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Current Antifibrinolytic Therapy for Coronary Artery Revascularization Jason Trudell, CRNA, MSN Nicholas McMurdy, CRNA, MSN The use of antifibrinolytic therapy is commonplace in coronary artery revascularization procedures. Cardiac surgery accounts for more than 700,000 surgeries per year, with approximately 70% of these cases requiring antifibrinolytic therapy for coronary artery bypass graft (CABG) procedures. Two main classes of antifibrinolytics are used in CABG procedures: synthetic lysine analogues and serine protease inhibitors. Both classes of antifibrinolytics have been shown to decrease the inci- dence of blood transfusions. However, new data have emerged regarding an increase in adverse outcomes associated with serine protease inhibitors.The purpose of this review article is to describe the clinical significance of antifibrinolytic therapy and the current implications associated with its use. ardiovascular disease is one of the greatest health concerns facing the nation’s healthcare system. More than 17 million US citizens have some degree of cardiac disease. The majority of patients, upwards of 11 million, have coronary artery disease, 5 million have valvular heart disease, and 1 million have congenital heart disease.1 The most common cause of death in adults is related to coronary heart disease.2 Healthcare expenditures for cardiovascular disease are second to none in the United States. In 1995, healthcare expenditures related to cardiovascular disorders totaled $127.8 billion, or roughly 18% of all individual health expenditures.3 Of the roughly 72 million surgical procedures performed each year, 700,000 are primary cardiac procedures, and the vast majority of the cardiac surgeries, roughly 500,000, are coronary artery bypass graft (CABG) revascularization.2 In 2003, an estimated 1,244,000 inpatient angioplasty procedures, 467,000 inpatient bypass procedures, 1,414,000 inpatient diagnostic cardiac catheterizations, 64,000 inpatient implantable defibrillators, and 197,000 inpatient pacemaker procedures were performed in the United States.4 The use of interventional cardiology and, more specifically, percutaneous coronary intervention (formally referred to as percutaneous transluminal coronary angioplasty, or PTCA) demonstrated a dramatic increase of 326% from 1987 to 2003.4 Platelet dysfunction is the most prevalent cause of hemostatic abnormalities after cardiopulmonary bypass (CPB), with the duration of on-pump bypass time having the most detrimental effect on platelet function.3,5,6 Hemodilution, consumption of coagulation factors, and degradation of coagulation factors by microvascular coagulation cause the deficiencies in blood coagulation seen after CPB. The initiation of extracorporeal circulation elicits a microvascular activation of the factor XII in- trinsic pathway of coagulation despite heparin therapy.5 The body’s own fibrinolysis further exacerbates platelet dysfunction during CPB.5 Fibrinolysis is primarily or secondarily mediated during coronary artery revascularization. Primary fibrinolysis occurs via the release of endothelial plasminogen activators.6,7 Secondary fibrinolysis occurs as a result of the intrinsic homeostasis feedback loop in response to fibrin formation. The resultant circulating plasmin degradation products negatively affect platelet function.8 The initiation of bleeding prophylaxis in CPB should be discussed with the cardiovascular surgeon before heparinization and initiation of extracorporeal circulation in patients undergoing coronary artery revascularization and valvular replacement. Antifibrinolytic agents such as epsilon-aminocaproic acid (EACA), tranexamic acid (TXA), and aprotinin are benchmark standards in onpump coronary artery revascularization.8 Antifibrinolytics have demonstrated benefits in regard to blood conservation, platelet preservation, and thrombi formation.5,6,8-11 The different mechanisms of action, side effects, and overall concerns for anesthesia providers when administering antifibrinolytics will be reviewed. C www.aana.com/aanajournal.aspx Keywords: Antifibrinolytics, aprotinin, cardiac bypass, hemostasis, transfusion. Review of the Literature A literature review was conducted using MEDLINE and the Cumulative Index to Nursing and Allied health Literature, or CINAHL. Search criteria included articles and texts published from 1990 to the present. Potential information