Transfusion and Apheresis Science 51 (2014) 152–161
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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Review
Use of aprotinin to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis Fei Huang a,1, Quancheng Zhao b,1, Chongyong Guo c, Guangwen Ma a,*, Qing Wang a, Yong Yin a, Yunfeng Wu a a
Department of Orthopaedics, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China Department of Neurosurgery, Binzhou People’s Hospital, Binzhou, China c Department of General Surgery, Binzhou People’s Hospital, Binzhou, China b
A R T I C L E
I N F O
Article history: Received 18 September 2013 Received in revised form 23 February 2014 Accepted 25 July 2014 Keywords: Aprotinin Blood loss Transfusion Meta-analysis
A B S T R A C T
Backgroud: Conflicting reports have been published regarding the effectiveness and safety of aprotinin in reducing blood loss and transfusion in patients undergoing orthopedic surgery. We performed a meta-analysis to evaluate the effectiveness and safety of aprotinin in reducing blood loss and transfusion in major orthopedic surgery. Materials and methods: MEDLINE, PubMed, EMBASE and Cochrane databases were searched for relevant studies. Only randomized controlled trials were eligible for this study. The weighted mean difference in blood loss, and number of transfusions per patient and the summary risk ratio of transfusion requirements, and deep-vein thrombosis (DVT) were calculated in the aprotinin-treated group and the control group. Results: Eighteen randomized controlled trials involving 1276 patients were included. The use of aprotinin reduced total blood loss by a mean of 498.88 ml (95% confidence interval [CI]; −735.03 to −262.72), intra-operative blood loss by a mean of 246.11 ml (95% CI; −352.11 to −140.11), post-operative blood loss by a mean of 169.11 ml (95% CI; −234.06 to −105.55), the number of blood transfusions per patient by 0.93 units (95% CI; −1.36 to −0.51). Aprotinin led to a signficant reduction in transfusion requirements (RR 0.59; 95% CI; 0.51 to 0.69) and no increase in the risk of DVT (RR 0.58; 95% CI; 0.38 to 1.08). Conclusion: The meta-analysis shows that aprotinin could significantly reduce blood loss and blood transfusion requirements in patients undergoing orthopedic surgery, and it did not appear to increase the risk of DVT. © 2014 Elsevier Ltd. All rights reserved.
Contents 1.
Methods ................................................................................................................................................................................................................................. 1.1. Study design ........................................................................................................................................................................................................... 1.2. Search methodology ............................................................................................................................................................................................ 1.3. Inclusion and exclusion criteria ....................................................................................................................................................................... 1.4. Study selection ...................................................................................................................................................................................................... 1.5. Data abstraction .................................................................................................................................................................................................... 1.6. Quality assessment .............................................................................................................................................................................................. 1.7. Statistical analysis .................................................................................................................................................................................................
* Corresponding author. Tel.: +86 551 62862617; fax: +86 551 62862617. E-mail address: [email protected] (G. Ma). 1 These authors have equal contribution to this work and should be considered as co-first author. http://dx.doi.org/10.1016/j.transci.2014.07.009 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
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2.
3.
Results .................................................................................................................................................................................................................................... 2.1. Characteristics of the included studies ......................................................................................................................................................... 2.2. Blood loss ................................................................................................................................................................................................................ 2.2.1. Total .......................................................................................................................................................................................................... 2.2.2. Intra-operative ..................................................................................................................................................................................... 2.2.3. Post-operative ....................................................................................................................................................................................... 2.3. Transfusion requirements .................................................................................................................................................................................. 2.4. Number of transfusions per patient .............................................................................................................................................................. 2.5. DVT complications ............................................................................................................................................................................................... 2.6. Subgroup analysis ................................................................................................................................................................................................ Discussion ............................................................................................................................................................................................................................. References .............................................................................................................................................................................................................................
