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CARDIOVASCULAR ANESTHESIA

Aprotinin Versus Placebo in Major Orthopedic Surgery: A Randomized, Double-Blinded, Dose-Ranging Study

Charles Marc Samama, MD PhD^*, Olivier Langeron, MD, Nadia Rosencher, MD, Xavier Capdevila, MD PhD, Patricia Rouche, MD^||, Michel Pegoix, MD^¶, Josée Bernière, MD^#, and Pierre Coriat, MD for the Hémorragies et Aprotinine en Chirurgie Orthopédique Lourde Study Group

*Département d’Anesthésie-Réanimation, Centre Hospitalo-Universitaire (CHU) Avicenne, Bobigny; Département d’Anesthésie-Réanimation, CHU Pitié-Salpêtrière, Paris; Département d’Anesthésie-Réanimation, CHU Cochin, Paris; Département d’Anesthésie-Réanimation A, Hôpital Lapeyronie, CHU de Montpellier, Montpellier; ||Département d’Anesthésie-Réanimation, Hôpital Saint Joseph, Paris; ¶Département d’Anesthésie-Réanimation, CHU de Caen–Côte de Nacre, Caen; and #Département d’Anesthésie-Réanimation, CHU Trousseau, Paris, France

Address correspondence and reprint requests to Charles Marc Samama, Département d’Anesthésie-Réanimation, Hôpital Avicenne 125, Route de Stalingrad, 93009 Bobigny Cedex, France. Address e-mail to cmsamama{at}invivo.edu

	Abstract

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We conducted a prospective, multicenter, double-blinded, dose-ranging study to compare the risk/benefit ratio of large- and small-dose aprotinin with placebo after major orthopedic surgery. Fifty-eight patients were randomized into three groups: Large-Dose Aprotinin (4 M kallikrein inactivator unit [KIU] bolus before surgery followed by a continuous infusion of 1 M KIU/h until the end of surgery), Small-Dose Aprotinin (2 M KIU bolus plus 0.5 M KIU/h), and Placebo. Bleeding was measured and calculated. Bilateral ascending venography was systematically performed on the third postoperative day. Measured and calculated blood loss decreased in the Large-Dose Aprotinin group (calculated bleeding, whole blood, hematocrit 30%, median [range], 2,023 mL [633–4,113] as compared with placebo, 3,577 mL [1,670–21,758 mL]). The total number of homologous and autologous units was also significantly decreased in the Large-Dose Aprotinin group (2 U [0–5 U] as compared with placebo, 4 U [0–42 U]). No increase in deep vein thrombosis or pulmonary embolism was observed in the aprotinin groups. Large-dose aprotinin was safe and effective in dramatically reducing the measured and calculated bleeding and the amount of transfused red blood cell units after major orthopedic surgery.

IMPLICATIONS: Large doses of aprotinin decrease blood loss and transfusion amount in major orthopedic surgery.

	Introduction

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Antifibrinolytic therapy constitutes an effective method to control or reduce bleeding and to limit or avoid blood transfusion in current medical practice. Until recently, blood products have served as the primary treatment for patients with mild congenital and acquired disorders. Concerns about transmission of infectious diseases—such as human immunodeficiency virus and, more recently, the Creutzfeld-Jacob new variant disease—have led clinicians to seek alternatives to homologous blood products. Attention has focused on new techniques involving blood-sparing, predonation, hemodilution, and the use of hemostatic drugs.

