American Journal of Health-System Pharmacy

Sedrakyan,, Artyom

doi: 10.2146/ajhp050304pmid: 16227192

Abstract Purpose. Medical decisions are often made based on personal experience or on limited clinical trial information. Results from systematic reviews of clinical trials, however, provide a more thorough understanding of available data and can foster evidence-based decision making. Data from a recent systematic review and meta-analysis of clinical outcomes after aprotinin treatment during coronary artery bypass graft (CABG) surgery have recently been published. This analysis was performed to further address concerns that aprotinin safety often outweighs the well-established transfusion reduction benefits. Summary. Data from placebo controlled, randomized, aprotinin trials published in MEDLINE, EMBASE, and PHARMLINE were analyzed. Relative risk (RR) and 95% confidence intervals (CI) were calculated for mortality, myocardial infarction, renal failure, stroke, atrial fibrillation, and blood transfusion. Fixed effect or random effect models were used. Homogeneity was tested across studies using χ2 statistics and i-square (I2) values. Analysis of data from 35 placebo controlled trials (n = 3,887) confirms that aprotinin, when compared to placebo, reduces transfusion requirements (RR, 0.61; 95% CI, 0.58–0.66). Risks of mortality (RR, 0.96; 95% CI, 0.65–1.40), myocardial infarction (RR, 0.85; 95% CI, 0.63–1.14) and renal failure (RR, 1.01; 95% CI, 0.55–1.83) were neither increased nor decreased with aprotinin treatment. Aprotinin treatment was, however, associated with a reduced risk of stroke (RR, 0.53; 95% CI, 0.31–0.90) and a trend toward a reduced incidence of atrial fibrillation (RR, 0.90, 95% CI, 0.78–1.03). Conclusion. Results from this systematic review and meta-analysis of randomized controlled trials in CABG surgery patients have shown that aprotinin was associated with a reduction in the need for blood transfusion, but was not associated with an increase in mortality, myocardial infarction, or renal failure risk. Evidence also suggests that aprotinin was associated with a reduced stroke risk and a trend toward a reduced incidence of atrial fibrillation. Aprotinin, Blood, Coronary artery bypass, Decision-making, Evidence-based medicine, Hemostatics, Mortality, Toxicity Historical analyses conducted by McKeown from the early 60s to the late 70s have suggested that the primary determinants of health improvement are related to improved nutrition, living conditions, non-medical technology, hygiene (water quality and sewage disposal), and demographic changes rather than to medical advances.1 While McKeown’s theory is considered controversial, further work by Cochrane, in 1972, highlighted the fact that “commonly used procedures and therapies were not always the most efficacious” and that “a not insubstantial amount of practice had not been well evaluated.”2 Cochrane’s work laid the foundations of the Cochrane Collaboration, one of the most influential organizations promoting evidence based medical practice through the conduct of systematic reviews. Research has shown that systematic and objective reviews of data are a more reliable source of information than conventional wisdom or expert opinion. For example, data showing the benefits of thrombolysis in acute myocardial infarction (MI) treatment could have been available as early as 1975 if available research had been systematically reviewed and meta-analyzed.3 Instead, thrombolysis was only recommended in 1986. Similarly, the evidence showing the beneficial effects of β-blockers was available in the 1970s, but largely neglected until the mid-1980s.3,4 Recently, evidence based medicine has been used, in some instances, to justify reductions in the cost of health care. However, such a use of the data reflects a misunderstanding of the fundamental goal of evidence based medicine, which is to inform practicing clinicians about how to identify and apply the most efficacious interventions to maximize the quality and quantity of life for individual patients. Evidence based medicine may in fact raise the cost of care rather than decrease it.5 With the development of evidence based medicine and the infrastructure to support it, physicians and surgeons will learn to ask answerable clinical questions, recognize the levels of evidence, access the best evidence, evaluate its validity and relevance, and incorporate patient preferences into their decisions. Systematic reviews, with or without meta-analysis, form the core of the data that should inform evidence based decisions. Evidence can be categorized according to its validity (Table 11). The highest level of evidence is the systematic review of randomized clinical trials with homogeneity; the least valid and systematic is expert opinion. Systematic reviews are often confused with meta-analyses. A systematic review addresses a clearly formulated question and uses explicit methodology. It should recognize, select, and critically evaluate the research and aim to analyze data from relevant studies. This method improves the power and precision of estimates of treatment effect and establishes generalizibility (number of studies included), consistency of findings across populations, and reduces unnecessary time and spending on new primary research. A meta-analysis is the statistical production of a single estimate of the treatment effect; the most powerful systematic reviews include a meta-analysis. Systematic review and meta-analysis of outcomes in aprotinin clinical trials Data from a recent systematic review and meta-analysis of clinical outcomes after aprotinin treatment during coronary artery bypass graft (CABG) surgery have recently been published.6 Aprotinin is the only FDA approved drug that is indicated to reduce prophylactically blood usage during CABG surgery. Although the blood sparing properties of aprotinin are well-established, concerns about MI, stemming from data by Cosgrove and colleagues,7 persist despite the wealth of contradicting data. Although a meta-analysis suggesting that aprotinin does not increase MI rates has already been performed, its methodology has been criticized and numerical errors have been identified.8,9 The following study is a rigorous systematic review and meta-analysis designed to learn more about clinical outcomes following aprotinin treatment during CABG surgery. Methods Randomized, placebo controlled, clinical trials, in which CABG patients were treated with a prophylactic, continuous aprotinin regimen, were identified in the MEDLINE, EMBASE, and PHARMLINE databases. Trials were included if the study only enrolled CABG patients and if aprotinin treatment was not combined with another experimental medication or device. Of the 115 papers initially identified, 51 studies fit the inclusion criteria. Their authors were contacted. Outcomes of interest were recorded in 35 trials. Data were collected on frequency of the events in the aprotinin and placebo groups, demographics, ejection fraction, pre-operative aspirin use (7-day cut-off), dose of aprotinin, and type of surgery (primary or repeat CABG). The methodological quality of these individual trials was evaluated using previously published criteria.10 These included a description of the method of randomization, blinding, allocation concealment, treatment after randomization, post-trial follow up, and endpoint data collection. Relative risk (RR) and 95% confidence intervals (CI) were calculated and combined using fixed effect or random effect models. Homogeneity was tested across studies using χ2 statistics and I2 value (percent of total variance not explained by random variation). Results A total of 35 trials enrolled 3,887 patients. Most of these studies were high quality, double-blind studies. The mean age was 61 years. Gender was reported in 28 trials; only 16.5% of patients were female. Patient race was only reported in six randomized, controlled trials. Based on data collected from 3,779 patients in 32 trials, no differences in mortality between the aprotinin and the placebo groups (2.5% and 2.4%, respectively) were detected. Aprotinin neither increased nor decreased the risk of mortality (RR, 0.96; 95% CI, 0.65–1.40) (Figure 11). No heterogeneity among the trials (p-value for heterogeneity not significant) was detected, thereby suggesting that the results of the Cosgrove study can be attributed to random variation around the estimate. Myocardial infarction was assessed in 28 trials, which enrolled a total of 3,555 patients. Myocardial infarction rates were similar between groups; 4.7% and 5.0% for aprotinin and placebo, respectively. These results suggest that with respect to MI, aprotinin is as safe as placebo. The forest plot shows that several studies, including the Cosgrove study, reported a higher risk of MI with aprotinin treatment (Figure 22). However, overall, a trend toward a reduction in MI risk was noted with aprotinin treatment (RR, 0.85; 95% CI, 0.63–1.14). Renal failure was assessed in 17 trials which enrolled a total of 3,003 patients. Renal failure rates were similar between groups; 1.5% and 1.3% for aprotinin and placebo, respectively. The meta-analytic RR estimate was 1.01 with a 95% CI of 0.55–1.83. As renal failure has only been reported in a few trials, this analysis is incomplete. However, the evidence available here does not indicate a higher risk of renal failure for aprotinin patients. Stroke was assessed in 18 trials which enrolled a total of 2,976 patients. Stroke rates were lower in the aprotinin group (1.1%) than in the placebo group (2.2%). Aprotinin was associated with a statistically significant 47% relative risk reduction (RR, 0.53; 95% CI, 0.31–0.90). These data suggest that 10 strokes per 1,000 CABG surgeries were prevented. The forest plot reveals some variability around the estimate, but overall consistency in that most studies reported a reduction in stroke rates (Figure 33). Atrial fibrillation was assessed in 11 trials which enrolled a total of 2,640 patients. Atrial fibrillation rates were slightly lower in the aprotinin group (22.7%) than in the placebo group (25.0%). In the meta-analysis, aprotinin was associated with a trend toward relative risk reduction (RR, 0.90; 95% CI, 0.78–1.03) (Figure 44). These data suggest that 30 atrial fibrillation events per 1,000 CABG surgeries were prevented. The reduction in atrial fibrillation may partially contribute to the reduction in stroke risk. Blood transfusion requirements were reported in 25 trials which enrolled a total of 3,430 patients. Transfusion rates were lower in the aprotinin group (40.3%) than in the placebo group (63.3%). Aprotinin was associated with a statistically significant 39% relative risk reduction (RR, 0.61; 95% CI, 0.58–0.66). These data suggest that 250 fewer transfusions per 1,000 CABG surgeries were needed. When individual studies were analyzed, statistical significance was reported in almost every study. Generalizability As only 17% of enrolled patients were female and race was reported in very few trials, generalizations should be made with caution. Furthermore, few patients were over 75 years of age and overall the patients in controlled trials may be healthier patients than those in the general CABG population. At least five criteria11 should be considered before generalizing these results: 1) Are my patients different from the trial population? 2) Is treatment feasible in my center? Does the center have training if necessary? 3) For what adverse events is my patient at risk? Is my patient at risk for excess bleeding or stroke? 4) What are the potential harms of this intervention? 5) What are my patient’s values and preferences? Conclusion Results from this systematic review and meta-analysis of randomized controlled trials in patients undergoing CABG surgery have shown that aprotinin was associated with a reduction in the need for blood transfusion but was not associated with an increase in mortality, MI, or renal failure risk. Evidence also suggests that aprotinin was associated with a reduced stroke risk and a trend toward a reduced incidence of atrial fibrillation. Table 1. Levels of evidencea Evidence Levels aRCT = randomized controlled trial, SR = systematic review. 