Major orthopedic procedures may be associated with significant blood loss requiring transfusion of several units of blood [1]. However, blood transfusion carries the risk of immunological and non-immunological adverse effects, such as a higher rate of post-operative infections, intravascular haemolysis, transfusion induced coagulopathy, renal impairment or failure, and even increased mortality [2]. Numerous strategies, including autologous blood donation, autologous drain transfusion, regional anesthesia and acute normovolaemic haemodilution, have been used to reduce allogenic blood transfusion rates. However, their application is limited by their clinical and financial efficacy [3]. Antifibrinolytic therapy constitutes an effective method to control or reduce bleeding and to limit or avoid blood transfusion in current medical practice [4,5]. Aprotinin, a naturally occurring single-chain 58 amino acid polypeptide with a molecular weight of 6512 Da, is a proteinase inhibitor with antifibrinolytic properties that has found widespread application during cardiac surgical procedures due to its ability to decrease blood loss and transfusion requirements [6,7]. Numerous studies have investigated its efficacy in reducing blood loss and transfusion requirements in patients undergoing orthopedic surgery with various results. Thus, we conducted a meta-analysis of randomized controlled trials to assess the effectiveness and safety of aprotinin in reducing blood loss and transfusion in major orthopedic surgery. 1. Methods 1.1. Study design This review was based on Cochrane methodology for conducting meta-analysis. All data were reported according to the Quality of Reporting for Meta-analyses provided by the Handbook for Systematic Reviews of Interventions Version 5.0.0 [8].
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included “antifibrinolytics”, “cyklokapron”, “aprotinin”, “orthopedic surgery”, “hip surgery”, “knee surgery”, “spine surgery” and “randomized controlled trials”. Manufacturers were contacted for additional unpublished trials. Reference lists of included studies and relevant reviews were checked for additional trials. 1.3. Inclusion and exclusion criteria Studies were included if they met the following criteria: (i) participants undergoing orthopedic surgery; (ii) randomly assigned patients to the treatment group who received aprotinin and the control group who received a placebo or no treatment; (iii) neither the aprotinin-treated group nor the control group used anticoagulant drugs; (iv) both groups reported one of the following outcomes: the amount of blood loss, the number of patients receiving allogeneic transfusion, the number of blood transfusion units per patient and the number of patients with deep-vein thrombosis. Studies were excluded if they were non-English language, or if there were nonrandomized controlled trials or randomized controlled trials that did not contain any of the above outcomes. 1.4. Study selection The initial electronic databases searches to identify potential studies for inclusion based on title and abstract information were performed by two independent authors (H.F, Z.Q.C). When there was a dispute, the full article was retrieved for further scrutiny. Completely study reports were assessed for inclusion independently by both authors, and authors were contacted for more information and clarification of data as necessary. Any disagreement was resolved by consensus or consultation with the senior authors (M.G.W). References and data for each included study were carefully cross-checked to ensure no overlapping data was presented.
1.2. Search methodology 1.5. Data abstraction We sought published randomized controlled trials that evaluated aprotinin in patients undergoing orthopedic surgery. The published literature was searched by a literature search from 1966 to April 2013 using the electronic databases including the MEDLINE, PubMed, EMBASE and Cochrane Database of Systematic Reviews. The search terms
Data extracted from the included studies were entered by two independent authors (H.F, Z.Q.C). Any disagreement was resolved by consensus or consultation with the senior authors (M.G.W). Data extracted included: sample size, study design, subject age, type of surgery, dose and
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timing of aprotinin and outcome data. In addition, adverse outcomes were recorded. For studies without adverse outcomes, author(s) were contacted for confirmation or more information regarding adverse events, if necessary. 1.6. Quality assessment Assessment of the methodological quality of the included studies was performed by two independent investigators (H.F, Z.Q.C). Disagreements were resolved by consensus or consultation with the senior authors (M.G.W). Each study was assessed according to the 5-point scale introduced by Jadad et al. [9]. The maximum quality score given to a study by this instrument is five points (up to two points for random assignment, up to two points for blinding investigators and patients, and one point if all enrolled patients are accounted for at the conclusion of the study, with reasons given for all dropouts and withdrawals). A score of ≤2 indicates “low” quality, while ≥3 indicates “high” quality.
Fig. 1. Selection of studies for meta-analysis. RCTs = randomized controlled trials; n = number of papers.
