JBJS | Aprotinin Decreases Exposure to Allogeneic Blood During Primary Unilateral Total Hip Replacement*

The Journal of Bone & Joint Surgery, Volume 82, Issue 5

Articles | May 01, 2000

Aprotinin Decreases Exposure to Allogeneic Blood During Primary Unilateral Total Hip Replacement*

J. M. Murkin, M.D.†; G. M. Haig, Pharm.D.‡; K. J. Beer, M.D.‡; N. Cicutti§, Ph.D.; J. McCutchen, M.D.#; M. E. Comunale, M.D.**; R. Hall, M.D.††; B. B. Ruzicka, Ph.D.‡‡

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*One or more of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding source was Bayer Corporation, Pharmaceutical Division, West Haven, Connecticut. The data in the present study was derived from protocol D95-006 sponsored by Bayer Corporation, Pharmaceutical Division.
†Department of Anaesthesia, London Health Sciences Center-UC, University of Western Ontario, 339 Windermere Road, London, Ontario N6A 5A5, Canada.
‡The Toledo Hospital, 2142 North Cove Boulevard, Toledo, Ohio 43606.
§The Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
#Jewett Orthopaedic Clinic, 1285 Orange Avenue, Winter Park, Florida 32789.
**Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Masschusetts 02215.
††Queen Elizabeth II Health Sciences Centre, 1796 Summer Street, Halifax, Nova Scotia B3H 3A7, Canada.
‡‡Bayer Corporation, 400 Morgan Lane, West Haven, Connecticut 06516.

The Journal of Bone & Joint Surgery. 2000; 82:675-675

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Abstract

Background: Aprotinin, a hemostatic agent, regulates fibrinolysis, modulates the intrinsic coagulation pathway, stabilizes platelet function, and exhibits anti-inflammatory properties through inhibition of serine proteases, such as trypsin, plasmin, and kallikrein. Aprotinin has been used successfully for many years in cardiac operations, and there have been preliminary investigations of its use in hip replacement operations. The objectives of this multicenter, randomized, placebo-controlled, double-blind trial were to evaluate the efficacy and safety of aprotinin as a blood-sparing agent in patients undergoing an elective primary unilateral total hip replacement and to examine its effect on the prevalence of deep-vein thrombosis in this population.

Methods: Seventy-three patients received a placebo; seventy-six patients, a low dose of aprotinin (a load of 500,000 kallikrein inhibitor units [KIU]); seventy-five, a medium dose of aprotinin (a load of 1,000,000 KIU, with infusion of 250,000 KIU per hour); and seventy-seven patients, a high dose of aprotinin (a load of 2,000,000 KIU, with infusion of 500,000 KIU per hour). The end points for the determination of efficacy were transfusion requirements and blood loss. Patients received standard prophylaxis against deep-vein thrombosis and underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis.

Results: Aprotinin reduced the percentages of patients who required any form of blood transfusion (47 percent of the patients managed with a placebo needed a transfusion compared with 28 percent of those managed with low-dose aprotinin [p = 0.02], 27 percent of those managed with high-dose aprotinin [p = 0.008], and 40 percent of those managed with medium-dose aprotinin [p = 0.5]). Only 6 percent (twelve) of the 212 patients treated with aprotinin required allogeneic blood compared with 15 percent (ten) of the sixty-eight patients treated with the placebo (p = 0.03). Aprotinin decreased the estimated intraoperative blood loss (p = 0.02 for the low-dose group, p = 0.04 for the medium-dose group, and p = 0.1 for the high-dose group), the measured postoperative drainage volume (p = 0.4 for the low-dose group, p = 0.006 for the medium-dose group, and p = 0.000 for the high-dose group), and the mean reduction in the hemoglobin level on the second postoperative day (thirty-four grams per liter for the placebo group, twenty-eight grams per liter for the low-dose group [p = 0.000], twenty-six grams per liter for the medium-dose group [p = 0.000], and twenty-three grams per liter for the high-dose group [p = 0.000]). The rate of deep-vein thrombosis was similar for all groups.

Conclusions: We concluded that aprotinin is safe and effective for use as a hemostatic agent in primary unilateral total hip replacements. In patients who are at high risk of receiving allogeneic blood, use of aprotinin may be of particular clinical and economic benefit.

Figures in this Article

Introduction

Introduction | Materials and Methods | Results | Discussion | References

Hip replacement operations are associated with notable blood loss, averaging three to four units^24,32. While transfusions can counter this loss, minimizing blood replacement is desirable for several reasons. First, blood is often in short supply. Second, the use of allogeneic blood is associated with a risk of infection from hepatitis C, the human immunodeficiency virus, and bacteria⁶. Third, blood use is associated with increased costs⁵. Thus, the development of techniques to reduce the use of allogeneic blood is important for medical and economic reasons. Donation of autologous blood before an elective operation may avoid the need for allogeneic transfusion, although this approach may be associated with an increased risk of transfusion overall, increased costs, and other disadvantages^{15,18,25,26,39}. Alternatively, acute normovolemic hemodilution, blood salvage, and hemostatic agents may reduce the need for donor blood¹⁸. The use of hemostatic agents has the added potential advantage of yielding a drier operative field and thereby reducing operative times and complications.