1a—SR of RCTs with homogeneity Highest level ++++++++ 1b—single RCT with narrow confidence intervals +++++++ 2a—SR of cohort studies with homogeneity ++++++ 2b—single cohort study or low quality RCT +++++ 3a—SR with homogeneity of case-control studies ++++ 3b—single case control study +++ 4—case series or poor quality cohort or case control studies ++ 5—expert opinion Lowest level + Evidence Levels aRCT = randomized controlled trial, SR = systematic review. 1a—SR of RCTs with homogeneity Highest level ++++++++ 1b—single RCT with narrow confidence intervals +++++++ 2a—SR of cohort studies with homogeneity ++++++ 2b—single cohort study or low quality RCT +++++ 3a—SR with homogeneity of case-control studies ++++ 3b—single case control study +++ 4—case series or poor quality cohort or case control studies ++ 5—expert opinion Lowest level + Table 1. Levels of evidencea Evidence Levels aRCT = randomized controlled trial, SR = systematic review. 1a—SR of RCTs with homogeneity Highest level ++++++++ 1b—single RCT with narrow confidence intervals +++++++ 2a—SR of cohort studies with homogeneity ++++++ 2b—single cohort study or low quality RCT +++++ 3a—SR with homogeneity of case-control studies ++++ 3b—single case control study +++ 4—case series or poor quality cohort or case control studies ++ 5—expert opinion Lowest level + Evidence Levels aRCT = randomized controlled trial, SR = systematic review. 1a—SR of RCTs with homogeneity Highest level ++++++++ 1b—single RCT with narrow confidence intervals +++++++ 2a—SR of cohort studies with homogeneity ++++++ 2b—single cohort study or low quality RCT +++++ 3a—SR with homogeneity of case-control studies ++++ 3b—single case control study +++ 4—case series or poor quality cohort or case control studies ++ 5—expert opinion Lowest level + Figure 1. Open in new tabDownload slide Mortality in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 1. Open in new tabDownload slide Mortality in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 2. Open in new tabDownload slide Myocardial infarction in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 2. Open in new tabDownload slide Myocardial infarction in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 3. Open in new tabDownload slide Stroke in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 3. Open in new tabDownload slide Stroke in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 4. Open in new tabDownload slide Atrial fibrillation in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Figure 4. Open in new tabDownload slide Atrial fibrillation in aprotinin clinical trials. CI = confidence interval, RR = risk ratio. Based on the proceedings of a symposium held December 6, 2004, during the ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation. Dr. Sedrakyan received an honorarium for participating in the symposium and writing this article. References 1 McKeown T, Record RG. Reasons for the decline of mortality in England and Wales during the nineteenth century. Population Studies . 1962 ; 16 (2): 94 –122. Crossref Search ADS 2 Cochrane AL. Effectiveness and efficiency. Random reflections on health services. London: Nuffield Provincial Hospitals Trust; 1972 . 3 Antman EM, Lau J, Kupelnick B et al. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA . 1992 ; 268 (2): 240 –8. Crossref Search ADS PubMed 4 Yusuf S, Peto R, Lewis J et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis . 1985 ; 27 (5): 335 –71. Crossref Search ADS PubMed 5 Sackett DL, Rosenberg WM, Gray JA et al. Evidence based medicine: what it is and what it isn’t. BMJ . 1996 ; 312 (7023): 71 –2. Crossref Search ADS PubMed 6 Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg . 2004 ; 128 (3): 442 –8. Crossref Search ADS PubMed 7 Cosgrove DM, 3rd, Heric B, Lytle BW et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg . 1992 ; 54 (6): 1031 –6. Crossref Search ADS PubMed 8 Weightman WM, Gibbs NM. Pharmacological strategies for blood loss. Lancet . 2001 ; 357 (9262): 1131 –2. Crossref Search ADS PubMed 9 Levi M, Cromheecke ME, de Jonge E et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet . 1999 ; 354 (9194): 1940 –7. Crossref Search ADS PubMed 10 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials . 1996 ; 17 (1): 1 –12. Crossref Search ADS PubMed 11 Mant D. Can randomised trials inform clinical decisions about individual patients? Lancet . 1999 ; 353 (9154): 743 –6. Crossref Search ADS PubMed Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Levy, Jerrold, H.

doi: 10.2146/ajhp050303pmid: 16227191

Abstract Purpose. The pharmacologic management of hemostasis in patients undergoing surgery with cardiopulmonary bypass is discussed. Summary. Nearly 45 studies involving 7,000 patients have reported efficacy of aprotinin in blood conservation. Both in primary coronary artery bypass graft (CABG) surgeries and in repeat surgeries, aprotinin treatment significantly reduces the incidence of blood transfusions and the number of units of blood transfused. These effects have been observed for red blood cell, platelet, and other blood products. The safety of aprotinin treatment has been extensively evaluated in randomized clinical trials, in postmarketing databases, and in systematic reviews of the literature. Overall, data do not indicate that aprotinin treatment increases mortality, myocardial infarction, or renal failure. These findings are supported by the results of a recent meta-analysis of 35 studies in patients undergoing CABG surgery. In addition, the meta-analysis suggests that aprotinin treatment was associated with a reduced incidence of stroke and a trend toward a reduced incidence of atrial fibrillation. Although lysine analogs, desmopressin, and recombinant factor VIIa are sometimes used to reduce bleeding, only aprotinin is indicated for use during CABG surgery. Conclusion. The future of cardiac surgery will be marked by an increasingly complex, high-risk group of patients and a greater need for multiple pharmacologic options for reducing bleeding. Pharmacologic approaches that attenuate the activation of the hemostatic system and inflammation need to be employed to decrease coagulopathies and the need for allogeneic blood administration. Aprotinin, Blood, Coronary artery bypass, Desmopressin, Factor VIIa, Hemostatics, Mechanism of action, Mortality, Pituitary hormones, Toxicity Blood conservation is important not only because of the cost associated with transfusions but also the risks. Transfusions are tissue organ transplants and are associated with a spectrum of inflammatory responses. Transfused blood often includes metabolically activated neutrophils, all of which mediate inflammation. Although many studies have focused on the need to reduce red blood cell transfusions, reducing platelets may also be important. A recent publication has shown that platelet transfusions are associated with adverse events, such as stroke, myocardial infarction, and death.1 Bleeding during cardiac surgery is due in part to the activation of the fibrinolytic system and the systemic inflammatory response. During this process small inflammatory stimuli are amplified through humoral and cellular pathways. Kallikrein plays a pivotal role in these pathways and their cross amplification. Increases in kallikrein activity can lead to bleeding because kallikrein activates plasmin, which degrades fibrin in clots, and initiates pathways that activate and exhaust platelets. Blood conservation can be facilitated by the use of pharmacologic agents. Aprotinin, lysine analogs, desmopressin, and recombinant factor VIIa have all been reported to reduce bleeding, although only aprotinin is indicated for use in coronary artery bypass graft (CABG) surgery patients.2,–6 Aprotinin Aprotinin is a broad spectrum agent that acts on a multiplicity of enzymes involved in the inflammatory response. It is currently the only available kallikrein inhibitor that also inhibits a broad spectrum of proteases involved in inflammation, including trypsin, plasmin, elastase, and thrombin. The antiinflammatory effects of aprotinin may also occur by inhibition of the complement system, the fibrinolytic system, tumor necrosis factor, neutrophil activation, and protease-activated receptor effects. Aprotinin is a small polypeptide with predictable pharmacokinetics. Its half-life varies from 2.5 to 5 hours and its volume of distribution approximates the intravascular volume. After injection of a full dose, aprotinin plasma concentrations reach about 4 μmolar (250 kallikrein inhibiting units/ml), a concentration that inhibits both fibrinolysis and inflammation.7 The pivotal studies that led to the approval of aprotinin by the United States (U.S.) Food and Drug Administration offer important insight into some of the applications of aprotinin. Several studies were performed in high-risk, repeat or redo CABG patients.8,9 With aprotinin treatment, a statistically and clinically relevant reduction in the number of transfused products was recorded when compared to placebo treatment (Figure 11).8,9 Both studies reported similar reductions in blood product use; on average, placebo-treated patients received between 10 and 12 units of blood products whereas aprotinin-treated patients received between 1.6 and 2 units. Furthermore, allogeneic product use was reduced by approximately 2 units for red blood cells, 6 units for platelets, and varying degrees for fresh frozen plasma and cryoprecipitate.9 As an inflammatory response takes place even with allogeneic blood products, reducing the need for allogeneic products is also of clinical significance. In another study, approximately 800 patients received either a full dose of aprotinin or placebo during primary coronary vascularization surgery. Of the 800 patients enrolled, 700 underwent cardiac catheterization 5 to 30 days after surgery and evaluated for graft patency.10 In this primary CABG population, chest tube drainage was recorded as approximately 1200 ml in placebo patients and 700 ml in aprotinin patients. The incidence of allogeneic blood transfusions was reduced from 58% in placebo patients to 40% in aprotinin-treated patients.10 Importantly, data from 381 patients enrolled in U.S. sites revealed no differences in saphenous vein graft occlusion between aprotinin- and placebo-treated patients (Figure 22). By contrast, in three sites (two in Israel and one in Denmark), a higher incidence of smaller distal graft targets (≤1.5 mm) was noted in aprotinin treated patients. Despite these data on graft patency, 30-day hospital mortality outcome data showed no increases in death; and myocardial infarction rates were lower in aprotinin-treated patients than in placebo-treated patients.10 No correlation between perioperative myocardial infarction and graft occlusion was found. These seemingly contradictory data may be explained if some of the smaller distal grafts that occluded were not necessary for the total revascularization and were at high risk for occlusion. During cardiac surgery, many different procedures can produce adverse events in the perioperative and postoperative periods. Adverse events can be caused by inadequate treatment with heparin; thrombin-related problems such as low antithrombin III, low activated protein C, or low factor V; high platelet counts; transfusion of platelets; disseminated intravascular coagulation; and technical issues. Clinically, these events can translate into many different adverse events including excess bleeding, thrombosis, or organ damage. The safety of aprotinin has been extensively monitored in clinical trials and in postmarketing databases. Aprotinin is safe and generally well tolerated.2 In a recent systematic review of the literature, data from 35 trials were pooled for analysis.11 Compared to placebo treatment, aprotinin treatment decreased blood transfusion; aprotinin therapy was associated with a reduced incidence of stroke and a trend towards a reduced incidence of atrial fibrillation. Mortality, myocardial infarction, and renal failure did not increase with aprotinin treatment.11 The association of aprotinin treatment with a decreased stroke rate was first noted in a high-risk patient population.9 No strokes were reported in either full or half dose aprotinin-treated patients, whereas a 7% (n = 5) and 1% (n = 1) stroke incidence was noted in the placebo-treated and aprotinin-pump-prime-treated patients, respectively.9 This trend was also observed in data compiled in a large database, where full-dose aprotinin appeared to be associated with a reduced incidence of gross neurologic events.12 