sources were identified, and references were located and screened for significance to antifibrinolytic therapy and anesthesia caregivers. The articles and texts were included if they met the following specific inclusion criteria: (1) contained current information about antifibrinolytic therapy, (2) were published in a professional AANA Journal April 2008 Vol. 76, No. 2 121 medical or nursing journal and/or text, and (3) discussed coronary artery revascularization procedures or explained the action of antifibrinolytic agents. Lysine Analogues EACA and TXA are synthetic lysine analogues. EACA is a synthetic chemical analog of the amino acid lysine.5,6 It acts by binding to the lysine-binding sites of plasminogen and plasmin. Once bound, EACA displaces plasminogen from fibrin, resulting in inhibition of the natural tendency of plasminogen to split fibrinogen.8 A secondary proposed action of EACA is the ability to bind to fibrin and protect it from plasmin degradation. The mechanism of action of TXA is identical to that of EACA; however, it is roughly 10 times more potent per unit dose than EACA.5 In addition, EACA and TXA inhibit the transformation of plasminogen to plasmin by clot-bound tissue plasminogen activator (tPA) vs circulating tPA. Consequently, TXA and EACA may not be as effective as a serine protease inhibitor in preventing systemic fibrinolysis when elevated levels of tPA elicit a systemic increase in circulating plasmin and, eventually, increased bleeding times associated with elevated fibrinogen degradation products.5,8 Several studies have evaluated the clinical implications associated with EACA and TXA in reducing blood loss during and after cardiac surgery. These studies showed that TXA and EACA can reduce blood loss after cardiac surgery.6-8,10,12-14 EACA and TXA have been extensively studied and shown to have an excellent safety margin in cardiac procedures with fewer than 1% of cases demonstrating potential complications.5,6,8 Severe complications associated with synthetic lysine analogues administration include seizures, renal failure, and rhabdomyolysis.8,9,12 Serine Protease Inhibitor The mechanism of action of aprotinin differs from the previously discussed lysine analogues. As a nonspecific serine protease enzyme inhibitor, aprotinin helps modulate the systemic inflammatory response associated with CPB through its effects on kallikrein and plasmin inhibition. Inhibiting plasmin preserves the insoluble clot. Kallikrein serves an important role in accelerating the systemic inflammatory response. Kallikrein accelerates factor XII formation, initiates complement systems, and promotes fibrinolysis and renin formation.15 It also promotes bradykinin release, which increases vascular permeability and tPA formation.15 Aprotinin is associated with preventing fibrin degradation by inhibiting plasmin and kallikrein formation. Fibrin degradation products (FDP) have a high affinity for platelets, making them nonfunctional.16 The FDPs also increase the release and synthesis of monocytemacrophage–derived interleukins 1 and 6, which induce further endothelial and end-organ damage.16 Finally, 122 AANA Journal April 2008 Vol. 76, No. 2 FDPs weaken the ability of factor XIII to form a strong fibrin clot.16 By preventing kallikrein and plasmin activation and decreasing FDPs, aprotinin assists with blood preservation during CPB. In a thorough meta-analysis of aprotinin, large and small doses decreased the proportion of patients undergoing cardiac surgery patients who required blood products.7 In addition to blood conservation, aprotinin preserves platelet function. Although the direct mechanism of action of platelet preservation is unknown, a potential explanation is that aprotinin selectively protects platelets from desensitization that occurs throughout extracorporeal circulation time.17 This desensitization would decrease the degranulation and consumption of platelets that occurs with thrombin formation. van Oeveren et al18 reported that the preservation of glycoprotein 1b occurred with aprotinin use. Glycoprotein 1b assists with platelet adhesion to vascular endothelium. Proponents of aprotinin also cite neutrophil activation and reduction of atrial fibrillation as additional benefits.17,19 An increase in anaphylactic and anaphylactoid reactions has been reported with aprotinin.20 Despite decreasing blood product use, institutions may choose other options owing to immunogenicity, the