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Ann Thorac Surg 1998;66:S6-S11
© 1998 The Society of Thoracic Surgeons

The efficacy and safety of aprotinin use in cardiac surgery

^a Department of Surgery, Eastern Virginia Medical School, Sentara Norfolk General Hospital, Norfolk, Virginia, USA

Address reprint requests to Dr Rich, Mid-Atlantic Cardiothoracic Surgeons, Ltd, 400 West Brambleton Ave, Suite 200, Norfolk, VA 23510

Presented at "Risk Management in CABG: Significant Surgical Considerations," New Orleans, LA, Jan 24, 1998.

	Abstract

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 
Background. The serine protease inhibitor aprotinin has received much attention in cardiac surgical practice as a pharmacologic intervention to improve the hemostatic derangement associated with cardiopulmonary bypass. This review highlights the major studies undertaken to investigate the efficacy and safety of aprotinin use in both primary and repeat coronary artery bypass graft surgical procedures.

Methods. There have been at least 45 controlled studies in more than 7,000 patients in a variety of patient populations. These have ranged from primary coronary artery bypass graft and valve operations to complex reoperation procedures, including aortic arch reconstructions and thoracic organ transplantation. The recently completed International Multicenter Graft Patency Experience trial, the largest study to date, involved 870 patients at 13 international sites. The study examined the effects of aprotinin on graft patency, incidence of myocardial infarction, and blood loss in patients undergoing primary coronary artery bypass graft operations with cardiopulmonary bypass.

Results. Twenty-one studies in approximately 5,000 patients undergoing primary coronary artery bypass graft or valve operations reported 33% to 66% reduction in blood loss with full-dose aprotinin therapy; 15 of the same studies reported significant reductions in transfusion requirements, ranging from 31% to 85%. The recently completed International Multicenter Graft Patency Experience study observed a significant reduction in thoracic-drainage volume of 43% (p < 0.0001) and a 49% (p < 0.001) reduction in the requirement for allogeneic blood transfusions. Aprotinin did not affect the occurrence of definite myocardial infarction (aprotinin, 2.9% versus placebo, 3.8%) or mortality (aprotinin, 1.4% versus placebo, 1.6%). There was no observed difference in the patency of internal mammary artery bypass grafts from all study sites in aprotinin- versus placebo-treated patients (aprotinin, 98.2% versus placebo, 98.0%).

Conclusions. Given the risks and costs associated with excessive bleeding and transfusions and the limited supply of banked blood, aprotinin represents an important and safe approach to blood conservation.

	Introduction

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 
Blood loss during cardiac operations and the subsequent need for transfusion of red blood cells and their components have received much attention in the last decade, particularly in response to the risk of transmission of blood-borne infectious diseases. Improvements in surgical techniques and blood conservation and salvage methods have provided substantial reduction in the use of blood transfusions in this patient population. A major component of this effort has been the use of aprotinin, a broad-spectrum serine protease inhibitor. This presentation will provide an overview of the use of aprotinin in cardiac surgical practice and will highlight the findings from the major clinical trials designed to address the efficacy and safety profiles of this drug.

Aprotinin is a naturally occurring polypeptide derived from bovine lung. It was discovered independently in the 1930s by Kraut and coworkers [1] and identified by Kunitz and Northrop [2] as a trypsin-kallikrein inhibitor. It acts as an inhibitor of human trypsin, plasmin, and plasma and tissue kallikrein by forming reversible enzyme–inhibitor complexes at the active serine site of the enzyme. Aprotinin has been commercially available for a considerable number of years, but only in the last 10 years have the blood-sparing actions of the drug, in particular as related to cardiopulmonary bypass (CPB), been widely acknowledged. The exact mechanism of action of aprotinin’s hemostatic properties remains to be fully elucidated, but the ubiquitous involvement of serine proteases in the coagulation, fibrinolytic, and inflammatory cascades clearly demonstrates a role for aprotinin in the modulation of many of these processes.

Kallikrein and plasmin are important components of the inflammatory response to CPB. Contact phase activation of factor XII by the negatively charged surface of the bypass circuit in the presence of prekallikrein and high-molecular-weight kininogen results in kallikrein production (Fig 1). Kallikrein greatly accelerates factor XII activation, and a positive feedback loop thus amplifies the intrinsic coagulation cascade. Kallikrein will generate the potent inflammatory substance bradykinin, activate the complement system, and convert plasminogen to plasmin, resulting in increased fibrinolysis. Activation of the inflammatory pathways has numerous effects on the circulating blood cells, with particular regard to upregulating adhesion receptors on neutrophils and degrading platelet glycoprotein receptors. One important consequence of the contact activation of these enzyme systems by CPB is the tendency for patients undergoing cardiac operations to have increased perioperative bleeding, requiring the use of increased amounts of blood and blood products. Transfusions pose an infectious risk to the patient and are costly. Furthermore, the bleeding patient will spend more time in the operating room, an expensive environment. The use of aprotinin both to improve perioperative hemostasis and to reduce the associated costs of bleeding can be a cost-efficient pharmacologic therapy.