Aprotinin, a naturally occurring peptide with a molecular weight of 6512 daltons, has been used successfully for years as a blood-sparing agent during coronary artery bypass grafting operations^3,12,21. Aprotinin, a broad-spectrum serine-protease inhibitor, inhibits trypsin, plasmin, and plasma and tissue kallikreins. It improves hemostasis during coronary artery bypass grafting, most likely through regulation of fibrinolysis, modulation of the intrinsic coagulation pathway, and stabilization of platelet function^{11,23,29,34,35}. In addition, through inhibition of serine proteases, aprotinin exhibits anti-inflammatory properties including decreased adhesion and activation of neutrophils as well as reduced production of complement and inflammatory cytokines, which may ultimately act to decrease tissue injury^29,31.

Two early single-center studies performed by Haas et al.²⁰ and Wollinsky et al.³⁷ indicated that aprotinin decreased blood loss during total hip replacement. In addition, Haas et al. showed that aprotinin reduced the number of patients requiring perioperative transfusions. More recently, Janssens et al. evaluated patients undergoing primary total hip replacement in a prospective, single-center, double-blind, placebo-controlled clinical trial²⁴. Forty patients were randomized to receive either a high dose of aprotinin (a loading dose of 2,000,000 kallikrein inhibitor units [KIU]) followed by a continuous infusion of 500,000 KIU per hour) or an equivalent volume of saline solution. The investigators found that patients managed with aprotinin had significantly less blood loss (p = 0.05) and required fewer blood transfusions (p < 0.001) than patients treated with a placebo. Subsequently, one of us (J. M. M.) and colleagues conducted a prospective, single-center, double-blind, randomized, placebo-controlled trial in which fifty-three patients undergoing bilateral total hip replacement or revision total hip replacement received either a high dose of aprotinin or an equivalent volume of saline solution; again, aprotinin significantly reduced blood loss (p = 0.022) and the amount of red blood cells transfused (confidence interval for the difference, -1.69 to -0.07)²⁸.

A potential concern regarding blood-sparing therapies during hip operations is the relatively high risk of deep-vein thrombosis. None of the above studies demonstrated a higher risk of deep-vein thrombosis in patients treated with aprotinin. Haas et al. reported very similar rates of deep-vein thrombosis for patients treated with aprotinin and for control patients²⁰. Both Janssens et al.²⁴ and Murkin et al.²⁸ observed cases of deep-vein thrombosis but only in patients treated with a placebo. These investigations were relatively limited with regard to the number of patients, with a maximum of fifty-three patients per study. Therefore, to address the question of efficacy and safety definitively, a larger study with sufficient statistical power was undertaken.

The objectives of the present multicenter, randomized, placebo-controlled, double-blind clinical trial were twofold. First, the safety of three different aprotinin dosage regimens and the efficacy for decreasing blood loss and transfusion requirements in patients undergoing an elective primary unilateral total hip replacement were compared with those of a placebo. Second, while all patients received standard prophylaxis against deep-vein thrombosis, the effect of aprotinin on the prevalence of deep-vein thrombosis was examined.

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Fig. 1:: Graph showing the effect of aprotinin, according to predonation stratum, on the percentage of patients with a primary unilateral total hip replacement who required a blood transfusion. LDA = low-dose aprotinin (loading dose of 500,000 kallikrein inhibitory units [KIU]), MDA = medium-dose aprotinin (loading dose of 1,000,000 KIU, with continuous infusion of 250,000 KIU per hour), and HDA = high-dose aprotinin (loading dose of 2,000,000 KIU, with continuous infusion of 500,000 KIU per hour). The asterisk indicates that the finding was significantly different from that for the patients who received the placebo (p < 0.05).

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Fig. 2:: Graph showing the effects of aprotinin, according to predonation stratum, on the percentage of patients with a primary unilateral total hip replacement who required allogeneic blood transfusion. The asterisk indicates that the finding was significantly different from that for the patients who received the placebo (p < 0.05).

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Fig. 3:: Graph showing the effects of aprotinin on the estimated intraoperative blood loss, the postoperative drainage volume, and the total of both for patients who had a primary unilateral total hip replacement. LDA = low-dose aprotinin (loading dose of 500,000 kallikrein inhibitory units [KIU]), MDA = medium-dose aprotinin (loading dose of 1,000,000 KIU, with continuous infusion of 250,000 KIU per hour), and HDA = high-dose aprotinin (loading dose of 2,000,000 KIU, with continuous infusion of 500,000 KIU per hour). The asterisk indicates that the finding was significantly different from that for the patients who received the placebo (p < 0.05).

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Fig. 4:: Graph showing the effects of aprotinin on the change from the mean baseline hemoglobin levels in patients who had a primary unilateral total hip replacement. LDA = low-dose aprotinin (loading dose of 500,000 kallikrein inhibitory units [KIU]), MDA = medium-dose aprotinin (loading dose of 1,000,000 KIU, with continuous infusion of 250,000 KIU per hour), and HDA = high-dose aprotinin (loading dose of 2,000,000 KIU, with continuous infusion of 500,000 KIU per hour). The asterisk indicates that the finding was significantly different from that for the patients who received the placebo (p < 0.05).

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TABLE I: Baseline Characteristics of the Patients*

*The data is given for the patient population that was considered valid for inclusion in the efficacy analysis.†The values are given as the number of patients with the percentage in parentheses.‡The values are given as the least squares mean.Â§P values for pairwise comparisons with the placebo group were 0.155 for the group managed with low-dose aprotinin, 0.005 for the group managed with medium-dose aprotinin, and 0.877 for the group managed with high-dose aprotinin.#P value for the distribution.