higher cost, and other possible side effects associated with its use. Comparison of Lysine Analogues and Serine Protease Inhibitors Meta-analyses comparing EACA, TXA, and aprotinin concluded that all 3 agents, when used in conjunction with extracorporeal circulation, reduced blood loss and additional use of allogeneic blood products.19-21 Aprotinin is an expensive drug, and its immunogenicity, which can potentially cause an allergic response with reexposure, has led to the comparison, in multiple studies, of the cheaper lysine-analog antifibrinolytic drugs for efficacy.22-29 It is important to note that these studies had limited size, were often not blinded clinical trials, and did not incorporate redo surgical procedures. The mean ± SD costs for pharmacological and transfusional treatments were significantly lower for TXA ($58.10 ± $105.10) vs EACA ($100.70 ± $158.60) vs aprotinin ($432.60 ± $118.70).13 An additional prospective randomized, partially blinded study compared the costs of lysine analogues and serine protease inhibitors with the cost of allogeneic blood requirements.30 The study concluded that TXA was less costly than aprotinin and achieved a comparable benefit. These results are similar to those previously published comparing aprotinin with EACA and TXA.29 The cost-effective advantage of the lysine analogues with similar end results has led to their use at many institutions. Perhaps the most conclusive literature that promotes use of lysine analogues over aprotinin is a recent article that reported an association of aprotinin with renal toxic effects and ischemic events in patients undergoing CABG www.aana.com/aanajournal.aspx surgery.23 Among patients undergoing complex coronaryartery surgery, the use of aprotinin was associated with a 2-fold increase in renal failure requiring dialysis a 55% increase in myocardial infarction or heart failure, and a 181% increase in stroke or encephalopathy.23 The study, which included 4,373 patients undergoing coronary revascularization, at more than 69 hospitals, concluded that neither EACA nor TXA was associated with an increase risk in renal, cerebral, or cardiac events. The study used statistical procedures to adjust for the known differences between the treatment groups. The descriptive observational study does not demonstrate cause and effect and did not randomly assign patients to aprotinin, TXA, EACA, or no medical intervention groups. The patients had imbalances in baseline characteristics, and patients treated with aprotinin had a higher propensity for multiple morbidities than did patients receiving different antifibrinolytic therapy.23 To adjust for these imbalances, complex statistical methods involving propensity scores was used. Despite the complexity adjustment, aprotinin, in low and high doses, showed an increase in morbidity and mortality.23 Although all 3 agents decreased blood loss, the propensity of end-organ damage, specifically the kidney, heart, and brain, was associated only with aprotinin. Aprotinin was associated with adverse outcomes in another observational study of 898 patients, half of whom were treated with aprotinin and the other half with TXA, undergoing CABG with CPB. Baseline characteristics among participants were similar.30 Although the rates of adverse events were similar between groups, there was a noticeable rate of renal dysfunction in the aprotinin group, especially in patients with preexisting renal dysfunction.30 Allogeneic blood transfusion requirements were similar for both groups.30 The US Food and Drug Administration (FDA) issued an alert in relation to the recently published reports of serious renal and cardiovascular toxic effects following aprotinin administration to patients undergoing CABG surgery.30 On September 27, 2006, Bayer Pharmaceuticals told the Food and Drug Administration that it had conducted an additional safety study of aprotinin. The preliminary findings from this new observational study of patients from a hospital database showed that use of aprotinin may increase the chance of death, serious kidney damage, congestive heart failure, and stroke. The worldwide study funded by Bayer, the maker of aprotinin, supported the data from the 2 previous observational studies.31 When using aprotinin, providers should carefully monitor the occurrence of toxic effects, in particular focusing on the kidneys, heart, and brain.30 Aprotinin should be used only when blood conservation