View larger version (23K): [in this window] [in a new window]   Fig 1. Cardiopulmonary bypass-induced contact activation of the coagulation, fibrinolytic, kinin, and complement cascades.

	Clinical trials

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

In most of the placebo-controlled randomized studies, the primary end point for assessing the efficacy of aprotinin therapy was the proportion of patients requiring blood transfusions. Secondary end points included the amount of blood and blood products transfused and the volume of loss through postoperative drains. Safety issues were also addressed by these studies. The possibility that aprotinin’s action might, in part, be caused by decreased fibrinolysis as a consequence of plasmin inhibition was an important issue. Data needed to be collected to ensure that there was no increase in the incidence of thrombotic events, for example, myocardial infarction (MI), early bypass graft occlusion, stroke, and deep vein thrombosis. Aprotinin is cleared by the kidney and undergoes active reabsorption by the proximal tubules. Studies were therefore designed to ensure that renal dysfunction would not be a serious side effect of the treatment.

There have been at least 45 controlled studies in more than 7,000 patients in a variety of patient populations. These have ranged from primary CABG and valve operations to complex reoperation procedures, including aortic arch reconstructions and thoracic organ transplantation. Efficacy has been investigated in patients at special risk of operative bleeding, in particular those taking preoperative anticoagulants and during left ventricular assist device insertion.

Efficacy of full-dose aprotinin in primary and repeat operations
Twenty-one studies in approximately 5,000 patients undergoing primary CABG or valve operations reported 33% to 63% reduction in blood loss with full-dose aprotinin therapy; this difference was significant in 20 of 21 studies. Fifteen of the same studies reported significant reductions in transfusion requirements, ranging from 31% to 85%. The largest of these studies was reported in 1992 by Dietrich and coworkers [4]: 61% of the 1,784 patients underwent CABG operations, 31% had valve replacement, and 8% had both procedures. Blood loss was reduced from 1,037 mL in placebo-treated patients to 678 mL (p < 0.05) with full-dose aprotinin therapy, and blood-transfusion requirements from 1,999 mL to 942 mL (p < 0.05).

Eight studies in approximately 850 patients undergoing reoperation CABG or valve operations reported similar reductions in blood loss (26% to 81%) and transfusion requirements (47% to 97%). The multicenter, randomized, double-blind, placebo-controlled study published by Lemmer and colleagues [5] in 1994 reported efficacy of aprotinin in a US population of patients undergoing CABG operations. A total of 151 patients underwent primary operation; 65 underwent repeat procedures. One hundred forty-one patients fulfilled the criteria for efficacy evaluation in the primary operation group, and 55 patients fulfilled the criteria in the repeat procedures group. Significant reductions in the percentage of patients requiring donor blood and blood-product transfusions and in total blood-product exposure were associated with the use of aprotinin in both primary and repeat groups (Table 1). Furthermore, a significantly shorter time to chest closure was reported in the reoperation patient group in the aprotinin cohort, implying a cost–benefit effect.

View larger version (45K): [in this window] [in a new window]   Fig 2. Percentage of patients who required transfusion of blood or blood products for the three aprotinin dosing schedules and for the placebo group. (CABG = coronary artery bypass graft.) (Reoperation data drawn from [6]; primary operation data drawn from [7].)

View larger version (33K): [in this window] [in a new window]   Fig 3. Mean total blood exposures per patient (units) for the three aprotinin dosing schedules and for the placebo group. (CABG = coronary artery bypass graft.) (Reoperation data drawn from [6]; primary operation data drawn from [7].)

	Antiinflammatory effects of aprotinin

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

	Aprotinin safety

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 
Overall, aprotinin was found to have a good safety profile. Data pooled from the US placebo-controlled clinical trials found no significant differences in mortality incidence between aprotinin-treated and placebo-treated patients. Other reported adverse events were common sequelae of cardiac operations and were not observed more frequently in the aprotinin-treated patients.

Several studies observed a small, insignificant rise in plasma creatinine concentration in the postoperative period, peaking between 3 and 5 days. Typically, the values were within the normal range but about 0.5 mg higher in aprotinin-treated patients [10]. This rise has not been associated with any impairment of renal function or the need for support with dialysis. The initial report of renal impairment in patients undergoing aortic surgical procedures with deep hypothermic circulatory arrest [11] has not been confirmed [12, 13].

A more contentious safety issue relates to the drug’s action as a serine protease inhibitor. Any increase in antifibrinolytic activity has the potential to increase thrombus formation in small vessels, in particular the coronary arteries, and to augment the risk of early graft occlusion and other thrombotic events. No increased rates of generalized thrombotic events, deep vein thrombophlebitis, or pulmonary embolism were observed in the US trials. In fact, a reduction in incidence of stroke was reported by Levy and associates [6]: full-dose aprotinin, 0% versus placebo, 1.7%.

