Efficacy and Safety of Aprotinin in Cardiac Surgery

ABSTRACT

Cardiac surgery and cardiopulmonary bypass produces bleeding and the need for allogenic blood product transfusions in many patients. Blood conservation is important in the perioperative management of patients. Aprotinin, a serine protease inhibitor isolated from bovine lung, is a complex protease inhibitor that is an antifibrinolytic, inhibits contact activation, and decreases the inflammatory response to cardiopulmonary bypass. Aprotinin reduces blood loss and transfusion requirements in adult and pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Full-dose aprotinin significantly reduces postoperative blood loss and has been demonstrated in multiple prospective blinded studies to be safe and effective. One of the major adverse effects is anaphylaxis that occurs on re-exposure to aprotinin.

Pharmacologic and other techniques to reduce bleeding and the need for transfused blood after cardiac surgery have been studied. Allogeneic blood products are in limited supply and costly, and pose potential short- and long-term transfusion risks. My early interest in blood conservation methods was related to potential risks of life-threatening hypersensitivity reactions including transfusion-related acute lung injury and anaphylactic reactions.¹ Aprotinin has been studied extensively and is the only Food and Drug Administration (FDA)-approved pharmacological treatment to reduce blood transfusion in coronary artery bypass grafting associated with cardiopulmonary bypass. Aprotinin is the only agent currently approved for such an indication and has been studied extensively in randomized, blinded, and placebo-controlled trials that have demonstrated its efficacy and safety. Other agents from smaller studies have been reported in the literature. This article focuses on the efficacy and safety of aprotinin in patients undergoing cardiac surgery.

Clinical Studies of Aprotinin

Aprotinin is a serine proteinase inhibitor that inhibits a broad spectrum of proteases including plasmin, trypsin, kallikrein, chymotrypsin, activated protein C, and thrombin. Approximately 45 studies involving 7000 patients have reported the efficacy of aprotinin.² The results of early reports suggesting that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to examine this outcome. In patients undergoing repeat coronary artery bypass grafting, Cosgrove et al³ reported that aprotinin was effective in decreasing blood loss and blood transfusion requirements. However, retrospective analysis of the data suggested a higher risk for myocardial infarction and graft closure that was not statistically significant.³

Despite the question regarding adequacy of anticoagulation, the study created safety concerns that were addressed in two additional prospective studies reported by Levy et al⁴ in patients undergoing repeat coronary artery bypass grafting, and by Alderman et al⁵ in patients undergoing primary coronary artery bypass grafting. In patients undergoing repeat coronary artery bypass grafting surgery, 287 patients were randomly assigned to receive high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in blood transfusion up to postoperative day 12. Red blood cell transfusions in the high- and low-dose aprotinin groups were reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin = 54%, low-dose aprotinin = 46%, pump-prime only = 72%, and placebo = 75%; P=.001). Units of donor red blood cells transfused were significantly lower in the patients treated with aprotinin compared with placebo (high-dose aprotinin, 1.6 ± 0.2 U; low-dose aprotinin = 1.6 ± 0.3 U, pump-prime-only = 2.5 ± 0.3 U, and placebo = 3.4 ± 0.5 U). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin = 2.2 ± 0.4 U, low-dose aprotinin = 3.4 ± 0.9 U, pump-prime-only = 5.1 ± 0.9 U, placebo = 10.3 ± 1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction.⁴

Any drug or blood product that decreases bleeding and transfusion requirements has the potential to affect graft patency. Bidstrup et al,⁶ Havel et al,⁷ and Lemmer et al⁸ found no significant difference in the patency of grafted vessels when examined postoperatively.

We reported a prospective study that evaluated the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass (IMAGE study). Patients from 13 international sites were randomized to receive aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated. In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% and requirement for red blood cell administration by 49%. Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of patients treated with aprotinin and 10.9% of patients receiving placebo (P=.03). After adjusting risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of previous aspirin therapy, small and poor distal vessel quality, and, possibly, use of aprotinin-treated blood as excised vein perfusate.

At sites in the United States, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P=.72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of patients treated with aprotinin and 12.4% of patients treated with placebo (P=.01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin = 2.9%, placebo = 3.8%) or mortality (aprotinin = 1.4%, placebo = 1.6%).