1.7. Statistical analysis The Review Manager software (RevMan version 5.0, Cochrane Collaboration, Freiburg, Germany) was used to analyze elected studies. For continuous data, such as blood loss, mean ± standard deviation (mean ± SD) was used to calculate the weighted mean difference (WMD) and 95% confidence interval. For dichotomous data, relative risk (RR) and 95% CI were applied. Statistical heterogeneity was assessed using the value of I 2 and the result of the chisquared test. A P-value < 0.1 and an I2 value >50% were considered suggestive of statistical heterogeneity, prompting a random effects modeling estimate. Otherwise, a fixed effects approach was used. However, a non-significant chisquared test result (a P-value ≥ 0.1 and an I2 value ≤ 50%) only indicated a lack of evidence for heterogeneity, but not implied necessarily homogeneity, as there may have been insufficient power to be able to detect heterogeneity [10]. When the data allowed, we performed subgroup analysis of the trials according to the type of surgery, general anesthesia and administration of heparin. 2. Results 2.1. Characteristics of the included studies A total of 157 abstracts and titles were reviewed. According to the inclusion and exclusion criteria, we identified 18 randomized controlled trials associated with orthopedic surgery (Fig. 1) [11–28]. A total of 1276 patients were enrolled in the randomized controlled trials. Nine studies involved hip surgery [11–19], three studies involved spinal surgery [20–22], two studies involved knee surgery [23,24] and four studies involved other surgery [25–28]. The number of patients included in these randomized controlled trials ranged from 17 to 352. A systematic clinical and (or) duplex ultrasound screening for thrombosis was undertaken during the post-operative period, and patients received standard thromboprophylaxis in the majority of included trials. The median Jadad score was 3 (range, 2–5). Details of the se-
lected trials are shown in Table 1. DVT complications, the most frequently cited outcome, were used to generate the funnel plot analysis of publication bias. The asymmetric characteristic of the funnel plot indicated the presence of publication bias (Fig. 2). 2.2. Blood loss 2.2.1. Total Total blood loss was examined in 11 trials with 436 patients. The use of aprotinin significantly reduced total blood loss by a mean of 498.88 ml (95% CI; −735.03 to −262.72; P < 0.0001). However, there was significant heterogeneity (I2 = 85%) among included studies (Fig. 3). 2.2.2. Intra-operative Thirteen studies with a total of 839 patients were eligible for this outcome. These trials randomized 420 patients to receive aprotinin and 419 patients as controls. The use of aprotinin significantly reduced intra-operative blood loss by a mean of 246.11 ml (95% CI; −352.11 to −140.11; P < 0.00001) (Fig. 4). 2.2.3. Post-operative Thirteen studies with a total of 844 patients were eligible for this outcome. The effect of aprotinin was similar, significantly reduced post-operative blood loss by a mean of 169.81 ml (95% CI; −234.06 to −105.55; P < 0.00001) (Fig. 5). 2.3. Transfusion requirements Data on transfusion requirements were examined in 11 trials, including a total of 1172 patients. Aprotinin reduced the probability of receiving a blood transfusion by 41% (RR 0.59; 95% CI; 0.51 to 0.69; P < 0.00001) (Fig. 6).
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Fig. 2. Funnel plot of DVT to assess publication bias. SE = standard error. DVT = deep-vein thrombosis.
2.4. Number of transfusions per patient
2.6. Subgroup analysis
This outcome measure was available in 10 studies with 706 patients. The use of aprotinin significantly reduced the average number of blood transfusion per patient when compared with the control group (weighted mean difference; −0.93 units [95% CI −1.36 to −0.51 units]; P < 0.0001) (Fig. 7).
There was significant heterogeneity in the study outcomes. Subgroup analysis according to surgery type, anesthesia and DVT prophylaxis did not adequately explain the variation in outcomes (Table 2). 3. Discussion
2.5. DVT complications Twelve studies with 987 patients reported DVT complications. Patients receiving aprotinin (567 patients) had 21 episodes of DVT while 420 patients who did not receive aprotinin had a total of 19 episodes. The rate of DVT was not affected by the use of aprotinin when the aprotinin group was compared with the control group (RR 0.58; 95% CI; 0.31 to 1.08; P = 0.09) (Fig. 8).
The significant blood loss and risk for blood transfusion are important features that must be considered in orthopedic surgery. This is a result of several characteristics inherent to the surgery, such as extensive bone decortication, fluid therapy-induced dilutional coagulopathy, and the microthrombi present in transfusion blood. Several methods have been reported to reduce blood loss and blood transfusion after surgery. Techniques such as autologous
Fig. 3. Forest plot diagram showing the effect of aprotinin on total blood loss.