Variable	Placebo (N = 68)	Low-Dose Aprotinin (N = 69)	Medium-Dose Aprotinin (N = 68)	High-Dose Aprotinin (N = 75)	P Value
Gender†
Men	32 (47)	34 (49)	27 (40)	46 (61)	0.08
Women	36 (53)	35 (51)	41 (60)	29 (39)
Race†
White	64 (94)	66 (96)	68 (100)	72 (96)	0.242
Black	2 (3)	2 (3)	0 (0)	2 (3)
Hispanic	2 (3)	1 (1)	0 (0)	1 (1)
Mean age (yrs.)	63.2	63.7	65.5	63.4	0.67
Mean weight (kg)	80.9	81.1	76.4	84.4	0.09
Mean height (cm)	168	168	167	170	0.13
Hemoglobin level‡ (grams per liter)	133	130	127	133	Â§
No. (percent) of patients who predonated autologous blood	46 (68)	45 (65)	42 (62)	52 (69)	0.66
Units of predonated autologous blood†
0	22 (32)	24 (35)	26 (38)	23 (31)	0.66#
1	17 (25)	9 (13)	8 (12)	8 (11)
2	24 (35)	28 (41)	27 (40)	38 (51)
3	5 (7)	8 (12)	7 (10)	5 (7)
4	0 (0)	0 (0)	0 (0)	1 (1)
Mean	1.2	1.3	1.2	1.4

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TABLE I: Baseline Characteristics of the Patients*

Variable	Placebo (N = 68)	Low-Dose Aprotinin (N = 69)	Medium-Dose Aprotinin (N = 68)	High-Dose Aprotinin (N = 75)	P Value
Gender†
Men	32 (47)	34 (49)	27 (40)	46 (61)	0.08
Women	36 (53)	35 (51)	41 (60)	29 (39)
Race†
White	64 (94)	66 (96)	68 (100)	72 (96)	0.242
Black	2 (3)	2 (3)	0 (0)	2 (3)
Hispanic	2 (3)	1 (1)	0 (0)	1 (1)
Mean age (yrs.)	63.2	63.7	65.5	63.4	0.67
Mean weight (kg)	80.9	81.1	76.4	84.4	0.09
Mean height (cm)	168	168	167	170	0.13
Hemoglobin level‡ (grams per liter)	133	130	127	133	Â§
No. (percent) of patients who predonated autologous blood	46 (68)	45 (65)	42 (62)	52 (69)	0.66
Units of predonated autologous blood†
0	22 (32)	24 (35)	26 (38)	23 (31)	0.66#
1	17 (25)	9 (13)	8 (12)	8 (11)
2	24 (35)	28 (41)	27 (40)	38 (51)
3	5 (7)	8 (12)	7 (10)	5 (7)
4	0 (0)	0 (0)	0 (0)	1 (1)
Mean	1.2	1.3	1.2	1.4

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TABLE II: Prevalence of Adverse Events*

*The data is given for the patient population that was considered valid for inclusion in the safety analysis, and the values are given as the percentage of patients.†Analysis was based on the ultrasound and follow-up examinations.‡The number of patients in this analysis was slightly less than the total given for each group, as only seventy-one patients in the placebo group, seventy-one in the low-dose group, seventy-two in the medium-dose group, and seventy-four in the high-dose group were monitored with an electrocardiogram.

Variable	Placebo (N = 73)	Low-Dose Aprotinin (N = 76)	Medium-Dose Aprotinin (N = 75)	High-Dose Aprotinin (N = 77)
Any adverse event	79	80	80	77
Any drug-related adverse event	42	50	43	47
Any mild adverse event	62	63	64	58
Any moderate adverse event	51	43	45	55
Any severe adverse event	11	9	3	4
Deep-vein thrombosis†	10	5	10	11
Any worsening interpretation of electrocardiogram‡	38	39	38	18

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TABLE II: Prevalence of Adverse Events*

Variable	Placebo (N = 73)	Low-Dose Aprotinin (N = 76)	Medium-Dose Aprotinin (N = 75)	High-Dose Aprotinin (N = 77)
Any adverse event	79	80	80	77
Any drug-related adverse event	42	50	43	47
Any mild adverse event	62	63	64	58
Any moderate adverse event	51	43	45	55
Any severe adverse event	11	9	3	4
Deep-vein thrombosis†	10	5	10	11
Any worsening interpretation of electrocardiogram‡	38	39	38	18

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Study Design

The present double-blind, placebo-controlled study compared three doses of aprotinin with a placebo consisting of saline solution. The sixteen participating sites were located in the United States and Canada. The protocol was approved by each institutional ethics board, and the patients provided written informed consent. Three hundred and one patients were randomized into four groups and were stratified on the basis of whether or not preoperative autologous blood donations had been made^15,25,38.