Studies in Children

Aprotinin consistently reduces blood loss and transfusion requirements in adults during and after cardiac surgical procedures, but its effectiveness in children is often debated. Miller et al⁹ evaluated the hemostatic and economic effects of aprotinin in children undergoing reoperative cardiac procedures with cardiopulmonary bypass. Control, low-dose aprotinin and high-dose aprotinin groups were established with 15 children per group. Platelet counts, fibrinogen levels, and thromboelastographic values at baseline and after protamine sulfate administration, number of blood product transfusions, and 6-hour and 24-hour chest tube drainage were used to evaluate the effects of aprotinin. Time needed for skin closure after protamine administration and lengths of stay in the intensive care unit and hospital were prospectively evaluated to determine the economic impact of aprotinin. The thromboelastographic variables indicated a preservation of platelet function by aprotinin. Decreased blood product transfusions, shortened skin closure times, and shortened durations of intensive care unit and hospital stays were found in the aprotinin groups — most significantly in the high-dose group with a subsequent average decrease of nearly $25,000 in patient charges.

Meta-Analysis

Because the results of previously reported small randomized clinical trials comparing epsilon aminocaproic acid with aprotinin were inconclusive, Munoz et al¹⁰ performed a meta-analysis to compare the relative effectiveness and adverse effect profile. The authors took information from 55 randomized clinical trials published between 1985 and 1998 involving the use of epsilon aminocaproic acid (n = 9) or aprotinin (n = 46) in patients undergoing cardiac surgery. The primary outcomes were total blood loss, red blood cell transfusion rates and amounts, re-exploration, stroke, myocardial infarction, and mortality. There were five times as many aprotinin studies as there were epsilon aminocaproic acid studies. Most of the epsilon aminocaproic acid studies involve primary coronary artery bypass grafting patients who do not bleed excessively.

The authors report identical reductions in total postoperative transfusions with epsilon aminocaproic acid (61% reduction versus placebo) and high-dose aprotinin (62% reduction versus placebo). In these studies, the data from the patients treated with aprotinin involve a series of repeat sternotomy and valvular surgeries compared to the small number of patients treated with epsilon aminocaproic acid undergoing primary coronary artery bypass grafting surgery. Although both drugs reduced rates of re-exploration to similar degrees, this effect was statistically significant only with high-dose aprotinin. Finally, most of the methods used to study the incidence of adverse events in the patients treated with epsilon aminocaproic acid do not conform to the rigorous evaluation of FDA-sponsored clinical studies to evaluate safety issues with aprotinin.

Levi et al¹¹reported a meta-analysis of all randomized, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). Studies included in the meta-analysis reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss.

In addition, a separate meta-analysis was performed for studies concerning complicated cardiac surgery. Researchers identified 72 trials (8409 patients) that met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0.55 [95% CI, 0.34-0.90]) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0.37 CI [0.25-0.55], and 0.44 CI [0.22-0.90], respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion.

By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results. The authors suggest that pharmacological strategies that decrease perioperative blood loss in cardiac surgery, particularly aprotinin and lysine analogues, also decrease mortality, the need for rethoracotomy, and the proportion of patients receiving a blood transfusion.

Aprotinin’s ability to reduce the need for allogeneic blood transfusion in cardiac surgery was confirmed in the recent International Study of Peri-Operative Transfusion meta-analysis, which included 45 trials with 5805 patients. Combining all doses of aprotinin, the overall odds ratio was 0.31(range: 0.25-0.39).

Anaphylaxis

As a xenogeneic protein (bovine derived), aprotinin possesses antigenic properties, and anaphylactic reactions to aprotinin have been described. Dietrich et al^12,13 reported the prevalence of adverse reactions to re-exposure to high-dose aprotinin in patients undergoing cardiac surgery in Germany between 1988 and 1995 with at least two exposures. Two hundred and forty-eight re-exposures to aprotinin occurred in 240 patients: 101 adult and 147 pediatric cases. The time between the first and second aprotinin exposure was 344 (interquartile range 1039) days, and seven reactions to aprotinin were reported (2.8%) that ranged from mild to severe. Patients with an interval less than 6 months since the previous exposure had a statistically higher incidence of adverse reactions than patients with a longer interval (5/111 or 4.5% versus 2/137 or 1.5%; P<.05). Two patients reacted to a test dose of 10,000 KIU aprotinin.