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Table 1 Characteristics of included studies. Number (Tx/C)
Mean age (year) (Tx/C)
Surgical methods
Intervention
DVT prophylaxis
DVT screen
Blood transfusion protocol
Anesthetic technique
Jadad score
Ray et al. (2005) [11]
15/15
72/69
THA
Aspirin
Ultrasound
3
69, 68, 75/68
(a) 63.7/63.2 (b) 65.5/63.2
THA
Warfarin
Ultrasound
Depending on patient’s condition Hct < 18% or clinical decision
General
Murkin et al. (2000) [12]
Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h for 3 h Control: saline Aprotinin: (a) 5 × 105 KIU after aneathesia (b) 1 × 106 KIU followed by 2.5 × 105 KIU/h during surgery (c) 2 × 106 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 1.5 × 106 KIU at the time fo aneathesia Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline Aprotinin: 2 × 106 KIU as a single dose Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline Aprotinin: 3.8 × 106 KIU total Control: saline Aprotinin: 5 × 105 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 2 × 104 KIU/kg at anesthesia followed by 5 × 104 KIU/hr Control: saline Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h over the next 2 h Control: —
NA
3
NA
NA
NA
Spinal
4
LMWH
Clinical
Hct < 30%
General
3
LMWH
NA
Clinical
Spinal
3
LMWH
Clinical
Hct < 18%
NA
4
Heparin
Ultrasound
Hb < 80 g/L
General
5
LMWH
Clinical
NA
General
3
Enoxaparin
NA
NA
NA
2
Heparin
Angiography
Depending on patient’s condition
General
3
(c) 63.4/63.2
Langdown et al. (2000) [13] Janssens et al. (1994) [14] Hayes et al. (1996) [15] Colwell et al. (2007) [16]
30/30
NA
THA
20/20
64.9/65.3
THA
20/20
70/72.9
THA
175/177
63.4/64.4
THA
Murkin et al. (1995) [17] D’Ambrosio et al. (1999) [18] Petsatodis et al. (2006) [19] Thorpe et al. (1994) [26]
29/24
66.9/65.5
THA
15/15
66.6/60.5
THA
25/25
58/59.6
THA
8/9
NA
TKA
(continued on next page)
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Author/s
Table 1 (continued) Number (Tx/C)
Mean age (year) (Tx/C)
Surgical methods
Intervention
DVT prophylaxis
DVT screen
Blood transfusion protocol
Anesthetic technique
Jadad score
Engel et al. (2001) [27]
12/12
68/66
TKA
LMWH
Clinical & venography
Hb < 100 g/L
Spinal
2
Capdevila et al. (1998) [28]
12/11
48.6/48.5
Surgery of the hip, femur, or plevis for sepsis, or malignant tumor
Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h for 4 h Control: — Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline
Heparin
Ultrasound
General
4
Jeserschek et al. (2003) [23]
9/9
67/72.7
Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h Control: saline
LMWH
Clinical
NA
3
Samama et al. (2002) [24]
18, 22/ 18
(a) 44/44
Venography
Hct < 24%
General
4
23/24
48/55
Mechanical
Clinical
Hb < 80 g/L or Hct < 25%
General
5
Lentschener et al. (1999) [20] Cole et al. (2003) [21]
32/32
46/51
Heparin
Clinical
Hct < 26%
General
4
21/23
13/12.2
Posterior spinal fusion
NA
Ultrasound
Hb < 85 g/L or Hct ≤ 27%
General
4
Urban et al. (2001) [22]
20/18
20/18
Anteroposterior spine fusion
Aprotinin: (a) 4 × 106 KIU followed by 1 × 105 KIU/h during surgery (b) 2 × 106 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: normal saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until skin closure Control: saline Aprotinin: 240 mg/m2 followed by 56 mg/m2/h continuing 4h after surgery Control: saline Aprotinin: 1 × 106 KIU followed by 2.5 × 105 KIU/h during surgery Control: —
LMWH
Amar et al. (2005) [25]
Revision of arthroplasty of the hip or knee, or for resection of a softtissue sarcoma Revision spine or hip surgery, trauma surgery, cancer surgery, or surgery for sepsis Malignancy for pelvis, extremity or spine surgery Lumbar spinal fusion
Maintaing intraoperative Hct > 25%, and postoperative Hct > 28% NA
NA
Clinical
Hb < 80 g/L or Hct < 25%
General
4
(b) 48/44
F. Huang et al./Transfusion and Apheresis Science 51 (2014) 152–161
Author/s
DVT deep-vein thrombosis, THA total hip arthroplasty, TKA total knee arthroplasty, KIU kallikrein inhibitor units, LMWH low-molecular-weight heparin, Hb hemoglobin, Hct hematocrit, Tx treatment group, C control group, NA not available, a, b, c indicate multiple treatment arms.