The interest in antifibrinolytic drugs dramatically increased when Royston et al. (1) demonstrated for the first time the effect of large-dose aprotinin in reducing intraoperative blood loss and transfusions in cardiac surgery. Since then, many studies have been performed in this type of setting, aprotinin is widely used in cardiac surgery, and there have been trials in vascular (2) and liver transplantation surgery (3), studying different doses and modes of administration. Generally, aprotinin was able to decrease intra- and postoperative bleeding and blood transfusion in these settings. Few studies have been conducted with orthopedic surgery (4–10). Aprotinin moderately decreases blood loss and transfusion requirements during total hip replacement (4–6). One or two packed red cell units per patient may be saved when aprotinin is used. In a double-blinded study (7) in high-risk septic and cancer patients undergoing pelvic and hip surgery, aprotinin proved to be effective in significantly reducing the need for blood transfusion as compared with a placebo group. However, the optimal aprotinin dose was not determined, and objective deep vein thrombosis (DVT) assessment was not systematically performed. Therefore, we conducted a prospective, randomized, double-blinded, multicenter trial to assess the efficacy and safety of two doses of aprotinin as compared with placebo in major orthopedic surgery.

	Methods

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This study was conducted in accordance with the Helsinki Declaration, European Good Clinical Practice, and French law. This protocol was approved by the Ethical Committee of La Pitié-Salpêtrière Hospital in Paris, France, and written informed consent was obtained from all patients.

Six orthopedic units participated. Patients were recruited from January 1997 to December 1998. ASA physical status I–III patients scheduled for major orthopedic surgery (revision spine or hip surgery, trauma surgery, cancer surgery, or surgery for sepsis) with an expected blood loss of >2000 mL were included in the HACOL (Hémorragies et Aprotinine en Chirurgie Orthopédique Lourde) study. Patients with the following conditions were ineligible: age <15 yr; congenital or acquired coagulopathy; history of, or evolving, thromboembolic disease; renal insufficiency (creatinine >200 µmol/L); unstable angina; recent myocardial infarction; severe atherothrombosis; preoperative treatment with nonsteroidal antiinflammatory drugs, aspirin, ticlopidine, heparin, or oral anticoagulants; emergency operation; known allergy to aprotinin or to contrast media; or refusal to participate in the study.

General anesthesia and perioperative care were at the discretion of the attending anesthesiologists. After surgery, DVT prophylaxis was secured in all patients by a daily subcutaneous injection of low-molecular-weight heparin (enoxaparin 40 mg; Aventis, Paris, France). The first injection was given on the day of surgery, in the evening, unless major bleeding occurred.

Patients were randomly assigned to receive one of the two doses of aprotinin (Trasylol^®; Bayer, Wuppertal, Germany) or placebo. Random allocation followed different randomization tables for each center. The trial drug was provided double-blinded by the manufacturer and was supplied in identical-looking 50-mL bottles containing either 0.5 x 10⁶ kallikrein inactivator units (KIU) of aprotinin (70 mg) in 0.9% saline or placebo (0.9% saline). Centers were provided with sealed envelops with the randomization codes to enable an individual patient’s code to be broken in an emergency. A separate set of the sealed randomization tables was kept at the central data center (Department of Anesthesiology, La Pitié-Salpêtrière Hospital, Paris).

Three groups were compared:

1. Large Dose: 4 x 10⁶ KIU of aprotinin as an initial dose given IV over 20 min before and during the induction of anesthesia, followed by a continuous infusion of 1 x 10⁶ KIU until skin closure.
   
2. Small Dose: 2 x 10⁶ KIU of aprotinin as an initial dose given IV over 20 min before and during the induction of anesthesia, followed by a continuous infusion of 0.5 x 10⁶ KIU until skin closure.
   
3. Placebo: saline in an identical time schedule and volume.
   

To maintain masking, all patients received identical volumes of solution and an identical number of bottles for the initial dose and for the continuous infusion, regardless of treatment group.