The investigators recommend the following for re-exposure to aprotinin: delay the first bolus injection of aprotinin until the surgeon is ready to begin cardiopulmonary bypass; test dose of 10,000 KIU aprotinin in all patients with aprotinin treatment; H1/H2 blockade in known or possible re-exposures; and avoid re-exposure within the first 6 months after the previous exposure to aprotinin. The investigators also suggest re-exposure to aprotinin in patients with a high risk of bleeding is justified because the benefits of aprotinin treatment outweigh the relative risk of a serious allergic reaction.

Jacquis et al¹⁴ reported the incidence of aprotinin reactions in children undergoing cardiac surgery in a retrospective review of aprotinin (n = 865) administration. In this study, 681 first exposures, 150 second exposures, and 34 third or higher exposures were examined. Reactions were classified as mild (generalized cutaneous erythema) or severe (unexplained cardiopulmonary instability after aprotinin exposure). Records of patients sustaining a reaction were reviewed to assess the impact of the reaction on outcome and to survey reaction management strategies. Reactions occurred in seven of 681 first exposures (1%), of which two were minor and five were severe. In second exposures, severe reactions occurred in two of 150 (1.3%). In 34 third or higher exposures, there was only one reaction (2.9%), which was severe. Reactions were no more likely on second, third, or higher exposure than on initial exposure. Skin testing had a negative predictive value of 98.9% and a positive predictive value of 20%. Anti-aprotinin IgE (fluorescence enzyme immunoassay) was undetectable in seven of eight reactor cases tested. No adverse sequelae were attributed to aprotinin reaction.

Scheule et al¹⁵ reported the evaluation of the preoperative prevalence of aprotinin-specific antibodies in patients scheduled for cardiac operations. Sera of 520 consecutive cardiac surgical patients were collected preoperatively and screened retrospectively for aprotinin-specific IgG using a standard enzyme-linked immunosorbent assay. Positive sera were analyzed also for aprotinin-specific IgA (enzyme-linked immuno-sorbent assay) and IgE (fluorescence enzyme immunoassay). The histories of all patients were reviewed with focus on aprotinin pre-exposure. Of 520 patients, 22 (4%) had specific IgG. Only three of these had a documented aprotinin pre-exposure. Of 448 patients exposed to aprotinin intraoperatively, 15 had preformed specific antibodies. The only patient presenting with severe anaphylaxis was positive for both IgG and IgE and had a recent intravenous pre-exposure in cardiovascular surgery. The presence of aprotinin-specific IgG alone does not induce adverse reactions on exposure. Exposure history alone is not sensitive enough to identify patients with aprotinin-specific antibodies. Scheule et al¹⁵ suggests that the clinical significance of preformed aprotinin-specific IgG remains questionable, whereas preformed IgE was present in the only patient who suffered from severe anaphylaxis on re-exposure to aprotinin. Preformed antibodies are not reliably predicted by exposure history.

Renal Effects

Aprotinin is rapidly eliminated by renal excretion, with a half-life of 4 hours. After 4 hours, 80% to 90% of aprotinin is stored in the proximal tubule cells and excreted over 12-24 hours.^16-18 In higher doses, aprotinin may produce a reversible overload of the tubular reabsorptive mechanisms, resulting in transient renal dysfunction.^18,19Aprotinin may also have a transient effect on the proximal tubule cells or alter intrarenal blood flow through inhibition of renin and kallikrein activity.²⁰ However, clinical studies after cardiac surgery have shown no adverse effects of aprotinin on postoperative renal function.^20-23Three randomized trials in patients undergoing cardiac surgery reported a trend of a mild to moderate increase in postoperative serum creatinine (approximately 0.5 mg/dL) but no increase in clinically important adverse outcomes such as irreversible renal failure or need for dialysis.^3,19 Follow-up at 4 to 6 weeks suggested that the effect is transient.