Patient Population

Patients who were at least eighteen years old and were scheduled for an elective unilateral primary total hip replacement were screened for inclusion in the study. Those who had received aprotinin previously or who had a known or suspected allergy to aprotinin or warfarin were excluded. Pregnant women and those of child-bearing age, patients who had participated in an investigational drug study within the previous thirty days, and those who refused donor-blood products were ineligible for participation. Patients with a history of deep-vein thrombosis, pulmonary embolism, diabetes mellitus with a serum creatinine level above the upper limit of normal (1.5 milligrams per deciliter [133 micromoles per liter]), impaired renal function (a serum creatinine level of greater than 2.5 milligrams per deciliter [221 micromoles per liter]), failure of a major organ system, or an important medical illness (for example, decompensated congestive heart failure or notably elevated levels of hepatic enzymes) were excluded.

According to the study protocol, patients received whole blood or packed red blood cells if the hematocrit was 18 percent or less or if the hematocrit was greater than 18 percent and administration of blood or red blood cells was considered medically necessary. Therefore, no patient in the study had a low preoperative red blood-cell volume requiring preoperative administration of blood or use of intraoperative blood salvage equipment. Those who had a history of a bleeding disorder necessitating administration of a drug as prophylaxis against bleeding during the operation were also excluded from the study.

Treatment Groups

The study medication for intravenous infusion was supplied in sterile, sealed, fifty-milliliter vials that appeared identical for all doses of aprotinin (Trasylol) and placebo. The labels on all vials were the same except for the consecutive patient number. The medication for each patient was supplied in a box that was affixed with a two-part label. Part one of the label had a sealed, blinded area that concealed the identity and lot number of the contents. After transfer to the operating room and initiation of monitoring, all patients received a one-milliliter test dose intravenously (taken from the loading dose) before or after the induction of anesthesia. If there was no evidence of hypersensitivity to the drug after at least ten minutes, the full loading dose was administered after the induction of anesthesia, either regional or general. The contents of four fifty-milliliter vials of study medication were drawn up, injected into a sterile infusion bag, and continuously infused at a rate of fifty milliliters per hour until the procedure was completed and the skin was closed. Seventy-six patients received a loading dose of 500,000 KIU of aprotinin but no subsequent continuous infusion (low dose), seventy-five patients received a 1,000,000-KIU loading dose followed by continuous infusion of 250,000 KIU per hour (medium dose), seventy-seven patients received a loading dose of 2,000,000 KIU followed by continuous infusion of 500,000 KIU per hour (high dose), and seventy-three patients received the placebo.

The study medication, an adjunct to treatment, did not preclude the use of any drug necessary for the safe conduct of routine, preoperative, intraoperative, or postoperative procedures. Hemostatic agents, including desmopressin and e-aminocaproic acid, were not given prophylactically but were administered if mandated by an acute deterioration in the condition of the patient. Blood salvage was not permitted. Prophylaxis against deep-vein thrombosis, ten milligrams of warfarin administered orally on the evening of the day of the operation (within twelve hours after skin closure), was administered to patients with an international normalized ratio of less than 1.3. Patients received subsequent doses of warfarin to maintain an international normalized ratio between 2.0 and 3.0. Treatment was continued for one to three weeks or longer if clinically indicated. Warfarin was not administered to patients with an international normalized ratio of 1.3 or greater. Plasma expanders were not routinely given. Hypovolemic patients who did not require blood transfusion and were unresponsive to crystalloid fluid replacement received colloid replacement therapy.

Efficacy Evaluations

The primary variable to determine efficacy was the percentage of patients who required allogeneic or autologous blood or packed red blood cells through the seventh postoperative day. A secondary variable was the number of units transfused. A quantitative estimate of intraoperative blood loss was provided by the anesthesiologist. The overall volume of drainage from the operative site was recorded for the first six hours after skin closure and subsequently until the operative drains were removed. Patients had transfusion of whole blood or packed red blood cells if the postoperative hematocrit was 18 percent or less or if clinically warranted.

Safety Evaluations

Patients underwent a complete physical examination at screening and prior to discharge. These examinations included measurement of vital signs (heart rate, blood pressure, temperature, and respiration rate), standard twelve-lead electrocardiography, and routine laboratory evaluations consisting of blood tests (including prothrombin time and activated partial thromboplastin time) and urinalysis. Postoperatively, patients were questioned in a systematic but nonspecific way about possible adverse or unusual effects. All adverse events were recorded, and the intensity and duration of such events were noted. The investigator indicated whether the event was probably, possibly, or not related to the study drug. On the tenth postoperative day, or just prior to discharge if that occurred before the tenth postoperative day but not before the fifth postoperative day, patients underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis^19,28,30. A follow-up visit was conducted three months after discharge from the hospital to examine the lower extremities and to determine if there had been any serious adverse events.

Statistical Analysis

Estimation of the sample size was based on an expectation that 50 percent of the patients treated with a placebo would require a transfusion with blood or packed red blood cells. A clinically meaningful effect of aprotinin was defined as 50 percent fewer patients treated with high-dose aprotinin requiring a transfusion relative to the number of patients treated with a placebo who needed a transfusion. A study of seventy patients randomized to each treatment was determined to have an 80 percent power to reject the hypothesis that there was no difference between treatments when in fact a clinically meaningful difference existed. Calculations assumed two-sided testing at an alpha level of 0.05, with a 15 percent increase in sample size to account for the multicenter nature of the study.