Current working hypotheses suggest that this effect may be because of a reduced need for platelet transfusions, which have been associated with increased stroke rates,1 or to the antiinflammatory properties of aprotinin such as inhibition of neutrophil transmigration13,14 and protease-activated receptor-1 which mediates thrombin signaling.15,16 Because aprotinin is a polybasic polypeptide derived of bovine origin, the possibility of a hypersensitivity reaction to the drug exists. Hypersensitivity reactions may range from mild skin rashes and urticaria to anaphylaxis and circulatory collapse. Based on an analysis of the currently available literature, hypersensitivity reactions ranging from mild skin rashes to anaphylaxis are rarely reported in patients with no prior exposure to aprotinin (<0.1%).2 The risk of an allergic reaction increases with reexposure. Within six months of exposure the rate increases to 5%, but six months after exposure, the rate drops to 0.9%. Together these data suggest that cardiac surgical patients at risk for bleeding warrant therapy with aprotinin. Patients undergoing CABG surgery and observed to be at a high risk for bleeding include patients undergoing repeat sternotomy which fosters adhesions and microvascular bleeding; Jehovah’s Witnesses who, in general, object to blood transfusions; patients undergoing dialysis for renal failure; patients with endocarditis or another active infection, as these patients probably have preexisting inflammatory injuries; and patients preoperatively or concomitantly treated with antiplatelet or anticoagulant therapy. Lysine analogs Lysine analogs, such as aminocaproic acid and tranexamic acid, are indicated to enhance hemostasis when fibrinolysis contributes to bleeding. Both lysine analogs attenuate fibrinolysis by inhibiting lysis of plasminogen to plasmin and to a lesser degree by directly inhibiting plasmin activity. Tranexamic acid is specifically indicated in patients with hemophilia to reduce hemorrhage and the need for replacement therapy during and following tooth extraction.3 Aminocaproic acid is indicated as “useful in enhancing hemostasis when fibrinolysis contributes to bleeding [. . .] Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) [. . .]”6 Although the cost of lysine analogs is low,17 clinical efficacy and safety data in cardiac patients are limited. Effects on bleeding, transfusion rates during cardiac surgery, and graft closures have not been reported in the package inserts,3,6 and published studies in adult cardiac patients are often small and of varying designs. Aminocaproic acid has also been associated with an increased incidence of certain neurological deficits, and concerns about rhabdomyolysis and renal dysfunction have been raised.6 Desmopressin Desmopressin, a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin, increases the release of von Willebrand’s factor into the blood and increases levels of anti-hemophilic factor VIII activity in the plasma. Desmopressin is used to improve hemostasis in mild hemophilia and other conditions associated with defective platelet function. Although some data suggest a reduction in bleeding occurs with desmopressin use during cardiac surgery,18 overall evidence is unclear.19 Desmopressin is not indicated for use in cardiac surgery patients, but a meta-analysis in cardiac patients revealed that desmopressin treatment resulted in a two-fold increase in myocardial infarction, a small decrease in perioperative blood loss, and no added benefits on clinical outcomes.20 Recombinant factor VIIa Recombinant human coagulation factor VIIa is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived factor VIIa. It is indicated for treating bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX.5 It promotes hemostasis by activating the coagulation cascade. At sites of vascular and microvascular injury, recombinant factor VIIa is believed to cause local thrombin generation21 and platelet recruitment.22 Recombinant factor VIIa has been shown to inhibit the action of low molecular weight heparin and pentasaccharide fondaparinux.23 This important effect may be the result of the ability of recombinant factor VIIa to act locally on platelet surfaces and thrombin levels.22,24,25 Several reports of beneficial use in cardiac patients with refractory bleeding have been published.26,–31 Conclusion Data presented suggest that aprotinin, a broad-spectrum protease inhibitor, reduces bleeding and the need for allogeneic transfusions during CABG surgery. As cardiac surgery becomes increasingly complex due to older, higher risk patients, the need for pharmacologic approaches to reduce bleeding will continue to increase. Figure 1. Open in new tabDownload slide Open in new tabDownload slide Total blood product exposures in two randomized clinical trials in redo coronary artery bypass patients. Totals are computed as the sum of the means. For A, p < 0.05 for all columns except cryoprecipitate. For B, p < 0.05 for all columns. Adapted with permission from references 8 (A) and 9 (B). Figure 1. Open in new tabDownload slide Open in new tabDownload slide Total blood product exposures in two randomized clinical trials in redo coronary artery bypass patients. Totals are computed as the sum of the means. For A, p < 0.05 for all columns except cryoprecipitate. For B, p < 0.05 for all columns. Adapted with permission from references 8 (A) and 9 (B). Figure 2. Open in new tabDownload slide Graft occlusion 5–30 days after primary coronary vascularization surgery. SVG = saphenous vein graft. p < 0.05 for “all centers” and “non-United States centers.” Adapted with permission from reference 10. Figure 2. Open in new tabDownload slide Graft occlusion 5–30 days after primary coronary vascularization surgery. SVG = saphenous vein graft. p < 0.05 for “all centers” and “non-United States centers.” Adapted with permission from reference 10. Based on the proceedings of a symposium held December 6, 2004, during the ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation. Dr. Levy received an honorarium for participating in the symposium and writing this article. References 1 Spiess BD, Royston D, Levy JH et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion . 2004 ; 44 (8): 1143 –8. Crossref Search ADS PubMed 2 Trasylol® (aprotinin injection) package insert. West Haven, CT: Bayer Pharmaceuticals Corporation; 2003 Dec. 3 Cyklokapron® (tranexamic acid tablets and tranexamic acid injection) package insert. Kalamazoo, MI: Pharmacia Corporation; 2001 Dec. 4 DDVAP® desmopressin acetate injection package insert. Limhamn, Sweden: Ferring Pharmaceuticals Inc.; 2003 Apr. 5 Novoseven® Coagulation Factor VIIa (Recombinant) package insert. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc.; 2004 Aug. 6 Amicar® (aminocaproic acid), injection, syrup, and tablets, package insert. Florence, KY: Xanodyne Pharmaceuticals, Inc.; 2004 Sept. 7 Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology . 1994 ; 80 (5): 1013 –8. Crossref Search ADS PubMed 8 Lemmer JH, Jr., Stanford W, Bonney SL et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg . 1994 ; 107 (2): 543 –51. PubMed 9 Levy JH, Pifarre R, Schaff HV et al. 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Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: effects on perioperative bleeding and allogeneic transfusions. J Thorac Cardiovasc Surg . 2000 ; 120 (3): 520 –7. Crossref Search ADS PubMed 18 Salzman EW, Weinstein MJ, Weintraub RM et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med . 1986 ; 314 (22): 1402 –6. Crossref Search ADS PubMed 19 Hackmann T, Gascoyne RD, Naiman SC et al. A trial of desmopressin (1-desamino-8-D-arginine vasopressin) to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med . 1989 ; 321 (21): 1437 –43. Crossref Search ADS PubMed 20 Levi M, Cromheecke ME, de Jonge E et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet . 1999 ; 354 (9194): 1940 –7. Crossref Search ADS PubMed 21 Friederich PW, Levi M, Bauer KA et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation . 2001 ; 103 (21): 2555 –9. Crossref Search ADS PubMed 22 Hoffman M, Monroe DM, Roberts HR. Platelet-dependent action of high-dose factor VIIa. Blood . 2002 ; 100 (1): 364 –5. Crossref Search ADS 23 Bijsterveld NR, Moons AH, Boekholdt SM et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation . 2002 ; 106 (20): 2550 –4. Crossref Search ADS PubMed 24 Hedner U, Erhardtsen E. Future possibilities in the regulation of the extrinsic pathway: rFVIIa and TFPI. Ann Med . 2000 ; 32 Suppl: 168 –72. 25 Gabriel DA, Li X, Monroe DM, 3rd et al. Recombinant human factor VIIa (rFVIIa) can activate factor FIX on activated platelets. J Thromb Haemost . 2004 ; 2 (10): 1816 –22. Crossref Search ADS PubMed 26 Tanaka KA, Waly AA, Cooper WA et al. Treatment of excessive bleeding in Jehovah’s Witness patients after cardiac surgery with recombinant factor VIIa (NovoSeven). Anesthesiology . 2003 ; 98 (6): 1513 –5. Crossref Search ADS PubMed 27 von Heymann C, Hotz H, Konertz W et al. Successful treatment of refractory bleeding with recombinant factor VIIa after redo coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth . 2002 ; 16 (5): 615 –6. Crossref Search ADS PubMed 28 Kastrup M, von Heymann C, Hotz H et al. Recombinant factor VIIa after aortic valve replacement in a patient with osteogenesis imperfecta. Ann Thorac Surg . 2002 ; 74 (3): 910 –2. Crossref Search ADS PubMed 29 Tobias JD, Berkenbosch JW, Muruve NA et al. Correction of a coagulopathy using recombinant factor VII before removal of an intra-aortic balloon pump. J Cardiothorac Vasc Anesth . 2002 ; 16 (5): 612 –4. Crossref Search ADS PubMed 30 Hendriks HG, van der Maaten JM, de Wolf J et al. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII. Anesth Analg . 2001 ; 93 (2): 287 –9. PubMed 31 Stratmann G, Russell IA, Merrick SH. Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair. Ann Thorac Surg . 2003 ; 76 (6): 2094 –7. Crossref Search ADS PubMed Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Engles,, Laura

doi: 10.2146/ajhp050300pmid: 16227196

Abstract Purpose. Current pharmacologic agents, aprotinin, epsilon aminocaproic acid, and tranexamic acid, used to decrease blood loss and transfusion requirements during coronary artery bypass graft (CABG) surgery are discussed. Aprotinin is the only agent that also modulates the systemic inflammatory responses that are generated by contact activation during CABG surgery. These responses are largely mediated by serine proteases such as kallikrein, thrombin, and plasmin. Summary. Aprotinin is a naturally occurring polypeptide that has a concentration-dependent effect to inhibit serine proteases. Two aprotinin dosing regimens are indicated in the United States (U.S.) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) during the course of CABG surgery. Serum concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin activity resulting in attenuation of the systemic inflammatory response to bypass, whereas serum concentrations achieved with the half-dose regimen only inhibit plasmin activity. The efficacy and safety of aprotinin have been studied in randomized controlled trials in over 5,000 patients. Aprotinin is well tolerated compared to placebo. Treatment-emergent adverse events are similar to those associated with CPB surgery. However, because aprotinin is a bovine protein, there is a small, but manageable risk of hypersensitivity reactions. Epsilon aminocaproic acid and tranexamic acid are lysine analogs that reduce bleeding by inhibiting the conversion of plasminogen to plasmin, a serine protease responsible for breaking down fibrinogen to fibrin. Although they are commonly used to decrease bleeding associated with CABG surgery with CPB, they are not currently approved by the U.S. Food and Drug Administration (FDA) for CABG surgery. Conclusion. Aprotinin is the only agent that has an FDA indication to prevent blood loss and transfusion during CABG surgery, and the additional benefit of attenuating the systemic inflammatory response associated with CABG with CPB. Allergies, Aminocaproic acid, Aprotinin, Blood, Blood levels, Coronary artery bypass, Dosage, Drugs, adverse reactions, Hemostatics, Mechanism of action, Toxicity, Tranexamic acid Aprotinin is a naturally occurring polypeptide that inhibits serine proteases, enzymes that have the amino acid serine at their active site.1 Serine proteases mediate a variety of reactions in the body, including activation of the coagulation cascade, the fibrinolytic system, and inflammatory responses. Aprotinin is a small molecule composed of 58 amino acids with 3 disulfide bridges. The active site, which forms a loop and contains a lysine and an alanine, is called the Kunitz domain after its discoverer. The lysine and alanine react with the serine site of a serine protease enzyme to form a tightly bound, reversible complex that inhibits the enzyme’s activity. Aprotinin has different binding affinities for serine proteases. In order of decreasing affinity, aprotinin binds to human trypsin, plasmin, kallikrein, elastase, urokinase, and thrombin. All of these enzymes are involved in the systemic inflammatory response that occurs during cardiac surgery.2 Because of the different binding affinities for the serine protease enzymes, aprotinin has concentration dependent effects. In other words, at lower concentrations (e.g., half-dose) aprotinin only inhibits plasmin, which plays a key role in fibrinolysis. Higher concentrations (e.g., full-dose, or the kallikrein-inhibiting dose) are required to inhibit kallikrein, a key amplifier of the systemic inflammatory response to coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB); this dose also inhibits plasmin. Please refer to Table 11 for the specific binding affinities of aprotinin for key serine proteases. Aprotinin mechanism of action To understand the mechanism of action of aprotinin, it is necessary to have a basic understanding of the systemic inflammatory response that occurs during CABG with CPB. Contact activation occurs when the foreign surface of the scalpel contacts the blood at the time of the first incision during CABG surgery. The large foreign surface area of the bypass machine and tubing amplifies this response when the patient goes on bypass. Contact activation leads to the conversion of pre-kallikrein to kallikrein, plasminogen to plasmin, and prothrombin to thrombin. These changes lead to initiation of hemostasis, increased levels of bradykinin, activation of the renin-angiotensin-aldosterone system, activation of neutrophils, release of elastase and other enzymes that damage otherwise healthy tissues, activation of platelets through the thrombin-activated protease-activated receptor signaling pathways, expression of platelet adhesion molecules, and activation of the complement system, which further amplifies the cascades and causes direct damage to cells and tissues. Please refer to Figure 11 for an overview of the role of thrombin in excessive hemostasis during CABG with CPB. The systemic inflammatory response leads to multiple clinical sequelae2 including: an imbalance in the fibrinolytic and hemostatic systems; platelet dysfunction, resulting in bleeding at the sites of the bypass grafts and the sternal wound; migration of inappropriately activated neutrophils into the tissues, resulting in tissue damage activation of the renin-angiotensin system, leading to hemodynamic instability; and increased vascular permeability and third spacing of fluids in the tissues due to bradykinin production. Because aprotinin is a broad-spectrum serine protease inhibitor, it attenuates many of these effects. The mechanism of action of aprotinin is stated in the prescribing information1 as “aprotinin is a broad-spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with CPB surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators (e.g., kallikrein, plasmin) results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b). The effects of aprotinin use in CPB involve a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal reexploration for bleeding.” The approved indication for aprotinin is for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CPB during the course of CABG surgery.1 The use of aprotinin has resulted in a more than 45% reduction in blood transfusion compared with placebo in many large multicenter trials.4 The significant decrease in transfusion requirements noted with aprotinin treatment is particularly important as the deleterious effects of transfusion become more apparent.5,–10 Even if a patient predonates his or her own blood, once the blood is in contact with the storage bag an inflammatory response is initiated. When the blood is transfused, the inflammatory mediators and activated leukocytes and neutrophils are also infused into the patient. Reduction in the incidence of mediastinal exploration for bleeding is also important. Most CABG surgeries are reimbursed based on diagnosis related groups (DRGs) and reexploration for bleeding normally occurs within a few days of the initial operation. The additional cost of several thousand dollars is often not reimbursed. In a retrospective review of aprotinin clinical trials, there was a significantly lower rate of reoperation for bleeding in aprotinin-treated patients compared with the placebo group.11 Aprotinin administration and dosing Aprotinin should be administered intravenously through a central line that is used only for aprotinin. It exhibits a two-stage distribution—the initial distribution phase takes approximately 0.5 hour and reflects the time it takes to distribute to the extracellular tissues. The primary half-life, which corresponds to its functional half-life, is approximately 2.5 hours. During this time, aprotinin is filtered by the glomeruli. Aprotinin is then taken up in the renal tubular cells in the brush border where it is slowly metabolized by lysosomal enzymes.12 As a result, the terminal elimination half-life is between 10 and 12 hours.1 Less than 10% of aprotinin is excreted as active drug. From a practical perspective, this pharmacokinetic profile suggests that once the loading dose is administered, a continuous infusion is needed to maintain clinically effective levels. As mentioned above, aprotinin has concentration-dependent effects. Plasmin is inhibited at a serum concentration of approximately 130 KIU/ml of aprotinin, whereas both plasmin and kallikrein are inhibited by 250 KIU/ml of aprotinin. At the lower concentration, aprotinin treatment only has antifibrinolytic effects; whereas at the higher concentration both fibrinolysis, via plasmin inhibition, and the systemic inflammatory response, via kallikrein inhibition, are attenuated.1,13,–15 Dosing and administration recommendations reflect these concentration effects. Please refer to Table 22 for a description of the concentration dependent effects of aprotinin. The dosing of aprotinin is expressed in milligrams (mg), in kallikrein inhibitor units (KIUs), and in milliliters (ml). One KIU is defined as the amount of aprotinin needed to decrease the activity of two biologic kallikrein units by 50%. In other words, 100,000 KIU equals 14 mg aprotinin, which also equals 2.15 μmol/l. A 1 ml test dose should be given prior to administering either dosing regimen. The kallikrein inhibiting dose, also referred to as the full-dose or the full Hammersmith dose, consists of a loading dose of 2 million KIU, a pump prime dose of 2 million KIU, and a constant infusion of 500,000 dose KIU/hr. The plasmin inhibiting dose, referred to as the half-dose or the half Hammersmith dose, is half of the full-dose.1 Because aprotinin is derived from a bovine source, it may be associated with hypersensitivity reactions. Patients may have been exposed to aprotinin previously and not be aware of it, since it is a component of some types of fibrin glues usually given during surgery. Therefore, all patients should be given a test dose of 1 ml (1.4 mg or 10,000 KIUs) at least 10 minutes prior to the loading dose. Once anesthesia has been introduced, the loading dose should be administered over a 20–30 minute period followed by a continuous infusion. The loading dose should be given and the continuous infusion should be started prior to sternotomy to achieve adequate serum concentrations prior to sternotomy. This is because, once the scalpel breaks through the skin, contact activation of the systemic inflammatory response begins and kallikrein levels start to rise. Prior to putting the patient on CPB, a pump prime dose should be administered into the pump prime fluid while the pump is recirculating. The continuous infusion should be continued until chest closure or the end of surgery.4,16 Please refer to Figure 22 for a schematic of aprotinin administration during CABG surgery. Aprotinin safety The systemic inflammatory response to CPB results in increased levels of inflammatory mediators, including thrombin. Therefore, heparin must be administered to inhibit the effects of thrombin directly and prevent thrombosis. The degree of anticoagulation must be monitored carefully during CABG with CPB. The activated clotting time (ACT) is a non-specific measure of anticoagulation. An activator, either celite or kaolin, is added to a sample of the patient’s blood to initiate contact activation. The ACT measures the time from the onset of contact activation to clot formation—it does not measure the effects of thrombin directly. However, because it is a bedside test and results are obtained quickly, it is the most common anticoagulation assay used in CABG with CPB to monitor anticoagulation. Since the ACT test is initiated by contact activation, and aprotinin inhibits contact activation, aprotinin prolongs the ACT. Because it attenuates kallikrein and other inflammatory mediators, aprotinin decreases the production of thrombin. It does not decrease the requirements for heparin during CABG with CPB.17 The effects of aprotinin on the ACT must be taken into account in order for a patient to be adequately anticoagulated. Specific recommendations for monitoring anticoagulation, including recommendations for adjusting the ACT goal in the presence of aprotinin, have been developed. A commonly used goal for the ACT during CABG surgery with CPB is ≥480 seconds. In the presence of aprotinin, the celite-based ACT goal is ≥750 seconds. The ACT from a test using kaolin should be ≥480 seconds. The kaolin-based test is different from the celite-ACT, because kaolin adsorbs aprotinin, thereby reducing the amount of free aprotinin in the test and the effect of aprotinin on the test result. Alternatively, a fixed, weight-based dose of heparin, given as a loading dose (350 IU/kg), followed by a weight-based dose during CPB can be used. Lastly, a heparin protamine titration can be used to measure heparin levels, which should be kept at >2.7 U/ml (2.0 mg/ml). Because aprotinin is a bovine protein, a small chance that a patient may have a hypersensitivity reaction exists. There is a black box warning in the package insert regarding this risk.1 The incidence of hypersensitivity reactions has been evaluated in adult and pediatric patients who were treated with aprotinin for a variety of cardiac surgery indications that required repeat surgical procedures.1,18 In patients with no prior exposure to aprotinin, hypersensitivity reactions, which range from skin rash, to bronchospasm, to anaphylaxis, are infrequent (≤0.1%). In patients who are reexposed to aprotinin, the overall incidence of hypersensitivity reactions is 2.7%.18 Interestingly, the incidence of hypersensitivity reactions decreases with increased duration from the first exposure. The incidence of hypersensitivity reactions after a reexposure to aprotinin within six months is 5%, whereas beyond six months the incidence drops to 0.9%, a rate that is consistent with a relatively weak antigen-antibody response.1,18 In the context of CABG surgery, exposure would be unusual, as most patients do not need a repeat surgery within six months.19 Please refer to Figure 33 for a schematic of the incidence of hypersensitivity reactions over time. In addition to conducting studies to evaluate the effect of aprotinin on clotting times and the incidence of hypersensitivity reactions, the safety profile of aprotinin has been studied in well-controlled trials in over 2,000 patients that were designed specifically to evaluate safety. Compared to placebo, aprotinin was well tolerated.1 Treatment-emergent adverse events were similar to those seen in the course of CABG surgery. The incidence of some adverse events is listed in Table 33. Of particular note, the incidence of cerebrovascular accidents is lower in aprotinin-treated patients than in placebo-treated patients. This trend was first reported by Levy