Conclusion

Aprotinin has been extensively evaluated in multiple double-blind, placebo-controlled, multicenter studies in cardiac surgery and is currently approved in the United States. Aprotinin has not been associated with an increased risk of postcardiopulmonary bypass myocardial infarction, graft closure, stroke, or increased risk of renal dysfunction from studies and may be associated with a decreased risk of stroke. The mechanism of action is complex; however, aprotinin exhibits antiinflammatory properties due to its complex array of protease inhibition. As with any polypeptide, there is a risk of anaphylaxis that is influenced not only by prior exposure, but also by time since prior exposure.

References

Levy JH. Anaphylactic Reactions in Anesthesia and Intensive Care. 2nd ed. Stoneham, Mass: Butterworth-Heinemann; 1992.
Peters DC, Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs. 1999; 57:233-260.
Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg. 1992; 4:1031-1038.
Levy JH, Pifarre R, Schaff H, et al. A multicenter, placebo-controlled, double-blind trial of aprotinin for repeat coronary artery bypass grafting. Circulation. 1995; 92: 2236-2244.
Alderman EL, Levy JH, Rich J, et al. International multi-center aprotinin graft patency experience (IMAGE). J Thorac Cardiovasc Surg. 1998; 116:716-730.
Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg. 1993; 105:147-153.
Havel M, Grabenwoger F, Schneider J. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg. 1994; 107:807-810.
Lemmer JH, Jr, Dilling EW, Mortin JR, et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial for three dose regimens. Ann Thorac Surg. 1996; 62:1659-1667.
Miller BE, Tosone SR, Tam VKH, et al. Hematologic and economic impact of aprotinin in reop pediatric cardiac surgery. Ann Thorac Surg. 1998; 66:535-540.
Munoz JJ, Birkmeyer NJ, Birkmeyer JD, et al. Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery?: a meta-analysis. Circulation. 1999; 99:81-89.
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; 354:1940-1947.
Dietrich W, Barankay A, Dilthey G, et al. Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application: clinical experience in 152 cardiac surgical patients. Thorac Cardiovasc Surg. 1989; 37:92-98.
Dietrich W, Spaeth P, Ebell A, Richter JA. Incidence of anaphylactic reactions to aprotinin: analysis of 248 reexposures to aprotinin. J Thorac Cardiovasc Surg. 1997; 113:194-201.
Jaquis DB, Ghanayem NS, Zacharisen MC, Mussatto KA, Tweddell JS, Litwin SB. Safety of aprotinin use and re-use in pediatric cardiothoracic surgery. Circulation. 2002; 106:90-94.
Scheule AM, Beierlein W, Arnold S, Eckstein FS, Albes JM, Ziemer G. The significance of preformed aprotinin-specific antibodies in cardiosurgical patients. Anesth Analg. 2000; 90:262-266.
Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology. 1994; 80:1013-1018.
Levy JH, Murkin J, Ramsay JG. Aprotinin reduces the incidence of strokes following cardiac surgery. Circulation. 1996; 94:1-535.
Feindt PR, Walcher S, Volkmer I. Effects of high-dose aprotinin on renal function in aortocoronary bypass grafting. Ann Thorac Surg. 1995; 60:1076-1080.
D'Ambra MN, Akins CW, Blackstone EH, et al. Aprotinin in primary valve replacement and reconstruction: a multicenter double-blind placebo-controlled trial. J Thorac Cardiovasc Surg. 1996; 112:1081-1089.
Lemmer JH, Stanford W, Bonney SL. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg. 1995; 59:132-136.
Lemmer JH, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass surgery: efficacy, safety, and influence on early saphenous vein graft patency. J Thorac Cardiovasc Surg. 1994; 107:543-553.
Lemmer JH, Stanford W, Bonney SL, et al. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg. 1995; 59:132-136.
Swart MJ, Gordon PC, Hayse-Gregson PB, et al. High-dose aprotinin in cardiac surgery: a prospective, randomized study. Anaesth Intensive Care. 1994; 22:529-533.

Authors

From the Department of Anesthesiology, Emory University School of Medicine, Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Ga.

Click here to print the Quiz (Adobe Acrobat [.PDF] format)