Detailed data forms were completed for each patient by the local investigator. For safety monitoring, serious adverse events had to be reported to the main investigator. The primary end points of the study were the amount of intra- and postoperative blood loss and number of blood transfusions (homologous or autologous red blood cell [RBC] units, cell salvage units, fresh frozen plasma, and platelet concentrates). Blood loss was measured by weighing swabs and operative drapes, measuring the volumes in the suction bottles after surgery, and checking the drain collectors on admission to the postanesthesia care unit and thereafter for 2 days after surgery. Bleeding was also calculated by using the formulas from Mercuriali and Inghilleri (11) (Appendix 1). Calculated bleeding was expressed in milliliters of RBC, hematocrit (Hct) 100%, and milliliters of whole blood with an Hct of 30%. The secondary end point was the occurrence of a venous thrombo-embolic event (DVT or pulmonary embolism) as assessed by a daily clinical examination and a systematic bilateral ascending venography performed at Day 4 after surgery in every patient.

Transfusion of blood products was standardized for all centers. The indication for postoperative transfusion of RBCs (autologous or homologous RBC units or cell salvage units) was set to maintain Hct at >24%. Fresh frozen plasma was given only when clinically significant bleeding was observed and when prothrombin time was <30%. Platelet concentrates were administered only when clinically significant bleeding was observed and when platelet count was <50 g/L.

Blood samples were drawn on three occasions: before surgery, immediately after surgery, and after 48 h. They were collected in 3.8% trisodium citrated tubes (9:1 vol/vol; Becton Dickinson-France, Le Pont de Claix, France) for prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimers (VIDAS D-dimer; BioMerieux, Marcy l’Etoile, France), and they were collected in EDTA tubes (Becton Dickinson) for platelet and white blood cell counts and for hemoglobin and Hct determinations.

Our original hypothesis was built on a comparable efficacy of the two aprotinin doses and an anticipated 25% difference concerning blood loss and transfusion requirements with the Placebo group. A 20% ß risk and a 5% risk were retained. Although the study was originally designed to include 100 patients, an interim analysis (n = 50) indicated a highly significant reduction of blood loss in the Large-Dose group, and the study steering committee decided to stop the inclusion of new patients. As a consequence, the power to detect a significant difference in total bleeding between the Placebo and the Small-Dose Aprotinin groups and between the two Aprotinin groups was decreased (respectively, 10% and 25%).

Data are expressed as median (range) for blood loss, volume loading, and transfusion variables. Values are expressed as mean ± SD for all other variables. Several means were compared by using analysis of variance, followed by a Scheffé test. Medians were compared by using the nonparametric Kruskal-Wallis test for independent measures, followed, when significant, by a Mann-Whitney U-test with Bonferroni correction and by a Friedman test for repeated measures and, when significant, by a Wilcoxon’s test with Bonferroni correction. Probability values of <0.05 were required to reject the null hypothesis. Statistical analysis was performed on a computer by using StatView SE Graphics^TM (Abacus Concepts, Berkeley, CA).

	Results

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Fifty-eight patients were included. The three groups were well matched with regard to demographics, duration and type of surgery (Table 1), preoperative Hct, platelet count, fibrinogen level, and D-dimers (Table 2). One patient (Small-Dose Aprotinin group) died in the operating room secondary to a massive bleeding episode.

Postoperative drainage was significantly decreased in the two Aprotinin groups (Table 3). The difference between calculated bleeding (Hct 30%) and measured bleeding (i.e., 782 mL in the Placebo group, 427 mL in the Small-Dose group, and 308 mL in the Large-Dose group) was significantly decreased in the Large-Dose group as compared with Placebo but did not achieve statistical significance in the Small-Dose group.

	Discussion

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The results of the HACOL study show that in patients undergoing major orthopedic surgery, large-dose aprotinin significantly reduced intra- and postoperative blood loss and packed RBC requirements. The observed difference between calculated bleeding and measured bleeding provides additional data assuming that occult postoperative bleeding (mainly hematomas) was also decreased by aprotinin. No increase in clinical or venographic DVT or pulmonary embolism was observed in the aprotinin-treated groups as compared with placebo.