and colleagues,5 and is supported by the results of a rigorous meta-analysis that included 18 coronary artery bypass graft trials including 2976 patients, in which stroke was an outcome measure. Aprotinin use was associated with consistently fewer strokes in most of the individual trials, and was associated with an overall 47% relative risk reduction for stroke.3,5 Lysine analogs Epsilon aminocaproic acid20 and tranexamic acid21 are lysine analogs that reduce bleeding. Although they have not been approved by the U.S. FDA for CABG surgery, their mechanism of action is of interest. In order to understand their mechanism of action, a brief review of the systemic inflammatory response that occurs during CABG with CPB will be helpful. Normally, the hemostatic response occurs at a localized site of tissue injury to form a clot and stop bleeding. The fibrinolytic system is activated as a “checks and balances” system to limit clot formation. Fibrinolysis is mainly mediated by the potent proteolytic serine protease plasmin, which cleaves the fibrin in clots. During the systemic inflammatory response, imbalance in the hemostatic and fibrinolytic systems occurs, resulting in amplification and systemic effects of both systems. Kallikrein causes the release of tissue plasminogen activator that lyses plasminogen into plasmin. Normally, plasminogen and tissue plasminogen activator circulate freely in the blood at concentrations that are too low for them to interact to form plasmin. In the presence of fibrin however, plasminogen binds to a lysine site on fibrin and tissue plasminogen activator binds to another adjacent fibrin site. The conformational proximity permits tissue plasminogen activator to convert plasminogen to plasmin which then degrades the fibrin and is eventually released into the bloodstream. When plasmin is free in the bloodstream, α-2 antiplasmin rapidly inactivates plasmin in 1/100th of a second, preventing any systemic effects from this potent proteolytic enzyme. When plasmin reacts with clot-bound fibrin, the reaction with α-2 antiplasmin takes much longer. During a systemic inflammatory response, the fibrinolysis pathway is amplified and the concentration of free plasmin increases, leading to cellular and tissue damage. Both this amplification of the fibrinolytic pathway and damage to platelets increase the risk of excessive bleeding. Lysine analogs inhibit fibrinolysis by binding to plasminogen at its lysine binding site, blocking it from binding to fibrin; therefore, plasminogen cannot be converted to plasmin. By contrast, serine protease inhibitors, like aprotinin, inactivate free plasmin in the bloodstream but allow clot-bound plasmin to function appropriately, thereby restoring the balance between hemostasis and fibrinolysis.22 Conclusion Aprotinin is the only compound currently indicated by the FDA to reduce prophylactically blood loss and the need for transfusion during CABG surgery that has a safety profile well-documented with clinical studies. Due to its broad spectrum inhibition of serine proteases, aprotinin attenuates the systemic inflammatory response by inhibiting several enzymes of the inflammatory cascades. Lysine analogs can also reduce bleeding by inhibiting the conversion of plasminogen to plasmin, but have not been approved for use during CABG surgery. Table 1. Aprotinin binding affinities. Affinities of aprotinin differ for each enzyme. Dissociation constants for inhibition (inhibition constant or Ki) are as follows (human source unless otherwise noted). Enzyme Kia a Ki is the concentration of drug at which the activity of enzyme is inhibited by 50%. Trypsin 6.0 × 10−14 M Plasmin 2.3 × 10−10 M Tissue kallikrein (porcine pancreas) 1.0 × 10−9 M Plasma kallikrein 3.0 × 10−8 M Elastase 3.5 × 10−6 M Urokinase 8.0 × 10−6 M Plasma thrombin 3.0 × 10−5 M Enzyme Kia a Ki is the concentration of drug at which the activity of enzyme is inhibited by 50%. Trypsin 6.0 × 10−14 M Plasmin 2.3 × 10−10 M Tissue kallikrein (porcine pancreas) 1.0 × 10−9 M Plasma kallikrein 3.0 × 10−8 M Elastase 3.5 × 10−6 M Urokinase 8.0 × 10−6 M Plasma thrombin 3.0 × 10−5 M Table 1. Aprotinin binding affinities. Affinities of aprotinin differ for each enzyme. Dissociation constants for inhibition (inhibition constant or Ki) are as follows (human source unless otherwise noted). Enzyme Kia a Ki is the concentration of drug at which the activity of enzyme is inhibited by 50%. Trypsin 6.0 × 10−14 M Plasmin 2.3 × 10−10 M Tissue kallikrein (porcine pancreas) 1.0 × 10−9 M Plasma kallikrein 3.0 × 10−8 M Elastase 3.5 × 10−6 M Urokinase 8.0 × 10−6 M Plasma thrombin 3.0 × 10−5 M Enzyme Kia a Ki is the concentration of drug at which the activity of enzyme is inhibited by 50%. Trypsin 6.0 × 10−14 M Plasmin 2.3 × 10−10 M Tissue kallikrein (porcine pancreas) 1.0 × 10−9 M Plasma kallikrein 3.0 × 10−8 M Elastase 3.5 × 10−6 M Urokinase 8.0 × 10−6 M Plasma thrombin 3.0 × 10−5 M Table 2. Concentration dependent properties of aprotinin.a Plasma Concentrations 137 KIU/mL (plasmin- inhibiting dose) 250 KIU/mL (kallikrein- inhibiting dose) aKIU = kallikrein inhibitor units, mL = milliliters. Inhibits plasmin13 ✓ ✓ Decreases bypass-induced fibrinolysis13 ✓ ✓ Reduces blood loss (thoracic drainage)1 ✓ ✓ Reduces transfusion requirements1 ✓ ✓ Stabilizes platelet membranes, platelet response, and platelet volume13,14 ✓ Inhibits granulocyte proinflammatory glycoproteins (CD 11b) and degranulation1,15 ✓ Inhibits kallikrein1,13 ✓ Modulates systemic inflammatory response1 ✓ Plasma Concentrations 137 KIU/mL (plasmin- inhibiting dose) 250 KIU/mL (kallikrein- inhibiting dose) aKIU = kallikrein inhibitor units, mL = milliliters. Inhibits plasmin13 ✓ ✓ Decreases bypass-induced fibrinolysis13 ✓ ✓ Reduces blood loss (thoracic drainage)1 ✓ ✓ Reduces transfusion requirements1 ✓ ✓ Stabilizes platelet membranes, platelet response, and platelet volume13,14 ✓ Inhibits granulocyte proinflammatory glycoproteins (CD 11b) and degranulation1,15 ✓ Inhibits kallikrein1,13 ✓ Modulates systemic inflammatory response1 ✓ Table 2. Concentration dependent properties of aprotinin.a Plasma Concentrations 137 KIU/mL (plasmin- inhibiting dose) 250 KIU/mL (kallikrein- inhibiting dose) aKIU = kallikrein inhibitor units, mL = milliliters. Inhibits plasmin13 ✓ ✓ Decreases bypass-induced fibrinolysis13 ✓ ✓ Reduces blood loss (thoracic drainage)1 ✓ ✓ Reduces transfusion requirements1 ✓ ✓ Stabilizes platelet membranes, platelet response, and platelet volume13,14 ✓ Inhibits granulocyte proinflammatory glycoproteins (CD 11b) and degranulation1,15 ✓ Inhibits kallikrein1,13 ✓ Modulates systemic inflammatory response1 ✓ Plasma Concentrations 137 KIU/mL (plasmin- inhibiting dose) 250 KIU/mL (kallikrein- inhibiting dose) aKIU = kallikrein inhibitor units, mL = milliliters. Inhibits plasmin13 ✓ ✓ Decreases bypass-induced fibrinolysis13 ✓ ✓ Reduces blood loss (thoracic drainage)1 ✓ ✓ Reduces transfusion requirements1 ✓ ✓ Stabilizes platelet membranes, platelet response, and platelet volume13,14 ✓ Inhibits granulocyte proinflammatory glycoproteins (CD 11b) and degranulation1,15 ✓ Inhibits kallikrein1,13 ✓ Modulates systemic inflammatory response1 ✓ Table 3. Adverse events of particular interest reported by <2% of patients in controlled United States trials. Information taken from the United States prescribing information.1 Event Patients treated with aprotinin (n= 2002) % Patients treated with placebo (n= 1084) % Thrombosis 1.0 0.6 Shock 0.7 0.4 Cerebrovascular accident 0.7 2.1 Thrombophlebitis 0.2 0.5 Deep thrombophlebitis 0.7 1.0 Lung edema 1.3 1.5 Pulmonary embolus 0.3 0.6 Kidney failure 1.0 0.6 Acute kidney failure 0.5 0.6 Kidney tubular necrosis 0.8 0.4 Event Patients treated with aprotinin (n= 2002) % Patients treated with placebo (n= 1084) % Thrombosis 1.0 0.6 Shock 0.7 0.4 Cerebrovascular accident 0.7 2.1 Thrombophlebitis 0.2 0.5 Deep thrombophlebitis 0.7 1.0 Lung edema 1.3 1.5 Pulmonary embolus 0.3 0.6 Kidney failure 1.0 0.6 Acute kidney failure 0.5 0.6 Kidney tubular necrosis 0.8 0.4 Table 3. Adverse events of particular interest reported by <2% of patients in controlled United States trials. Information taken from the United States prescribing information.1 Event Patients treated with aprotinin (n= 2002) % Patients treated with placebo (n= 1084) % Thrombosis 1.0 0.6 Shock 0.7 0.4 Cerebrovascular accident 0.7 2.1 Thrombophlebitis 0.2 0.5 Deep thrombophlebitis 0.7 1.0 Lung edema 1.3 1.5 Pulmonary embolus 0.3 0.6 Kidney failure 1.0 0.6 Acute kidney failure 0.5 0.6 Kidney tubular necrosis 0.8 0.4 Event Patients treated with aprotinin (n= 2002) % Patients treated with placebo (n= 1084) % Thrombosis 1.0 0.6 Shock 0.7 0.4 Cerebrovascular accident 0.7 2.1 Thrombophlebitis 0.2 0.5 Deep thrombophlebitis 0.7 1.0 Lung edema 1.3 1.5 Pulmonary embolus 0.3 0.6 Kidney failure 1.0 0.6 Acute kidney failure 0.5 0.6 Kidney tubular necrosis 0.8 0.4 Figure 1. Open in new tabDownload slide Pivotal role of thrombin in the mechanisms and effects of excessive hemostatic activation with cardiac surgery. The coagulation system, a complex web of interactions, is subdivided into three pathways: intrinsic or contact (enclosed by small dashed line), extrinsic or tissue factor (enclosed by a large dashed line), and common (enclosed by a solid line); the conversion of factor X to Xa is within all three pathways (enclosed by a solid thick line). Dashed lines designate release of protein cleavage by-products. Activated factors are designated using a small “a” whereas inactivated factors are designated using a small “i.” XII = factor XII; VII = factor VII; X = factor X; VIII = factor VIII; IX = factor IX; V = factor V; XIII = factor XIII; PT 1.2 = prothrombin fragment 1.2; Ca2+= calcium ions; FPA = fibrinopeptide A; PL = phospholipid; PAP = plasmin–antiplasmin complexes; EC = endothelial cells; tPA:PAI1 = tPA–PAI1 complexes; fibrin (M) = fibrin monomer; fibrin (P) = fibrin polynomer; PAI1 = plasminogen activator inhibitor; tPA = tissue plasminogen activator; D-dimer = polymerized fibrin degradation products. *Designates endothelial cell related. Reprinted with permission from reference 3. Figure 1. Open in new tabDownload slide Pivotal role of thrombin in the mechanisms and effects of excessive hemostatic activation with cardiac surgery. The coagulation system, a complex web of interactions, is subdivided into three pathways: intrinsic or contact (enclosed by small dashed line), extrinsic or tissue factor (enclosed by a large dashed line), and common (enclosed by a solid line); the conversion of factor X to Xa is within all three pathways (enclosed by a solid thick line). Dashed lines designate release of protein cleavage by-products. Activated factors are designated using a small “a” whereas inactivated factors are designated using a small “i.” XII = factor XII; VII = factor VII; X = factor X; VIII = factor VIII; IX = factor IX; V = factor V; XIII = factor XIII; PT 1.2 = prothrombin fragment 1.2; Ca2+= calcium ions; FPA = fibrinopeptide A; PL = phospholipid; PAP = plasmin–antiplasmin complexes; EC = endothelial cells; tPA:PAI1 = tPA–PAI1 complexes; fibrin (M) = fibrin monomer; fibrin (P) = fibrin polynomer; PAI1 = plasminogen activator inhibitor; tPA = tissue plasminogen activator; D-dimer = polymerized fibrin degradation products. *Designates endothelial cell related. Reprinted with permission from reference 3. Figure 2. Open in new tabDownload slide Aprotinin dosing and administration.15 CPB = cardiopulmonary bypass, OR = operating room. Figure 2. Open in new tabDownload slide Aprotinin dosing and administration.15 CPB = cardiopulmonary bypass, OR = operating room. Figure 3. Open in new tabDownload slide Hypersensitivity reactions to aprotinin reexposure over time.1,18,22 The recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction in patients reexposed to aprotinin: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids); 2) Administration of the test dose and loading dose should be done only when the conditions for rapid cannulation (if necessary) are present; 3) Delay the addition of aprotinin into the pump prime solution until after the loading dose has been safely administered. Additionally, administration of H1 and H2 blockers 15 minutes before the test dose may be considered. CABG = coronary artery bypass graft. Figure 3. Open in new tabDownload slide Hypersensitivity reactions to aprotinin reexposure over time.1,18,22 The recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction in patients reexposed to aprotinin: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids); 2) Administration of the test dose and loading dose should be done only when the conditions for rapid cannulation (if necessary) are present; 3) Delay the addition of aprotinin into the pump prime solution until after the loading dose has been safely administered. Additionally, administration of H1 and H2 blockers 15 minutes before the test dose may be considered. CABG = coronary artery bypass graft. Based on the proceedings of a symposium held December 6, 2004, during the ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation. Dr. Engles received an honorarium for participating in the symposium and writing this article. References 1 Trasylol® (aprotinin injection) package insert. West Haven, CT: Bayer Pharmaceuticals Corporation; 2003 Dec. 2 Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung . 1983 ; 33 (4): 479 –94. PubMed 3 Despotis GJ, Gravlee G, Filos K et al. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology . 1999 ; 91 (4): 1122 –51. Crossref Search ADS PubMed 4 Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg . 2004 ; 128 (3): 442 –8. Crossref Search ADS PubMed 5 Levy JH, Pifarre R, Schaff HV et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation . 1995 ; 92 (8): 2236 –44. Crossref Search ADS PubMed 6 Lemmer JH, Jr., Stanford W, Bonney SL et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg . 1994 ; 107 (2): 543 –51. PubMed 7 Alderman EL, Levy JH, Rich JB et al. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg . 1998 ; 116 (5): 716 –30. Crossref Search ADS PubMed 8 Rosengart TK, Helm RE, Klemperer J et al. Combined aprotinin and erythropoietin use for blood conservation: results with Jehovah’s Witnesses. Ann Thorac Surg . 1994 ; 58 (5): 1397 –403. Crossref Search ADS PubMed 9 Helm RE, Rosengart TK, Gomez M et al. Comprehensive multimodality blood conservation: 100 consecutive CABG operations without transfusion. Ann Thorac Surg . 1998 ; 65 (1): 125 –36. Crossref Search ADS PubMed 10 Spiess BD, Royston D, Levy JH et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion . 2004 ; 44 (8): 1143 –8. Crossref Search ADS PubMed 11 Smith PK, Datta SK, Muhlbaier LH et al. Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials. Ann Thorac Surg . 2004 ; 77 (2): 635 –42. Crossref Search ADS PubMed 12 Kramer HJ, Dusing R, Glanzer K et al. Effects of aprotinin on renal function. Contrib Nephrol . 1984 ; 42 : 233 –41. PubMed 13 Dietrich W. Reducing thrombin formation during cardiopulmonary bypass: is there a benefit of the additional anticoagulant action of aprotinin? J Cardiovasc Pharmacol . 1996 ; 27 Suppl 1: S50 –7. Crossref Search ADS PubMed 14 van Oeveren W, Harder MP, Roozendaal KJ et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg . 1990 ; 99 (5): 788 –96. PubMed 15 Wachtfogel YT, Kucich U, Hack CE et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg . 1993 ; 106 (1): 1 –9. PubMed 16 Royston D, Bidstrup BP, Taylor KM et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet . 1987 ; 2 (8571): 1289 –91. PubMed 17 Royston D, Bidstrup BP, Taylor KM et al. Reduced blood loss following open heart surgery with aprotinin (Trasylol) is associated with an increase in intraoperative activated clotting time (ACT). J Cardiothorac Anesth . 1989 ; 3 (5 Suppl 1): 80 . Crossref Search ADS PubMed 18 Dietrich W. Incidence of hypersensitivity reactions. Ann Thorac Surg . 1998 ; 65 (6 Suppl): S60 –4. Crossref Search ADS PubMed 19 Legrand VM, Serruys PW, Unger F et al. Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease. Circulation . 2004 ; 109 (9): 1114 –20. Crossref Search ADS PubMed 20 Amicar® (aminocaproic acid), injection, syrup, and tablets, package insert. Florence, KY: Xanodyne Pharmaceuticals, Inc.; 2004 Sept. 21 Cyklokapron® (tranexamic acid tablets and tranexamic acid injection) package insert. Kalamazoo, MI: Pharmacia Corporation; 2001 Dec. 22 Merk H, Jugert F, Mayer G et al. Immunological response in 303 patients after cardiac-surgery with first-time exposure to aprotinin (Trasylol®). Immunoblot analysis of specific IgE and IgG antibodies. J Invest Dermatol . 1995 ; 104 (4): 668 . Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Morgan, Timothy, O.

doi: 10.2146/ajhp050301pmid: 16227193

Abstract Purpose. Blood conservation programs have been successfully implemented in hospitals in which an overarching commitment to the reduction of the number of blood transfusions existed. This review will describe the rationale and some of the considerations involved in starting such a program. Summary. Management of a hospital’s blood supply is a high pressure area dominated by a resource shortage, increasing costs, a medical community that has been trained to use transfusion, public awareness and concern, and to a lesser extent an increasing body of evidence suggesting that transfusions are often deleterious. The implementation of new techniques and protocols to conserve blood during surgery can be facilitated if a physician champion addresses the medical staff and the hospital administrators clear political and budgetary issues. With a team approach and an understanding of the clinical and economic evidence supporting less blood use, many of the hurdles can be overcome. Conclusion. Blood conservation programs offer a solution to the multiple problems that surround blood use. When successfully implemented, such initiatives reduce safety concerns, hospital spending, and the dependency of hospitals on the national blood supply and improve clinical outcomes and patient satisfaction. Blood, Control, quality, Coronary artery bypass, Costs, Economics, Hospitals, Protocols, Risk management, Team, Toxicity The responsibilities of a hospital chief executive officer (CEO) include managing the financial performance of the hospital while addressing competitive threats from other hospitals, liability issues, regulatory compliance, and public and staff relations. Ensuring the quality of clinical practices, patient safety, patient satisfaction, and the availability of blood products are also essential responsibilities. Management of the blood supply is a high pressure area dominated by a supply shortage, increasing costs, a medical community that has been trained to resort to transfusion, public awareness and concern, and, to a lesser extent, an increasing body of evidence suggesting that transfusions are often deleterious. Despite newspaper headlines such as “safety not assured,” “supplies going down,” “prices going up,” and “fears run high” that have highlighted the concerns about the United States (U.S.) blood supply and created public awareness, the U.S. is not effectively managing its blood supply. In many institutions, elective surgeries have been cancelled due to blood shortages. In addition, the U.S. is not prepared to handle a large scale medical emergency that would require significant blood use. Concerns about the blood supply In the U.S. 26.5 million units of blood are collected every year. A portion of these units is discarded after testing, resulting in the annual need for 27 million units not being met. The current cost of acquiring and administratively processing blood and blood products ranges from $337 to $658 a unit. A hospital, such as Pennsylvania Hospital which has 515 beds, spends almost $2.5 million a year on acquiring blood products, with the fully allocated cost being three times higher. As testing for pathogens (e.g., human immunodeficiency virus, West Nile virus, and prions) increases, blood cost will undoubtedly continue to increase. Each hospital is faced with the need to reduce blood use in order to manage costs and to ensure that a sufficient supply is available in order to continue to perform the same number of surgical procedures. Beyond cost and supply issues, an important medical question is increasingly being raised. Are transfusions beneficial? Leaders in the field now believe that transfusions should be considered as organ transplantations, which can lead to immunosuppression, inflammatory responses, volume overload, and consequently increased risk of organ failure, stroke, cardiovascular complications, pulmonary dysfunction, and mortality.1,–3 Short term transfusion reactions, such as allergic reactions, and long term transfusion reactions, such as infectious disease transmission or graft versus host disease, can also occur. In addition to the intrinsic risks associated with blood transfusion, the 1999 Institute of Medicine report revealed that transfusion errors are considerable. Many of these errors (56%) occur outside hospital blood banks. These mistakes include problems in patient identification (37% of errors), testing (18%), and phlebotomy (13%). Not only do these errors impact patient health, but they also have cost and liability implications for the hospital. Implementation of blood conservation programs Blood conservation programs have been successfully implemented in a number of U.S. hospitals. These programs offer a solution to the multiple problems that surround blood use. In order for surgery without transfusion to be successful, multiple alternative techniques need to be incorporated into procedure protocols.4 They can include redefining transfusion triggers by increasing anemia tolerance; performing autologous blood donations; refining surgical and anesthetic techniques; optimizing preoperative hemoglobin, erythropoietin, and iron; and using normothermic hemodilution, oxygen therapeutics/blood substitutes, acute normovolemic hemodilution, cell salvage, anticoagulants, pharmacologic agents that reduce bleeding (such as aprotinin, lysine analogs, and desmopressin), surface thrombotic agents, platelet gels, starches, and fibrin glue. Many of these techniques and agents have been shown to reduce the number of blood units needed (Table 11).4 As a result of these programs, several studies have shown that reductions in transfusion rates do not correlate with increased rates of negative outcomes and are associated with significant reductions in cost (Figure 11).5,–8 In 1999, an effort to reduce transfusion rates during cardiac surgery was instituted at the Virginia Commonwealth University Hospital System using an eight-point program.5,–7 A change in the transfusion trigger from a hemoglobin level to a physiologically demonstratable oxygen delivery debt was the largest paradigm shift introduced in the new approaches. Transfusion rates dropped from 81.5% to 18.5% and the mean number of units transfused from 4.8 to 3.1. Patient outcome adverse events were not increased and renal failure, respiratory failure, and death were significantly reduced. Cost savings estimated using published financial data and models of adverse outcomes9,10 were approximately $300,000 for 500 patients per year (Figure 11). Once personnel costs and avoided adverse event costs were included, savings reached over $2 million for 500 patients per year.5,–7 In another study, use of aprotinin, an agent that reduces bleeding and the need for blood transfusion during cardiac surgery, was evaluated in a cost modeling analysis.11,12 With aprotinin use, redo coronary artery bypass surgery costs were approximately $2,000 less than without aprotinin use.12 In addition, aprotinin reduced the rates of reexploration for bleeding,13,14 which run $10,000–$20,000, and the number of patients exposed to blood by 24–40%.12 Aprotinin use was also associated with a reduced incidence of stroke12,14,15 which may cost $10,000–$40,000 per patient. From a practical perspective, such a profound change in approach can be implemented by creating a bloodless surgery program in a restricted patient population such as Jehovah’s Witnesses. A bloodless surgery program was created in 1998 at Pennsylvania Hospital. In addition to increasing the hospital’s patient base and lowering blood costs, an environment was created in which surgeons, nurses, and anesthesiologists became comfortable with the new philosophies and techniques involved in bloodless surgery. These techniques, which were used in stem cell transplantation, open heart surgery, urologic surgery, and orthopedic surgery, are now being safely applied to patients other than Jehovah’s Witnesses. The cost of the medical procedures without transfusions was analyzed by comparing 262 patients in the center for bloodless medicine with