clearly outweighs the potential side effects.30 There are ongoing studies evaluating the risks and benefits of aprotinin, and additional research is needed to determine its future use in antifibrinolytic therapy. www.aana.com/aanajournal.aspx Conclusion There are 2 main pharmacologic options for antifibrinolytic therapy for patients undergoing CPB. Lysine analogues and serine protease inhibitors have been shown to decrease the allogeneic blood transfusion requirements that are customary with extracorporeal circulation. Anesthetists need to understand the pharmacokinetics and pharmacodynamics of each class of drug. Despite the blood-salvaging benefit of these drugs, they come with known risks. As new information is revealed about these classes of drugs, anesthesia providers should be aware of the risks associated with lysine analogues and serine protease inhibitors. As of November 5, 2007, Bayer Pharmaceuticals has suspended the marketing of aprotinin due to patient safety concerns. Initial results from a Canadian study suggest that patients administered aprotinin have a greater risk of death than patients taking other antifibrinolytic drugs. Sales of aprotinin have been suspended until the FDA can conduct further studies into the risks and benefits of the drug. The FDA and Bayer are working together to phase aprotinin out of the workplace and prevent potential shortages of other antifibrinolytics.33,34 REFERENCES 1. Mangano DT. Preoperative assessment of cardiac risk. Cardiac Anesthesia. 4th ed. Philadelphia, PA: WB Saunders; 1999:3. 2. National Institutes of Health. Disease Statistics, Fact Book, Fiscal Year 2000, National Heart, Lung, and Blood Institute. Bethesda, MD: National Institutes of Health; 2004. 3. Hensley F, Martin D, Gravlee G. Anesthetic management of myocardial revascularization. In: Hensley F, ed. A Practical Approach to Cardiac Anesthesia. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:274-279. 4. Thomas T, Haase N, Rosamond W, et al. Heart disease and stroke statistics: 2006 update. Circulation. 2006;113:e85-e151. http://circ.aha journals.org/cgi/content/full/113/6/e85. Accessed January 31, 2006. 5. Shore-Lesserson L, Gravlee G, Horrow J. Coagulation management during and after cardiopulmonary bypass. In: Hensley F, ed. A Practical Approach to Cardiac Anesthesia. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:490-512. 6. Attar S, Hammon JW. Pharmacologic agents in perioperative bleeding. In: Attar S, ed. Hemostasis in Cardiac Surgery. Armonk, NY: Futura Publishing Co; 1999:203-214. 7. 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A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 1995;9(3):240-244. Blauhut B, Harringer W, Bettelheim P, et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1994;108(6): 1083-1091. Mongan PD, Brown RS, Thwaites BK. Tranexamic acid and aprotinin reduce postoperative bleeding and transfusions during primary coronary revascularization. Anesth Analg. 1998;87(2):258-265. Nutall GA, Oliver GA, Ereth MH, et al. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Anesthesiology. 2000;92(3):674-682. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score casecontrolled comparison of aprotinin and tranexamic acid in hightransfusion-risk cardiac surgery. Transfusion. 2006;46(3):327-338. Food and Drug Administration website. Information for Healthcare Professionals. Aprotinin (marketed as Trasylol). http://www.fda.gov/ cder/drug/InfoSheets/HCP/aprotininHCP.htm. Accessed March 3, 2006. Food and Drug Administration website. FDA Public Health Advisory. http://www.fda.gov/cder/drug/advisory/aprotinin20060929. htm. Accessed October 29, 2006. Harris G. Heart surgery drug pulled from market. New York Times. November 6, 2007. http://query.nytimes.com/gst/fullpage.html?res= 9405E4D7123CF935A35752C1A9619C8B63. Accessed November 7, 2007. FDA requests marketing suspension of Trasylol. FDA News. November 5, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW 01738.html. Accessed November 7, 2007. AUTHORS* Jason Trudell, CRNA, MSN, is a nurse anesthetist for Anesthesia Group of Onodaga, PC, Syracuse, New York. Email: [email protected]. Nicholas McMurdy, CRNA, MSN, is a nurse anesthetist at Fairfax Anesthesia Associates, Inc, Fairfax, Virginia. * The authors were students at the University of Pittsburgh School of Nursing Nurse Anesthesia Program, Pittsburgh, Pennsylvania, when this article was written. www.aana.com/aanajournal.aspx