Most of our patients fulfilled the inclusion criteria regarding perioperative bleeding, with a median measured bleeding of 2,795 mL (900–12,760 mL), assuming that in patients scheduled for major orthopedic surgery bleeding and transfusion are frequent and that blood-sparing protocols should systematically be part of perioperative care. All our patients underwent spine, pelvic, or hip surgery, and most of these procedures belonged to one of the four categories considered to be high risk with regard to bleeding: revision, trauma, cancer, and sepsis. The remaining patients without these risks had either spine or pelvis procedures. We initially thought that their bleeding risk would theoretically be somewhat decreased compared with the four other groups. Among all the patients of the study who bled >1000 mL (calculated bleeding, Hct 100%, n = 17 in 57), 7 of 18 patients belonged to the "other types of surgery" group (not significant), indicating that these procedures have a similar bleeding risk.

Several trials have investigated the usefulness of aprotinin in orthopedic surgery (4–10). Except for one of them (7), the results on blood loss and transfusion-sparing were not impressive and did not modify the care of patients. For instance, in the study from Murkin et al. (6), three aprotinin groups were compared with placebo in patients undergoing primary total hip replacement: aprotinin reduced total intraoperative blood loss and postoperative drainage volume with a mean total of 1408 mL for the placebo group compared with 1079 mL in the large-dose group (i.e., 2 M KIU bolus plus 0.5 M KIU/h), and a comparable moderate decrease was observed in the two other groups with much smaller aprotinin doses. Furthermore, the percentage of patients who required any form of transfusion was small—47% in the placebo group—leading to reconsideration of the benefit of hemostatic drugs in such a setting. In addition, two other trials conducted in hip surgery and using small or very small doses showed negative results (8,9).

Major bias can be evidenced in all these studies. First, primary hip surgery may not be the most appropriate setting to use aprotinin. Bleeding is limited, and the usual perioperative amount of transfused RBC units generally does not exceed 3 U, which can be provided by a scheduled predonation. Second, the proposed aprotinin doses in these studies were extrapolated from doses used in cardiac and liver transplantation surgery. Yet only one large randomized double-blinded study has been conducted to compare three small doses—0.5 M KIU bolus versus 1 M KIU bolus plus 0.25 M KIU/h versus 2 M KIU bolus plus 0.5 M KIU/h—showing a moderate benefit in blood loss and transfusion-sparing (6). Conversely, Capdevila et al. (7) showed that aprotinin dramatically reduced the blood loss (1783 mL versus 5305 mL in the placebo group) and the number of packed RBC units (3 vs 7) in patients undergoing major orthopedic surgery of the hip or pelvis for sepsis or malignant tumors. Of note, preoperative donation, intraoperative cell-saving procedures, or both are generally not performed in these patients with cancer or sepsis, although massive intraoperative bleeding frequently occurs. As stated by Hardy et al. (12), the greater the bleeding, the more beneficial the effects of aprotinin appear to be. These conditions and the severity of the patient clinical condition (i.e., severe sepsis or cancer) provide a good rationale for the use of this type of hemostatic drug.

Aprotinin is a naturally occurring single-chain 58-amino acid polypeptide with a molecular weight of 6.512 Da. It has a broad inhibitory specificity for serine proteases, but its most important effect is to inhibit plasmin, trypsin, and kallikreins of different origins (13). It forms a stoichiometric complex and completely inhibits the active site of each enzyme. Nevertheless, the mechanism underlying the beneficial effects of aprotinin in orthopedic surgery has not yet been fully elucidated. Several hypotheses can be proposed. Aprotinin acts mainly as an antiplasmin drug. However, systemic fibrinolysis does not occur in routine orthopedic surgery (4,7). The occurrence of local fibrinolysis has already been advocated but never demonstrated. The antikallikrein activity of aprotinin interferes with the intrinsic coagulation pathway that is activated during severe sepsis. Therefore, aprotinin could prevent this activation and, while decreasing thrombin generation, limit the extent of potential disseminated intravascular coagulation and platelet activation, both of which are responsible for intraoperative bleeding.

