graft or valve operations reported 33% to 66% reduction in blood loss with full-dose aprotinin therapy; 15 of the same studies reported significant reductions in transfusion requirements, ranging from 31% to 85%. The recently completed International Multicenter Graft Patency Experience study observed a significant reduction in thoracic-drainage volume of 43% (p < 0.0001) and a 49% (p < 0.001) reduction in the requirement for allogeneic blood transfusions. Aprotinin did not affect the occurrence of definite myocardial infarction (aprotinin, 2.9% versus placebo, 3.8%) or mortality (aprotinin, 1.4% versus placebo, 1.6%). There was no observed difference in the patency of internal mammary artery bypass grafts from all study sites in aprotinin- versus placebo-treated patients (aprotinin, 98.2% versus placebo, 98.0%). CONCLUSIONS: Given the risks and costs associated with excessive bleeding and transfusions and the limited supply of banked blood, aprotinin represents an important and safe approach to blood conservation.