The primary efficacy analysis included all patients who satisfied the inclusion and exclusion criteria, received the study medication, and underwent a scheduled procedure. It was considered valid to use the patients who received a test dose only in the safety analyses. The primary comparison was between the patients who received high-dose aprotinin and those who received the placebo. All tests for treatment effect were two-tailed and performed at an alpha level of 0.05. For continuous variables, a main effects analysis-of-variance model with effects for treatment, stratum, and center was used. By-stratum results were tabulated. Treatment-by-center and treatment-by-stratum interactions were evaluated separately. All variables related to units of blood or blood product were analyzed nonparametrically with use of Mantel-Haenszel tests based on modified ridit scores. Categorical variables were analyzed with use of chi-square, Fisher's exact, or Mantel-Haenszel tests as appropriate.

Results

Introduction | Materials and Methods | Results | Discussion | References

The patients in each of the four groups were comparable with respect to race, age, height, and weight (Table I). Despite randomization, the group managed with high-dose aprotinin had more men (p = 0.08). The group that received medium-dose aprotinin, but not the groups that received low-dose and high-dose aprotinin, had a significantly lower mean baseline hemoglobin level than did the group that received the placebo (127 compared with 133 grams per liter; p = 0.005). With the numbers available, no significant differences were observed among groups with respect to the percentage of patients who predonated blood, with respect to the operative approach (31 percent [eighty-eight of 280 patients] had a posterior approach, 29 percent [eighty] had an anterolateral approach, and 40 percent [112] had another approach) (p = 0.379), or with respect to the proportion of procedures performed with cement fixation (51 percent [143 patients]) (p = 0.165). The mean operating times tended to be reduced in the groups that received low-dose aprotinin (1.7 hours; p = 0.072) and medium-dose aprotinin (1.7 hours; p = 0.066) compared with the group that received the placebo (1.9 hours), although the effect was not found to be significant; the group that received high-dose aprotinin had a mean operating time of 1.8 hours (p = 0.714).

Efficacy Evaluations

Transfusion requirements were reduced significantly from 47 percent (thirty-two of sixty-eight patients) in the group that had received the placebo to 28 percent (nineteen of sixty-nine patients) in the group that had received low-dose aprotinin (p = 0.02) and 27 percent (twenty of seventy-five patients) in the group that had received high-dose aprotinin (p = 0.008) (Fig. 1). No significant effect was observed for the group that had received medium-dose aprotinin (40 percent [twenty-seven of sixty-eight patients]; p = 0.5). These findings remained consistent through the end of hospitalization.

Evaluation of the patients who had predonated blood (Fig. 1) revealed that the prevalence of transfusion was significantly reduced by high-dose aprotinin (31 percent [sixteen of fifty-two patients]; p = 0.02) compared with the placebo (54 percent [twenty-five of forty-six patients]). In comparison, 36 percent (sixteen) of the forty-five patients who had received low-dose aprotinin and had predonated blood (p = 0.05) and 57 percent (twenty-four) of the forty-two patients who had received medium-dose aprotinin and had predonated blood (p = 0.97) required a transfusion. The patients who had not predonated blood had a lesser tendency to receive a transfusion than did patients who had predonated blood, regardless of treatment group (Fig. 1). In the group that had not predonated blood, 32 percent (seven) of the twenty-two patients who had received the placebo had transfusion of blood or packed red blood cells compared with 13 percent (three) of the twenty-four patients managed with low-dose aprotinin (p = 0.19), 12 percent (three) of the twenty-six patients managed with medium-dose aprotinin (p = 0.17), and 17 percent (four) of the twenty-three patients managed with high-dose aprotinin (p = 0.22).

Allogeneic Blood Transfusion

The percentage of aprotinin-treated patients who required allogeneic blood (6 percent [twelve of 212]) was significantly reduced compared with the percentage of placebo-treated patients who required allogeneic blood (15 percent [ten of the sixty-eight]) (p = 0.03) (Fig. 2). Six percent of the patients who had low-dose aprotinin (p = 0.18), 4 percent of those who had medium-dose aprotinin (p = 0.06), and 7 percent of those who had high-dose aprotinin (p = 0.17) required allogeneic blood. In the group that had not predonated blood, aprotinin tended to result in fewer exposures to allogeneic blood (14 percent [ten] of seventy-three patients compared with 32 percent [seven] of twenty-two patients who had received the placebo; p = 0.06).

Volume of Blood Transfusion

Through the seventh postoperative day, blood transfusion was not required by 53, 72, 60, and 73 percent of the patients who had received the placebo and low-dose, medium-dose, and high-dose aprotinin, respectively. One unit of blood was given to 18, 10, 12, and 7 percent of the patients, respectively, and two units or more were administered to 29, 17, 28, and 15 percent of the patients, respectively. Compared with the placebo, aprotinin tended to reduce the number of units transfused (p = 0.08 for the low-dose aprotinin, p = 0.50 for the medium dose, and p = 0.05 for the high dose).

Blood Loss

The estimated mean intraoperative blood loss was significantly lower for the groups managed with low-dose aprotinin (558 milliliters; p = 0.02) and medium-dose aprotinin (573 milliliters; p = 0.04) (Fig. 3) than for the placebo group (698 milliliters); the group managed with high-dose aprotinin showed a trend in this regard (603 milliliters; p = 0.1). Aprotinin elicited a dose-related reduction in the total postoperative drainage volume; the mean volume was 634 milliliters in the placebo group and 580 milliliters (p = 0.4), 459 milliliters (p = 0.006), and 413 milliliters (p = 0.000) in the groups managed with low-dose, medium-dose, and high-dose aprotinin, respectively. Aprotinin also reduced total intraoperative blood loss and postoperative drainage volume, with a mean total of 1408 milliliters for the placebo group compared with 1169 milliliters (p = 0.034), 1090 milliliters (p = 0.005), and 1079 milliliters (p = 0.003) for the groups managed with low-dose, medium-dose, and high-dose aprotinin, respectively. Interestingly, no significant difference in blood loss was observed between the patients who received blood and those who did not (p = 0.800). Moreover, no consistent relationship was observed between blood loss and transfusion requirements across the four treatment groups.