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Fig. 4. Forest plot diagram showing the effect of aprotinin on intra-operative blood loss.
blood transfusion, intra-operative hemodilution, hypotensive anesthesia and modified use of the drain increase costs pose additional logistical problems and may be immunomodulatory. Aprotinin is measured using kallikrein inhibitor units (KIU) and inhibits multiple mediators such as trypsin, chymotrypsin, cathepsin, elastase, kallikrein, plasmin, protein C, thrombin, and urokinase that result in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin has been used in cardiac surgery and noncardiac procedures including liver transplantation and major vascular reconstruction [29,30], and its efficacy in reducing blood loss and requirements is widely recognized. In 2006, the use and safety of aprotinin became controversial due to its association with postoperative renal failure, myocardial infarction (MI), cerebral vascular accident (CVA), and death in patients undergoing cardiac surgery. In 2007, distribution of aprotinin was temporarily suspended in the United States by the Food and Drug Administration (FDA)
based on preliminary safety results from a Canadian heart study. However, several studies have previously shown that aprotinin is effective in decreasing surgical blood loss in various fields of orthopaedic surgery [31–33]. In a systematic review of orthopaedic clinical trials, Shiga et al. analyzed blood loss, transfusion rates and rates of DVT with aprotinin in major orthopedic surgery [34]. His review demonstrated that the use of aprotinin decreased blood loss and allogeneic blood transfusion requirement, and did not increase the risk of DVT. However, their findings are limited because of the limited sample size of the pooled subjects, and blood loss was collectively defined as ‘peri-operative blood loss’, despite including the results of total blood loss as well as post-operative blood loss under this definition. The most significant result of our review was the use of aprotinin for patients undergoing major orthopedic surgery is effective and safe for the reduction of blood loss and blood transfusion, and it did not appear to increase the risk of DVT. These results are similar to those in other studies [35].
Fig. 5. Forest plot diagram showing the effect of aprotinin on post-operative blood loss.
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Fig. 6. Forest plot diagram showing the effect of aprotinin on blood transfusion.
Significant difference was observed in blood loss, transfusion requirements and number of transfusions between the aprotinin-treated group and the control group. Our results showed that aprotinin reduced intra-operative blood loss by a mean volume of 246.11 ml, post-operative blood loss by a mean volume of 169.11 ml, total blood loss by a mean volume of 498.88 ml and number of transfusions by a mean of 0.93 U. Aprotinin also reduced the probability of receiving a blood transfusion by 41%. Furthermore, subgroup analysis showed that this positive effect persisted regardless of whether the patient had heparin and general anesthesia, and the surgery type. The evidence that aprotinin reduces the need for blood transfusion is strong but the increased risk of thrombosis with aprotinin is another concern in orthopedic surgery because of its mechanism of action. A modest increase in the risk of thrombosis could outweigh the benefits of reduced blood loss and transfusion requirements. However, in our meta-analysis of use of aprotinin in major orthopedic surgery, we did not observe
any statistically significant increases thromboembolic event risk. The rates of DVT in the aprotinin and control groups were 21 of 567 patients and 19 of 420 patients, respectively. The effective dosage of aprotinin remains a topic of controversy. We did not analyze the relation between dose and the amount of blood loss because of the small number of trials. Nevertheless, a dose-related reduction in blood loss has been suggested in some studies [12,24]. Further large randomized trials are needed. The quality assessment score for most of the included studies was high, which contributes to the strength of point estimates and conclusions drawn from the meta-analysis. Most included studies were of good methodological quality and well designed. However, it is inevitable to acknowledge several potential limitations in our meta-analysis. Firstly, we systematically searched a range of databases for published and unpublished trials. However, we can not exclude the possibility that some were missed. If many
Fig. 7. Forest plot diagram showing mean units of transfusion per patient.