Perioperative MI was examined in the earlier clinical trials by electrocardiography and enzyme criteria in patients undergoing both primary and repeat CABG operations. In a pooled analysis of all patients, there was no significant difference in the incidence of investigator-reported MI in aprotinin-treated patients (n = 2,002) compared with placebo-treated patients (n = 1,084). One US study indicated that full- or half-dose aprotinin is associated with a nonsignificant trend in the prevalence of MI in reoperation CABG [14]; however, different methods of managing heparin that led to possibly inadequate heparinization may have, in part, accounted for this discrepancy. None of these earlier studies used uniform criteria for the diagnosis of MI, and the issue was therefore readdressed in three studies in which data were analyzed in a blinded fashion by a core laboratory that used an algorithm to define possible, probable, or definite MI [5–7]. Heparin management was also rigorously controlled using the Hepcon heparin-monitoring system (Medtronic Hemotec, Englewood, CO). The incidence of definite MI from pooled data was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo-treated patients. This difference was not statistically significant. The largest study of 704 patients by Lemmer and colleagues [7] reported a small but significant rise in probable, possible, and definite MI in the study arm that received aprotinin in the pump prime only. In addition, if the pooled data are analyzed according to the three treatment groups (full dose, half dose, or pump prime only), a nonsignificant trend toward increased incidence of probable, possible, and definite MI is seen with anything less than the full dose (Fig 4) [15].

View larger version (17K): [in this window] [in a new window]   Fig 4. Incidence of possible, probable, and definite myocardial infarction (MI) by central laboratory determination with 95% confidence intervals for the three aprotinin dosing schedules and matched placebo groups. (Reprinted from [15] with permission of The Society of Thoracic Surgeons.)

	International Multicenter Graft Patency Experience (IMAGE) trial

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 
The most recently completed study is the International Multicenter Graft Patency Experience (IMAGE) trial, with a sample size sufficient to investigate angiographically any adverse effect of aprotinin on graft patency in primary CABG operations. The study also investigated the incidence of MI by electrocardiography and enzyme criteria and reassessed the effect of aprotinin on allogeneic transfusion requirements. A total of 870 patients were randomly assigned at 10 US and 3 European sites to receive aprotinin (n = 436) or placebo (n = 434) during primary CABG operations. Double-blind conditions were maintained throughout the study. In addition, randomization was stratified on the basis of whether patients received aspirin within 5 days of surgery or nonsteroidal antiinflammatory drugs within three serum half-lives. As in other studies, blood loss, creatine kinase-MB values, and electrocardiographic data were collected postoperatively. Angiography was performed a mean of 10.8 days after surgery. Electrocardiograms and all angiograms were evaluated using blinded readings at a core laboratory.

In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% (p < 0.0001) and decreased the need for allogeneic red blood cell transfusion by 49% (p < 0.0001). In addition, the aprotinin-treated patients required significantly fewer platelet transfusions, less fresh-frozen plasma, and less cryoprecipitate (p < 0.0001). Aprotinin treatment was associated with a 47% reduction in the number of patients returned to the operating room for bleeding (11 versus 19 patients) and did not affect the occurrence of definite MI (aprotinin, 2.9% versus placebo, 3.8%) or mortality (aprotinin, 1.4% versus placebo, 1.6%). There was no observed difference in the patency of internal mammary artery bypass grafts from all study sites in aprotinin- versus placebo-treated patients (aprotinin, 98.2% versus placebo, 98.0%).

There were 703 patients with assessable saphenous vein grafts. These data were reported at the American Association for Thoracic Surgery annual meeting in Boston, May 1998, and will be published accordingly.

	Summary

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 
Aprotinin has been proved to have remarkable efficacy in a wide variety of cardiac surgical situations. Moreover, recent well-designed clinical trials addressing potential safety issues have dispelled many concerns, in particular those relating to an increased thrombotic risk with use of the drug. Patients who will benefit include those with known coagulopathic states or septic endocarditis; those undergoing complex reoperations, including aortic surgical procedures; and those undergoing primary CABG operations in the presence of preoperative aspirin or nonsteroidal antiinflammatory drug use. Aprotinin use should also be considered in young patients and in transplant candidates who require a left ventricular assist device and in whom it is preferable to avoid blood-product transfusions. The benefits of aprotinin use in uncomplicated primary cardiac operations should be balanced against its cost to benefit ratio and the possibility of an anaphylactic reaction should the patient require aprotinin for a reoperation at a later date. In common with all foreign proteins, hypersensitivity reactions can occur. These are rare with no prior exposure, and the reported incidence of 5% on reexposure within 6 months falls to 0.9% beyond 6 months [20].

Given the risks and costs associated with excessive bleeding and transfusions and the limited supply of banked blood, aprotinin represents an important and safe approach to blood conservation.

	References

Top Abstract Introduction Clinical trials Antiinflammatory effects of... Aprotinin safety International Multicenter Graft... Summary References

 

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