The effect of treatment with aprotinin during the operation on the mean postoperative hemoglobin level was evaluated (Fig. 4). The groups had comparable mean baseline hemoglobin levels, with the exception of the group managed with medium-dose aprotinin (Table 1). Postoperatively, all treatment groups had a mean decrease in the hemoglobin level; however, aprotinin significantly attenuated this effect. The mean hemoglobin level on the second postoperative day, which was reduced by thirty-four grams per liter in patients who had received the placebo, was decreased by only twenty-eight grams per liter (p = 0.000), twenty-six grams per liter (p = 0.000), and twenty-three grams per liter (p = 0.000) in the patients who had received low-dose, medium-dose, and high-dose aprotinin, respectively.

Safety Evaluations

It was considered valid to include all patients in the safety analysis, and 99 percent (seventy-two) of the seventy-three patients managed with the placebo, 96 percent (seventy-three) of the seventy-six patients managed with low-dose aprotinin, 99 percent (seventy-four) of the seventy-five patients managed with medium-dose aprotinin, and 100 percent of the seventy-seven patients managed with high-dose aprotinin completed the study. No patient left the study due to adverse events (Table II). Treatment with aprotinin generally was well tolerated. Serious adverse events, including those leading to death, occurred with a similar frequency in all four treatment groups. Two patients died during the study period. One patient who was managed with the placebo had an acute myocardial infarction fourteen days postoperatively. The second patient, who had received low-dose aprotinin, manifested septic shock, rhabdomyolysis, and acute kidney failure beginning five days after the operation and died of respiratory failure on the twenty-third postoperative day.

All but nine patients underwent a postoperative ultrasound examination to evaluate for the presence of deep-vein thrombosis. Aprotinin had no effect on the prevalence of deep-vein thrombosis as detected by ultrasound examination alone; it developed in 10 percent (seven) of seventy-one patients managed with the placebo compared with 4 percent (three) of seventy-four patients managed with low-dose aprotinin (p = 0.128), 10 percent (seven) of seventy-one patients managed with medium-dose aprotinin (p = 0.955), and 9 percent (seven) of seventy-six patients managed with high-dose aprotinin (p = 0.879). The prevalences of deep-vein thrombosis as determined on the basis of the findings of the ultrasound and three-month follow-up examinations were similar (Table II). At the time of discharge, the international normalized ratio values resulting from treatment with warfarin tended to be higher in patients with deep-vein thrombosis than in those without it (p = 0.06), indicating that deep-vein thrombosis did not result from inadequate anticoagulation; no consistent effects were observed across the treatment groups. Accordingly, the prevalence of deep-vein thrombosis, after adjusting for the international normalized ratio at discharge, did not change (p = 0.65).

There were no clinically important abnormalities in the laboratory values or changes in vital signs among the patients. The findings on the electrocardiograms were also similar for all groups.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

In the present study, we examined the efficacy and safety of aprotinin when used to reduce blood loss and transfusion requirements for patients undergoing a primary unilateral total hip replacement. As 47 percent (thirty-two) of sixty-eight patients treated with the placebo received a transfusion (compared with a predicted rate of 50 percent), this study had an adequate power to show a difference in treatment effects for the group treated with high-dose aprotinin. Aprotinin significantly decreased perioperative blood loss in patients undergoing a total hip replacement. These findings confirmed those of previous studies^8,24,28.

High-dose and low-dose aprotinin significantly reduced the percentage of patients who received a transfusion (p = 0.008 and 0.02, respectively). Safety concerns, supply issues, and the cost of blood products all contribute to the desire to reduce blood transfusion in general^17,18. Although preoperative autologous blood donation may alleviate some of these concerns, the direct costs for collecting, testing, processing, storing, and delivering a unit of autologous blood may not accurately reflect the total costs associated with autologous transfusion^2,39. Preoperative autologous blood donation also increases the likelihood of receiving a transfusion, which may result from anemia or the application of a more liberal transfusion policy, or both^15,25,38. While this same bias was observed in the present investigation, the prevalence of transfusion for patients who had predonated blood was reduced significantly by the use of high-dose aprotinin (p = 0.02).