Two doses of aprotinin have been compared with placebo in the HACOL study: the small dose, as already described in several articles, and a larger dose. Our original hypothesis was based on an equal efficacy of the two doses. However, the final results showed a clear benefit for the large dose over the placebo. If the results in the Small-Dose group did not reach statistical significance despite real efficacy, obviously bleeding and the total amount of blood transfusion were dramatically decreased in the Large-Dose group. It could be assumed that intraoperative bleeding is responsible for a partial washout of the product. Small doses could be beneficial in cardiac surgery when shed blood is immediately reinfused in the bypass circuit, but appear clearly ineffective when a consistent blood volume is discarded. A sufficient plasma concentration has to be reached (14), and continuous infusion of a large dose seems to be mandatory to maintain such a level. Furthermore, larger doses may be responsible for a more important decrease in thrombin generation than common doses. An indirect anticoagulant effect of large doses of aprotinin may be postulated, in conflict with the supposed prothrombotic effect of large doses.

As a potent hemostatic drug and an in vitro inhibitor of activated protein C (15), aprotinin has been thought to induce a hypercoagulable state and to promote graft occlusion after coronary artery surgery (16,17) or liver transplantation (18). It could theoretically increase the venous thromboembolic risk in patients undergoing major orthopedic procedures, despite the use of daily low-molecular-weight prophylaxis. In the low-molecular-weight heparin studies in patients undergoing total hip replacement, the global venographic DVT rate on Day 10 generally reached 15% to 25% in patients treated with low-molecular-weight heparin (19). The theoretical venographic DVT rate in our patients was supposed to be as high. Our study was the first double-blinded aprotinin study to systematically assess venous thromboembolism with venography performed at Day 3. The number of thromboembolic events was very small and not significantly different from one group to another. This is consistent with previous reports. However, the sample of 58 patients is far too small to draw any definite conclusion in this regard and to exclude any prothrombotic effect of aprotinin. Nonetheless, no thrombotic event was detected in the Large-Dose group, and, in our study, the increase in the aprotinin dose did not increase the thrombotic risk.

One nonfatal allergic reaction was recorded, leading us to discontinue treatment in a young patient. Because aprotinin is a polypeptide derived from bovine lungs, it possesses antigenic properties. Therefore, there is a possibility of an adverse reaction to this drug, especially in patients reexposed to the drug. Allergic reactions after reexposure have been described (20,21). The incidence of hypersensitivity reactions in one study was 2.8% in 248 patients reexposed to aprotinin (22). There is a time dependency for the risk of adverse reactions: the shorter the time interval between the two exposures, the higher the risk of a reaction. Therefore, the drug should not be given within six months after the last exposure. In addition, exposure of patients with moderate expected bleeding (i.e., patients scheduled for total hip replacement) to this consequent allergic risk does not seem to be justified, considering the potential severity of aprotinin-induced anaphylaxis.

Our results clearly demonstrate that prophylactic large doses of aprotinin dramatically decrease perioperative blood loss, RBC transfusion, and the number of patients exposed to transfusion in major orthopedic surgery, without significant adverse effects. In high-risk orthopedic patients without prior exposure to aprotinin, this drug should be considered.

Appendix 1
Total blood loss was calculated by using the following formulas (1,2):

equation

equation

equation

equation

equation

equation

equation

equation

equation

Hb=hemoglobin.

	Acknowledgments

 
Supported by Bayer AG.

We thank Danièle Pasteur for her very helpful assistance and Bruno Riou for his help with the methodology.

	Footnotes

 
Presented in part at the 18th Congress of the International Society on Thrombosis and Haemostasis, Paris, France, July 6–12, 2001.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by Samama, C. M. Articles by Coriat, P. Search for Related Content PubMed PubMed Citation Articles by Samama, C. M. Articles by Coriat, P. Related Collections Blood Surgery

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999