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Fig. 8. Forest plot diagram showing the effect of aprotinin on DVT.
unpublished trials show little or no effect of aprotinin on the reduction of blood loss and transfusion requirements, then the treatment effect of aprotinin could be overestimated in this meta-analysis. Secondly, the funnel plot indicated the presence of publication bias in this metaanalysis. Publication bias is a well-know problem affecting the accuracy of the results of meta-analysis because positive results tend to be accepted by journals, and negative results is often subjected to rejection and be unpublished. Thirdly, there was significant heterogeneity among the studies when intra-operative, post-operative and total blood
loss, and blood units transfused per patient were evaluated. Estimating blood loss was variable, since blood due to hematomas or tissue extravasation were rarely measured, and this can cause inaccurate results. In the most of included study, intra-operative blood loss was simply measured by adding the volume of blood in suction bottles and the weight of sponges, and total blood volume in the reservoir could be misleading, since patient’s blood could be highly diluted by saline washing of the operatory field. Intraand post-operative blood transfusion threshold may largely vary among different institutions, as reported in Table 1:
Table 2 Subgroup analysis of outcome. Outcome or subgroup Total blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Intra-operative blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Post-operative blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Number of transfusions per patient Knee surgery Hip surgery Spine surgery General anesthesia Heparin
Studies
Number
Statistical method
Effect estimate
2 3 2 9 8
41 133 116 386 345
Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
−133.63 (−433.86, 166.6) −471.7 (−650.94, −294.4) −627.21 (−1134.79, −119.62) −521.33 (−788.62, −254.04) −569.93 (−839.16, −300.7)
P = 0.38 P < 0.00001 P = 0.02 P = 0.001 P < 0.0001
1 8 1 9 7
24 655 72 630 295
Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
10.00 (−199.08, 219.08) −181.19 (−287.16, −75.22) −443.00 (−831.00, −55.00) −279.80 (−410.54, −149.07) −279.08 (−412.42, −145.74)
P = 0.93 P = 0.0008 P = 0.03 P < 0.0001 P < 0.001
0 8 1 7 9
0 655 72 324 682
0 Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
0 −103.58 (−165.22, −41.94) −483.00 (−751.72, −241.28) −366.66 (−540.22, −193.01) −247.36 (−352.57, −142.15)
P = 0.001 P = 0.0004 P < 0.0001 P < 0.00001
1 5 2 5 6
24 535 82 222 553
Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
CI, confidence interval; IV, inverse variance.
−0.08 (−0.60, 0.76) −0.92 (−1.46, −0.38) −1.45 (−2.09, −0.81) −1.12 (−1.61, −0.63) −1.04 (−1.56, −0.52)
P = 0.32 P = 0.0009 P < 0.00001 P < 0.0001 P < 0.0001
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threshold Hct vary from 18% to 30%, and in 7 out of 18 studies the transfusion strategy is not reported. It is likely that these inconsistencies across all studies contributed to the high I2 values seen in statistical analyses. Thus, more accurate results could be obtained if the total red blood cell loss could be calculated by using reservoir’s blood hematocrit, and adopt a unified standard blood transfusion protocol. The other variations that may have accounted for such heterogeneity include the difference in surgery type, surgical techniques, sample sizes, the variations in patient characteristics. In summary, we conclude that aprotinin significantly reduced intra-operative, post-operative and total blood loss and transfusion requirements in patients undergoing major orthopedic surgery. At the same time, the application of aprotinin does not increase the prevalence of DVT. However, given the heterogeneity of the pooled estimates and relatively low number of studies included, further larger studies are needed to examine blood loss, transfusion and thromboembolic complications using aprotinin in orthopedic procedures. References [1] Sculco TP. Global blood management in orthopaedic surgery. Clin Orthop Relat Res 1998;357:43–9. [2] Cardone D, Klein AA. Perioperative blood conservation. Eur J Anaesthesiol 2009;26:722–9. [3] Etchason J, Petz L, Keeler E, Calhoun L, Kleinman S, Snider C, et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med 1995;332:719–24. [4] Schulman S. Pharmacologic tools to reduce bleeding in surgery. Hematology Am Soc Hematol Educ Program 2012;2012:517–21. [5] Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg 2010;18:132–8. [6] Dhir A. Antifibrinolytics in cardiac surgery. Ann Card Anaesth 2013;16:117–25. [7] Pasquali SK, Hall M, Li JS, Peterson ED, Jaggers J, Lodge AJ, et al. Safety of aprotinin in congenital heart operations: results from a large multicenter database. Ann Thorac Surg 2010;90:14–21. [8] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;354:1896–900. [9] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. [10] Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539–58. [11] Ray M, Hatcher S, Whitehouse SL, Crawford S, Crawford R. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty-a prospective randomized double-blind placebo-controlled study. J Thromb Haemost 2005;3:1421–7. [12] Murkin JM, Haig GM, Beer KJ, Cicutti N, McCutchen J, Comunale ME, et al. Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement. J Bone Joint Surg Am 2000;82:675– 84. [13] Langdown AJ, Field J, Grote J, Himayat H. Aprotinin (Trasylol) does not reduce bleeding in primary total hip arthroplasty. J Arthroplasty 2000;15:1009–12. [14] Janssens M, Joris J, David JL, Lemaire R, Lamy M. High-dose aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Anesthesiology 1994;80:23–9.