Aprotinin was found to significantly decrease the percentage of patients who were exposed to allogeneic blood in the series as a whole (p = 0.03); 6 percent (twelve) of the 212 patients managed with aprotinin needed a transfusion compared with 15 percent (ten) of the sixty-eight patients treated with the placebo. In addition, use of aprotinin tended to reduce exposure to allogeneic blood among the patients who had not predonated blood; 14 percent (ten) of the seventy-three patients who had received aprotinin and had not predonated blood needed allogeneic blood (p = 0.06) compared with 32 percent (seven) of the twenty-two patients who had received the placebo and had not predonated blood. Recent analysis of blood management in total hip or knee arthroplasty indicated that exposure to allogeneic blood is associated significantly with infection (p = 0.001), fluid overload (p = 0.001), and an increased duration of hospitalization (p = 0.01)⁴. The absence of predonated blood as well as a low preoperative hemoglobin level were consistent predictors of the need for allogeneic transfusion⁴. Our prospective, randomized study confirmed the survey data in that patients who had not predonated blood had a significantly higher risk of receiving allogeneic blood (18 percent [seventeen of ninety-five patients]) than those who had predonated (3 percent [five of 185 patients]) (p = 0.001). Baseline hemoglobin levels showed no relationship with the need for allogeneic blood, but this may have been affected by the study entry criteria. Notably, the direct cost of one unit of allogeneic blood (approximately $150 [United States dollars] per unit) is comparable with that of the starting dose of aprotinin, with a current hospital acquisition cost for use in a hip replacement of approximately $162 for a low dose of 100 milliliters of aprotinin to $486 for a high dose of 300 milliliters^13,33. Moreover, on the basis of the total incremental hospital costs of hip arthroplasty, allogeneic blood transfusion may be associated with $1000 to $1500 per unit in additional costs compared with the cost of no transfusion or of transfusion of one to five units of autologous blood⁵. Thus, use of aprotinin may be of particular clinical and economic benefit in patients at high risk of receiving allogeneic blood, such as those who have not predonated blood or perhaps those with a low baseline hemoglobin level.

In addition to its positive effects on transfusion requirements and blood loss, aprotinin significantly attenuated the decline in postoperative hemoglobin levels (p = 0.000). This also was observed in the group managed with medium-dose aprotinin, which exhibited significantly lower baseline hemoglobin levels (p = 0.005). The attenuated decline in postoperative hemoglobin levels resulting from treatment with aprotinin is consistent with its hemostatic actions and suggests that although patients treated with aprotinin tended to receive fewer transfusions they were not anemic as a result.

Reduced transfusion requirements were observed for patients managed with low-dose and high-dose aprotinin; however, on the basis of the numbers available, the group managed with medium-dose aprotinin did not have a significant reduction. The apparent lack of effect of medium-dose aprotinin may have resulted from subtle baseline differences (more women, increased age, and reduced stature) in this group coupled with a lower baseline hemoglobin level - all of which increase the likelihood of receiving a transfusion⁹. Patients undergoing an orthopaedic operation have been observed to have an increased risk of transfusion with baseline hemoglobin levels between 100 and 130 grams per liter compared with levels of greater than 130 grams per liter^4,7,10,14. Thus, despite reductions in intraoperative and postoperative blood loss associated with aprotinin compared with that associated with the placebo, the underlying baseline differences may have resulted in additional transfusion needs in the group managed with medium-dose aprotinin.

The current investigation, with use of standard anticoagulation prophylaxis, showed no significant difference among the four treatment groups with respect to the rate of deep-vein thrombosis, on the basis of the numbers available. Previous studies of patients who had a total hip replacement demonstrated no increase in the rate of deep-vein thrombosis with use of aprotinin^20,22,24,28. Diagnosis in the present study was based on compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs²⁸. Although contrast venography is considered the reference standard in objective diagnosis of deep-vein thrombosis, compression ultrasonography with color Doppler imaging provided a safe, noninvasive method for evaluating patients for postoperative deep-vein thrombosis^{1,19,27,30,36}. The 5 percent (four of seventy-six patients) to 11 percent (eight of seventy-seven patients) rates of deep-vein thrombosis observed in the present study, compared with a mean rate of 19 percent (thirty of 162 patients in three trials; 95 percent confidence limits, 0.13 to 0.26) reported in the literature¹⁶, imply that the ultrasound technology employed in the current study had a relatively lower sensitivity. Although asymptomatic deep-vein thrombosis developed in all treatment groups, its prevalence associated with use of aprotinin compared with that associated with the placebo cannot be stated categorically.

The present study showed that aprotinin safely reduces blood loss and transfusion requirements in patients undergoing an elective primary unilateral total hip replacement. Reducing transfusion needs decreases exposure to allogeneic blood. Minimizing blood loss during the operation has the added benefit of yielding a drier operative field. In conclusion, aprotinin is a safe agent for maintaining hemostasis in hip replacement operations.

Note: The members of the Aprotinin Study Group were George Babikian, M.D., Maine Medical Center, Portland, Maine; Karl Beer, M.D., The Toledo Hospital, Toledo, Ohio; Nick Cicutti, Ph.D., The Ottawa Hospital, Ottawa, Ontario, Canada; Richard Clark, M.D., Allegheny Singer Research Institute, Pittsburgh, Pennsylvania; Mark Comunale, M.D., Beth Israel Deaconess Medical Center, Boston, Massachusetts; Su Ganapathy, M.D., St. Joseph's Health Center, Ontario, Canada; Joanna Guay, M.D., Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada; Richard Hall, M.D., Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Jay Katz, M.D., Tucson Medical Center, Tucson, Arizona; Jeffrey Malka, M.D., Fairfax Hospital, Falls Church, Virginia; John McCutchen, M.D., Jewett Orthopaedic Clinic, Winter Park, Florida; Guirish Moudgil, M.D., Tulane Medical Center, New Orleans, Louisiana; John M. Murkin, M.D., London Health Sciences Center-UC, London, Ontario, Canada; Samuel Nasser, M.D., Hutzel Hospital-Wayne State University, Detroit, Michigan; and Jack L. Seaquist, M.D., Seton Medical Center, Austin, Texas.