patients outside the center. Surgeries were 16% less expensive if blood was not used and on a net margin basis were 17% less expensive due to decreased lengths of stay.16 Convincing the hospital CEO and medical staff The implementation of more effective blood supply management implies a fundamental change in an institution’s cultural approach to the need for transfusion of blood and blood products. Such changes will be facilitated if the hospital CEO and the medical staff fully endorse the paradigm shift. To become an advocate of the program the CEO will want to understand the potential positive impact of transfusion reductions on patient safety, patient satisfaction, cost, liability risk due to blood processing errors, hospital self-sufficiency, and long term control over rising costs. In addition, the CEO will want to be able to answer questions such as: Is blood conservation, as an organizational strategy, worth the change and political capital? Do we have the proper case mix and volume for it to be worthwhile? Does a fiscal outcome analysis prove promising? What is the return on investment? Will physicians be willing to adopt new skills? Can we monitor patient outcomes to assess overall quality improvement and cost reductions? The CEO will also have to be sensitive to departmental budget considerations. A blood conservation program will increase costs in some departments while decreasing them in others. For example, although the cost of using aprotinin is incurred by the pharmacy department, the cost benefit related to decreased lengths of stay, rates of reexploration due to bleeding, and blood bank costs will not be gained by the pharmacy department. Since changes in medical practice suggested by CEOs are generally poorly received, a physician champion will need to lead the effort among the hospital medical staff. This physician should expect to engage in a rigorous medical debate in order to acquire support. To overcome the deeply engrained impulse to perform transfusions, a profound questioning of the benefits of transfusion will most likely have to take place. If the ultimate intent of transfusions is to increase oxygen carrying capacity, then does stored allogeneic blood achieve that? When do patients benefit from a transfusion? When are outcomes worsened? What is the safest transfusion trigger? Should oxygen deficit be a trigger? Are our assumptions about transfusions correct? Finally, for a program to be successful it will require a team effort. The support of the whole medical staff, including nurses, pharmacists, and residents, will need to be acquired. Conclusion The reasons to establish blood conservation programs in hospitals are many and include: 1) the need to address concerns about blood safety and blood shortages, 2) the need to reduce direct and indirect costs associated with transfusions and to increase hospital revenues, 3) the ongoing need to improve clinical outcomes, and 4) the need to stay up to date with developing approaches to medicine such as multimodality use of techniques, devices, and pharmacologic agents that reduce bleeding. In hospitals in which a strong commitment of the medical staff and the administrators to blood reduction exists, such programs have been successfully implemented. Table 1. Approximate contributions of selected modalities of blood conservation in the surgical patient. Adapted with permission from reference 4. Options Number of units of blood Preoperative     Tolerance of anemia (reduce transfusion trigger) 1–2     Increase preoperative red blood cell mass 2     Preoperative autologous donation 1–2 Intraoperative     Meticulous hemostasis and operative technique 1 or more     Acute normovolemic hemodilution 1–2     Blood salvage 1 or more Postoperative     Restricted phlebotomy 1     Blood salvage 1 Options Number of units of blood Preoperative     Tolerance of anemia (reduce transfusion trigger) 1–2     Increase preoperative red blood cell mass 2     Preoperative autologous donation 1–2 Intraoperative     Meticulous hemostasis and operative technique 1 or more     Acute normovolemic hemodilution 1–2     Blood salvage 1 or more Postoperative     Restricted phlebotomy 1     Blood salvage 1 Table 1. Approximate contributions of selected modalities of blood conservation in the surgical patient. Adapted with permission from reference 4. Options Number of units of blood Preoperative     Tolerance of anemia (reduce transfusion trigger) 1–2     Increase preoperative red blood cell mass 2     Preoperative autologous donation 1–2 Intraoperative     Meticulous hemostasis and operative technique 1 or more     Acute normovolemic hemodilution 1–2     Blood salvage 1 or more Postoperative     Restricted phlebotomy 1     Blood salvage 1 Options Number of units of blood Preoperative     Tolerance of anemia (reduce transfusion trigger) 1–2     Increase preoperative red blood cell mass 2     Preoperative autologous donation 1–2 Intraoperative     Meticulous hemostasis and operative technique 1 or more     Acute normovolemic hemodilution 1–2     Blood salvage 1 or more Postoperative     Restricted phlebotomy 1     Blood salvage 1 Figure 1. Open in new tabDownload slide Blood costs encountered in cardiac patients before and after the implementation of a bloodless surgery program. Median costs based on 500 patients per year. Adapted with permission from reference 5. Figure 1. Open in new tabDownload slide Blood costs encountered in cardiac patients before and after the implementation of a bloodless surgery program. Median costs based on 500 patients per year. Adapted with permission from reference 5. Based on the proceedings of a symposium held December 6, 2004, during the ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation. Mr. Morgan received an honorarium for writing this article. References 1 Spiess BD, Royston D, Levy JH et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion . 2004 ; 44 (8): 1143 –8. Crossref Search ADS PubMed 2 Bucerius J, Gummert JF, Borger MA et al. Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg . 2003 ; 75 (2): 472 –8. Crossref Search ADS PubMed 3 Blumberg N. Allogeneic transfusion and infection: economic and clinical implications. Semin Hematol . 1997 ; 34 (3 Suppl 2): 34 –40. 4 Goodnough LT, Shander A, Spence R. Bloodless medicine: clinical care without allogeneic blood transfusion. Transfusion . 2003 ; 43 (5): 668 –76. Crossref Search ADS PubMed 5 Green JA, Reynolds PS, Makhoul K et al. Potential financial savings of a bloodless cardiac surgery initiative. Anesth Analg . 2003 ; 96 : 17 . 6 Green JA, Reynolds PS, Makhoul K et al. Evaluating the transfusion effects on outcome for patients undergoing primary coronary artery bypass grafting. Anesth Analg . 2003 ; 96 : 16 . 7 Green JA, Spiess BD, Reynolds PS et al. Evaluation of a bloodless cardiac surgery protocol for patients undergoing primary coronary artery bypass grafting. Anesth Analg . 2003 ; 96 : 46 . PubMed 8 Higgins R, DeAnda A, Kasirajan V et al. Challenging the transfusion trigger in cardiac surgery: impact on resource utilization, transfusion rates and outcomes. Circulation . 2002 ; 106 (15): 37 . 9 Etchason J, Petz L, Keeler E et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med . 1995 ; 332 (11): 719 –24. Crossref Search ADS PubMed 10 Sonnenberg FA, Gregory P, Yomtovian R et al. The cost-effectiveness of autologous transfusion revisited: implications of an increased risk of bacterial infection with allogeneic transfusion. Transfusion . 1999 ; 39 (8): 808 –17. Crossref Search ADS PubMed 11 Trasylol® (aprotinin injection) package insert. West Haven, CT: Bayer Pharmaceuticals Corporation; 2003 Dec. 12 Smith PK, Datta SK, Muhlbaier LH et al. Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials. Ann Thorac Surg . 2004 ; 77 (2): 635 –42. Crossref Search ADS PubMed 13 Lemmer JH, Jr., Dilling EW, Morton JR et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg . 1996 ; 62 (6): 1659 –67. Crossref Search ADS PubMed 14 Levy JH, Pifarre R, Schaff HV et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation . 1995 ; 92 (8): 2236 –44. Crossref Search ADS PubMed 15 Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg . 2004 ; 128 (3): 442 –8. Crossref Search ADS PubMed 16 Ford P, Mastoris J, Badani K et al. Profitability of medical procedures without the use of transfusion support. Blood . 2004 ; 104 (11): 5316 . Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/62.18_Supplement_4.S24pmid: N/A

Learning objectives After studying these articles, the reader should be able to Explain how to improve clinical outcomes in coronary artery bypass graft (CABG) surgery. Describe the systemic inflammatory response to CABG surgery. Summarize clinical efficacy and safety of pharmacologic strategies for blood conservation. Describe applications of serine protease inhibition in CABG. Explain how to measure and stop hidden costs of CABG surgery. Self-assessment questions For each question there is only one best answer. Aprotinin was found to be associated with Increased mortality. Increased myocardial infarction. Reduced blood transfusions. Increased stroke risk. Aprotinin was found to be associated with increased renal failure risk. True. False. Aprotinin was shown to be associated with a trend toward a reduced incidence of atrial fibrillation. True. False. Treatment with aprotinin during coronary artery bypass graft surgery should be considered as a way to attenuate Bleeding. Systemic inflammatory responses. Vasoconstriction. Alternatives a and b are both correct. Bradykinin mediates tissue edema by Increasing neutrophil activation. Decreasing capillary membrane permeability. Increasing capillary membrane permeability. Inhibiting plasma proteins. Aprotinin affects activation and activity of neutrophils. True. False. The need for pharmacologic approaches to reducing bleeding is likely to increase due to an increase in patients who are Female. Older. Higher risk. Alternatives b and c are both correct. A full dose of aprotinin causes aprotinin plasma concentrations to reach about how many μmol? 1. 2. 3. 4. Aprotinin has been demonstrated to be safe and well tolerated. True. False. Which of the following is true of contact activation? It occurs about an hour after the first contact with the scalpel during CABG surgery. It leads to the conversion of prothrombin to thrombin. It leads to the conversion of plasmin to plasminogen. It causes decreased levels of bradykinin. Aprotinin has a black box warning regarding the risk of hypersensitivity reaction to bovine protein. True. False. Which of the following is true of the administration of aprotinin? The primary half-life, which corresponds to its functional half-life, is approximately 3 hours. The terminal elimination half-life is between 8 and 10 hours. It should be administered intravenously through a central line that is used only for aprotinin. Less than 5% is excreted as active drug. Programs to reduce transfusion rates have been correlated with increased incidence of negative outcomes. True. False. Optimizing preoperative hemoglobin, erythropoietin, and iron has been shown to reduce the number of blood units needed. True. False. A factor in contributing to the rising cost of blood is the increased need to test for pathogens. True. False. AJHP continuing education AJHP CE process The continuing-education (CE) test for this supplement can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service. To view the list of available AJHP CE articles, go to www.ashp.org/ce-selfstudy/ajhp-ce.cfm. Supplement: Advancing patient safety and improving coronary artery bypass graft outcomes ACPE #: 204-000-05-006-H01 CE credit: 3.0 hours (0.3 CEUs) Expiration date: September 15, 2008 Instructions ASHP members may go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” type in ASHP ID and password, and then select the supplement for which CE credit is desired. AJHP CE is free to members. Nonmembers must go to the ASHP Shopping Cart (www.ashp.org/products-services), select “Browse Online Catalog,” select “Products” in the navigation bar, and select “Continuing Education.” The fee for non-ASHP members is $30.95 per test. Questions? Call ASHP Customer Service at 866-279-0681 (toll free) or 011-734-556-4536 (international callers). The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Copyright © 2005. American Society of Health-System Pharmacists, Inc. All rights reserved.