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[15] Hayes A, Murphy DB, McCarroll M. The efficacy of single-dose aprotinin 2 million KIU in reducing blood loss and its impact on the incidence of deep venous thrombosis in patients undergoing total hip replacement surgery. J Clin Anesth 1996;8:357–60. [16] Colwell CW Jr, Chelly JE, Murkin JM, Stevens D, O’Keefe TJ, Hall R, et al. Randomized study of aprotinin effect on transfusions and blood loss in primary THA. Clin Orthop Relat Res 2007;465:189–95. [17] Murkin JM, Shannon NA, Bourne RB, Rorabeck CH, Cruickshank M, Wyile G. Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 1995;80:343–8. [18] D’Ambrosio A, Borghi B, Damato A, D’Amato G, Antonacci D, Valeri F. Reducing perioperative blood loss in patients undergoing total hip arthroplasty. Int J Artif Organs 1999;22:47–51. [19] Petsatodis G, Samoladas E, Christodoulou A, Hatzokos I, Pournaras I. Does aprotinin reduce blood loss in total hip arthroplasty? Orthopedics 2006;29:75–7. [20] Lentschener C, Cottin P, Bouaziz H, Mercier FJ, Wolf M, Aljabi Y, et al. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. Anesth Analg 1999;89:590–7. [21] Cole JW, Murray DJ, Snider RJ, Bassett GS, Bridwell KH, Lenke LG. Aprotinin reduces blood loss during spinal surgery in children. Spine (Phila Pa 1976) 2003;28:2482–5. [22] Urban MK, Beckman J, Gordon M, Urquhart B, Boachie-Adjei O. The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery. Spine (Phila Pa 1976) 2001;26:1152–6. [23] Jeserschek R, Clar H, Aigner C, Rehak P, Primus B, Windhager R. Reduction of blood loss using high-dose aprotinin in major orthopaedic surgery: a prospective, double-blind, randomised and placebo-controlled study. J Bone Joint Surg Br 2003;85:174–7. [24] Samama CM, Langeron O, Rosencher N, Capdevila X, Rouche P, Pegoix M, et al. Aprotinin versus placebo in major orthopedic surgery: a randomized, double-blinded, dose-ranging study. Anesth Analg 2002;95:287–93. [25] Amar D, Grant FM, Zhang H, Boland PJ, Leung DH, Healey JA. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology 2003;98:337– 42. [26] Thorpe CM, Murphy WG, Logan M. Use of aprotinin in knee replacement surgery. Br J Anaesth 1994;73:408–10. [27] Engel JM, Hohaus T, Ruwoldt R, Menges T, Jürgensen I, Hempelmann G. Regional hemostatic status and blood requirements after total knee arthroplasty with and without tranexamic acid or aprotinin. Anesth Analg 2001;92:775–80. [28] Capdevila X, Calvet Y, Biboulet P, Biron C, Rubenovitch J, d’Athis F. Aprotinin decreases blood loss and homologous transfusions in patients undergoing major orthopedic surgery. Anesthesiology 1998;88:50–7. [29] Trzebicki J, Kosieradzki M, Flakiewicz E, Kuzminska G, Wasiak D, Pacholczyk M, et al. Detrimental effect of aprotinin ban on amount of blood loss during liver transplantation: single-center experience. Transplant Proc 2011;43:1725–7. [30] Ranaboldo CJ, Thompson JF, Davies JN, Shutt AM, Francis JN, Roath OS, et al. Prospective randomized placebo-controlled trial of aprotinin for elective aortic reconstruction. Br J Surg 1997;84:1110–13. [31] Kasimian S, Skaggs DL, Sankar WN, et al. Aprotinin in pediatric neuromuscular scoliosis surgery. Eur Spine J 2008;17(12):1671– 5. [32] Baldus CR, Bridwell KH, Lenke LG, et al. Can we safely reduce blood loss during lumbar pedicle subtraction osteotomy procedures using tranexamic acid or aprotinin?: a comparative study with controls. Spine 2010;35(2):235–9. [33] Colomina MJ, Bagó J, Vidal X, et al. Antifibrinolytic therapy in complex spine surgery: a case-control study comparing aprotinin and tranexamic acid. Orthopedics 2009;32(2):91. [34] Shiga T, Wajima Z, Inoue T, Sakamoto A. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. Anesth Analg 2005;101:1602–7. [35] Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006;105:1034–46.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Review
Use of aprotinin to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis Fei Huang a,1, Quancheng Zhao b,1, Chongyong Guo c, Guangwen Ma a,*, Qing Wang a, Yong Yin a, Yunfeng Wu a a
Department of Orthopaedics, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China Department of Neurosurgery, Binzhou People’s Hospital, Binzhou, China c Department of General Surgery, Binzhou People’s Hospital, Binzhou, China b
A R T I C L E
I N F O
Article history: Received 18 September 2013 Received in revised form 23 February 2014 Accepted 25 July 2014 Keywords: Aprotinin Blood loss Transfusion Meta-analysis