References

Introduction | Materials and Methods | Results | Discussion | References

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de Smet, A. A.; Joen, M. C.; van Oeveren, W.; Roozendaal, K. J.; Harder, M. P.; Eijsman, L.; and Wildevuur, C. R.:: Increased anticoagulation during cardiopulmonary bypass by aprotinin. J. Thorac. and Cardiovasc. Surg.,100: 520-527, 1990.100520 1990

Dietrich, W.; Spannagl, M.; Jochum, M.; Wendt, P.; Schramm, W.; Barankay, A.; Sebening, F.; and Richter, J. A.: Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology,73: 1119-1126, 1990.731119 1990 [PubMed]

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Faris, P. M.; Ritter, M. A.; Abels, R. I.; and The American Erythropoietin Study Group: The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. J Bone Joint Surg,78-A: 62-72, Jan 1996.78-A62 1996

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Gallus, A. S.; Salzman, E. W.; and Hirsch, J.: Prevention of venous thromboembolism. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice, edited by R. W. Colman, J. Hirsch, V. J. Marder, and E. W. Salzman. Ed. 3, pp. 1333-1345. Philadelphia, J. B. Lippincott, 1994.

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TABLE I: Baseline Characteristics of the Patients*

Variable	Placebo (N = 68)	Low-Dose Aprotinin (N = 69)	Medium-Dose Aprotinin (N = 68)	High-Dose Aprotinin (N = 75)	P Value
Gender†
Men	32 (47)	34 (49)	27 (40)	46 (61)	0.08
Women	36 (53)	35 (51)	41 (60)	29 (39)
Race†
White	64 (94)	66 (96)	68 (100)	72 (96)	0.242
Black	2 (3)	2 (3)	0 (0)	2 (3)
Hispanic	2 (3)	1 (1)	0 (0)	1 (1)
Mean age (yrs.)	63.2	63.7	65.5	63.4	0.67
Mean weight (kg)	80.9	81.1	76.4	84.4	0.09
Mean height (cm)	168	168	167	170	0.13
Hemoglobin level‡ (grams per liter)	133	130	127	133	Â§
No. (percent) of patients who predonated autologous blood	46 (68)	45 (65)	42 (62)	52 (69)	0.66
Units of predonated autologous blood†
0	22 (32)	24 (35)	26 (38)	23 (31)	0.66#
1	17 (25)	9 (13)	8 (12)	8 (11)
2	24 (35)	28 (41)	27 (40)	38 (51)
3	5 (7)	8 (12)	7 (10)	5 (7)
4	0 (0)	0 (0)	0 (0)	1 (1)
Mean	1.2	1.3	1.2	1.4

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TABLE I: Baseline Characteristics of the Patients*

Variable	Placebo (N = 68)	Low-Dose Aprotinin (N = 69)	Medium-Dose Aprotinin (N = 68)	High-Dose Aprotinin (N = 75)	P Value
Gender†
Men	32 (47)	34 (49)	27 (40)	46 (61)	0.08
Women	36 (53)	35 (51)	41 (60)	29 (39)
Race†
White	64 (94)	66 (96)	68 (100)	72 (96)	0.242
Black	2 (3)	2 (3)	0 (0)	2 (3)
Hispanic	2 (3)	1 (1)	0 (0)	1 (1)
Mean age (yrs.)	63.2	63.7	65.5	63.4	0.67
Mean weight (kg)	80.9	81.1	76.4	84.4	0.09
Mean height (cm)	168	168	167	170	0.13
Hemoglobin level‡ (grams per liter)	133	130	127	133	Â§
No. (percent) of patients who predonated autologous blood	46 (68)	45 (65)	42 (62)	52 (69)	0.66
Units of predonated autologous blood†
0	22 (32)	24 (35)	26 (38)	23 (31)	0.66#
1	17 (25)	9 (13)	8 (12)	8 (11)
2	24 (35)	28 (41)	27 (40)	38 (51)
3	5 (7)	8 (12)	7 (10)	5 (7)
4	0 (0)	0 (0)	0 (0)	1 (1)
Mean	1.2	1.3	1.2	1.4

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TABLE II: Prevalence of Adverse Events*

Variable	Placebo (N = 73)	Low-Dose Aprotinin (N = 76)	Medium-Dose Aprotinin (N = 75)	High-Dose Aprotinin (N = 77)
Any adverse event	79	80	80	77
Any drug-related adverse event	42	50	43	47
Any mild adverse event	62	63	64	58
Any moderate adverse event	51	43	45	55
Any severe adverse event	11	9	3	4
Deep-vein thrombosis†	10	5	10	11
Any worsening interpretation of electrocardiogram‡	38	39	38	18

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TABLE II: Prevalence of Adverse Events*

Variable	Placebo (N = 73)	Low-Dose Aprotinin (N = 76)	Medium-Dose Aprotinin (N = 75)	High-Dose Aprotinin (N = 77)
Any adverse event	79	80	80	77
Any drug-related adverse event	42	50	43	47
Any mild adverse event	62	63	64	58
Any moderate adverse event	51	43	45	55
Any severe adverse event	11	9	3	4
Deep-vein thrombosis†	10	5	10	11
Any worsening interpretation of electrocardiogram‡	38	39	38	18