Hess, Philip, J.

doi: 10.2146/ajhp050302pmid: 16227195

Abstract Purpose. Several aspects of the systemic inflammatory response to coronary artery bypass graft surgery are described. Summary. The inflammatory response is a fundamental biological protective mechanism that gathers together the body’s cellular and chemical defense mechanisms at the local site of tissue injury. The systemic inflammatory response syndrome refers to a systemic, whole body, non-localized response. This response, which occurs to some degree in most patients undergoing coronary artery bypass graft surgery, has the potential to affect all tissues and vital organs. When blood interacts with the cardiopulmonary bypass machine, several cellular and humoral pathways are activated including the complement system, the coagulation system, and the fibrinolytic system. These, in turn, activate inflammatory response cells, such as leukocytes and platelets. Together these molecular pathways and activated cells mediate the frequently observed clinical sequelae such as edema, tissue and organ damage, and hyperfibrinolysis. In order for a molecule drug to attenuate effectively this response, it would need to have a broad enough spectrum of activity to inhibit multiple pathways and to limit their cross-amplification. Aprotinin, a nonspecific serine protease, is an important attenuator of this response as it inhibits several important serine proteases, including kallikrein, plasmin, thrombin, and elastase, which are involved in fibrinolysis and cell transmigration and degranulation into soft tissues. Conclusion. Treatment with aprotinin during coronary artery bypass graft surgery should be considered as a way to attenuate bleeding and systemic inflammatory responses. Aprotinin, Coronary artery bypass, Hemostatics, Mechanism of action The systemic inflammatory response that occurs, to some degree, in most patients undergoing coronary artery bypass graft surgery is typically characterized by pathological hypotension, fever of non-infectious origin, disseminated intravascular coagulation, diffuse tissue edema and damage, and multi-organ failure. It is a generalized response to several events including ischemia reperfusion, surgical trauma, and blood contact with the artificial surfaces of the cardiopulmonary bypass (CPB) circuit. When blood cells interact with plastic or metal surfaces, several pathways are activated including the complement system, the coagulation system, and the fibrinolytic system. These, in turn, activate inflammatory response cells such as leukocytes and platelets.1 In a first step, in response to contact activation, thrombin, plasmin, and kallikrein are generated. Kallikrein leads to the formation of kinins, such as bradykinin, and to the activation of the complement system and white blood cells. Thrombin activates the coagulation system and plasmin activates the fibrinolytic system. Subsequently, cytokines are generated and adhesion molecules on inflammatory cells are upregulated.1 To attenuate these cascades effectively, a molecule or drug would need to have a broad spectrum of activity. It would also need to act as close to the top of the cascades as possible in order to impact the multiple feedback loops that amplify the systemic inflammatory response. Bradykinin Bradykinin is of particular interest because it mediates tissue edema by increasing capillary membrane permeability and by stimulating plasma proteins, such as tissue plasminogen activator from peripheral vascular endothelia.1 Bradykinin is primarily metabolized and inactivated in the pulmonary vascular endothelium by angiotensin converting enzyme. Normally, approximately 80% of bradykinin is metabolized on the first pass through the lungs. During bypass, a significant rise in kallikrein leads to the formation of bradykinin; however, as the bypass circuit removes the lungs from the circulation, the primary site of metabolism of bradykinin is lost. Clinically, elevated bradykinin levels are known to lead to a drop in systemic vascular resistance (SVR) and cardiac output, sequestration of fluid in tissues (third spacing), and bleeding due to increased fibrinolysis. The CPB-associated spike in bradykinin and the accompanying small decrease in blood pressure are described in Figure 11.2 Third spacing, or tissue edema, is believed to cause tissue damage. Brain tissue edema, which correlates with rises in bradykinin activity, is characterized by a loss of normal architecture due to swelling.3,–5 Neurologic injuries, which often impair basic day to day functioning of patients after coronary artery bypass graft surgery, are believed to be, at least in part, attributable to edema.4,5 Aprotinin, a small molecule drug that inhibits serine protease activity, attenuates the elevation of bradykinin levels during CPB by inhibiting kallikrein, which cleaves high molecular weight kininogen to bradykinin.6,7 Aprotinin also leads to a smaller drop in SVR and to a decrease in capillary fluid leak and fibrinolysis.6 The reduction in fibrinolysis-related bleeding is not only due to the inhibition of bradykinin formation, but also to the direct inhibition of plasmin by aprotinin. White blood bells White blood cells are another essential player in the systemic inflammatory response. Neutrophil activation is mediated by kallikrein, plasmin, factor XIIa, the complement system, and various pro-inflammatory cytokines, such as tumor necrosis factor and interleukin-1. Once activated, neutrophils up-regulate cell-surface glycoproteins such as L-selectin and integrins that lead to adhesion and rolling along endothelial cells. Neutrophils transmigrate into soft tissues where they degranulate releasing peroxidases, proinflammatory cytokines, elastases, myeloperoxidases, cathepsin B, free radicals, arachidonic acid metabolites, and platelet activating factor, all of which cause damage to soft tissues. Aprotinin directly affects neutrophils by inhibiting their activation and their activity. Activation is reduced by the inhibition of pathways related to kallikrein, factor XIIa, plasmin activation, and complement.8 Transmigration is reduced by the inhibition of integrin expression. Intravital microscopy has been used to film and quantify differences in rates of the transmigration of neutrophils through mesenteric endothelium into surrounding tissue. Fewer neutrophils transmigrate in the presence of aprotinin than in the presence of control.9 The release of cytotoxic enzymes and substances such as elastase, tumor necrosis factor-α, free radicals, and platelet activating factor is also attenuated.8,10,–12 Thus, as the reduction of transmigration suggests less tissue damage, aprotinin treatment may impact clinical response. Platelets Platelet function significantly affects overall morbidity and mortality associated with CPB outcomes. Platelet dysfunction can lead to excess bleeding which is often treated with platelet transfusions. However, evidence is starting to suggest that platelet transfusions are associated with negative outcomes including an increased risk of stroke.13 The overall morphology of active, normally functioning platelets is very important. Platelet activation undergoes four phases. First, platelet shape changes from flat to spherical with glycoprotein extensions from the cell surface. Adhesion is then mediated by the expression of glycoprotein Ib, and is followed by aggregation via glycoproteins IIb/IIIa. Lastly, platelets secrete attractants and platelet factor. The changes in platelet morphology that occur during CPB have been documented using electron microscopy. By the end of bypass, platelet morphology is abnormal; surface glycoproteins have been sheared off by the bypass pump and platelets have lost their spiny morphology. By contrast, with aprotinin treatment, morphology is maintained.14 Thus, data suggest that aprotinin preserves platelet function from the nefarious effects of CPB by protecting glycoprotein receptors, specifically the IIb and IIIa receptors. Platelets have multiple receptors on their surfaces, including receptors that are responsible for hemostasis at the site of tissue injury and receptors that are expressed when platelets are activated. The adenosine diphosphate and adrenaline receptors mediate hemostasis and platelet aggregation at the site of injury through glycoproteins IIb/IIIa. They are protease independent receptors that are not affected by aprotinin treatment. The protease activated receptor-1 is mainly activated by thrombin. When excess thrombin is produced in response to the CPB machine, platelets can become dysfunctional due to exhaustion of the protease activated receptor-1. Aprotinin is believed to inhibit thrombin binding to protease activated receptor-1. Therefore, treatment with aprotinin reduces activation of platelets through protease activated receptor-1 without affecting the hemostatic pathways mediated by adenosine diphosphate and adrenaline. These effects were illustrated through microaggregation experiments using platelets from healthy volunteers. Aprotinin was able to reduce thrombin and trypsin mediated aggregation, but not adrenaline and adenosine diphosphate mediated activation (Figure 22).15 Conclusion Since the systemic inflammatory response is a complex system of interrelated pathways, the broad spectrum of inhibition of serine proteases gives aprotinin the unique ability to simultaneously inhibit several pathways and to limit cross-amplification. Thus, patient treatment with aprotinin during coronary artery bypass graft surgery should be considered as a way to attenuate bleeding and systemic inflammatory responses. Figure 1. Open in new tabDownload slide Effect of cardiopulmonary bypass on bradykinin levels and mean arterial pressure (MAP). MAP and plasma bradykinin levels were measured in 21 patients undergoing CPB in basal conditions (basal), before CPB after the surgical procedure of connection (before CPB), after 15 min of CPB (CPB 15 min), at the end of CPB, at the end of the operation, and 24 hr later (recovery). Results are expressed as means. CPB = cardiopulmonary bypass. Reprinted with permission from reference 2. Figure 1. Open in new tabDownload slide Effect of cardiopulmonary bypass on bradykinin levels and mean arterial pressure (MAP). MAP and plasma bradykinin levels were measured in 21 patients undergoing CPB in basal conditions (basal), before CPB after the surgical procedure of connection (before CPB), after 15 min of CPB (CPB 15 min), at the end of CPB, at the end of the operation, and 24 hr later (recovery). Results are expressed as means. CPB = cardiopulmonary bypass. Reprinted with permission from reference 2. Figure 2. Open in new tabDownload slide Specific inhibition by aprotinin of thrombin- and trypsin-induced microaggregation in whole blood. The effect of aprotinin (160 KIU/ml) on microaggregation in whole blood was studied in response to the proteolysis-dependent agonists thrombin (1 nmol/l) and trypsin (1 μmol/l) and proteolysis-independent agonists epinephrine (adrenaline, 2.5 μmol/l) and adenosine diphosphate (2 μmol/l). Results are expressed as the mean ± SD percentage microaggregation from n = 8–14 for each experimental condition. Reprinted with permission from reference 15. Figure 2. Open in new tabDownload slide Specific inhibition by aprotinin of thrombin- and trypsin-induced microaggregation in whole blood. The effect of aprotinin (160 KIU/ml) on microaggregation in whole blood was studied in response to the proteolysis-dependent agonists thrombin (1 nmol/l) and trypsin (1 μmol/l) and proteolysis-independent agonists epinephrine (adrenaline, 2.5 μmol/l) and adenosine diphosphate (2 μmol/l). Results are expressed as the mean ± SD percentage microaggregation from n = 8–14 for each experimental condition. Reprinted with permission from reference 15. Based on the proceedings of a symposium held December 6, 2004, during the ASHP Midyear Clinical Meeting, Orlando, FL, and supported by an unrestricted educational grant from Bayer Pharmaceuticals Corporation. Dr. Hess received an honorarium for participating in the symposium and writing this article. References 1 Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg . 2001 ; 71 (2): 745 –54. Crossref Search ADS PubMed 2 Cugno M, Nussberger J, Biglioli P et al. 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