A B S T R A C T
Backgroud: Conflicting reports have been published regarding the effectiveness and safety of aprotinin in reducing blood loss and transfusion in patients undergoing orthopedic surgery. We performed a meta-analysis to evaluate the effectiveness and safety of aprotinin in reducing blood loss and transfusion in major orthopedic surgery. Materials and methods: MEDLINE, PubMed, EMBASE and Cochrane databases were searched for relevant studies. Only randomized controlled trials were eligible for this study. The weighted mean difference in blood loss, and number of transfusions per patient and the summary risk ratio of transfusion requirements, and deep-vein thrombosis (DVT) were calculated in the aprotinin-treated group and the control group. Results: Eighteen randomized controlled trials involving 1276 patients were included. The use of aprotinin reduced total blood loss by a mean of 498.88 ml (95% confidence interval [CI]; −735.03 to −262.72), intra-operative blood loss by a mean of 246.11 ml (95% CI; −352.11 to −140.11), post-operative blood loss by a mean of 169.11 ml (95% CI; −234.06 to −105.55), the number of blood transfusions per patient by 0.93 units (95% CI; −1.36 to −0.51). Aprotinin led to a signficant reduction in transfusion requirements (RR 0.59; 95% CI; 0.51 to 0.69) and no increase in the risk of DVT (RR 0.58; 95% CI; 0.38 to 1.08). Conclusion: The meta-analysis shows that aprotinin could significantly reduce blood loss and blood transfusion requirements in patients undergoing orthopedic surgery, and it did not appear to increase the risk of DVT. © 2014 Elsevier Ltd. All rights reserved.
Contents 1.
Methods ................................................................................................................................................................................................................................. 1.1. Study design ........................................................................................................................................................................................................... 1.2. Search methodology ............................................................................................................................................................................................ 1.3. Inclusion and exclusion criteria ....................................................................................................................................................................... 1.4. Study selection ...................................................................................................................................................................................................... 1.5. Data abstraction .................................................................................................................................................................................................... 1.6. Quality assessment .............................................................................................................................................................................................. 1.7. Statistical analysis .................................................................................................................................................................................................
* Corresponding author. Tel.: +86 551 62862617; fax: +86 551 62862617. E-mail address: [email protected] (G. Ma). 1 These authors have equal contribution to this work and should be considered as co-first author. http://dx.doi.org/10.1016/j.transci.2014.07.009 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
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2.
3.
Results .................................................................................................................................................................................................................................... 2.1. Characteristics of the included studies ......................................................................................................................................................... 2.2. Blood loss ................................................................................................................................................................................................................ 2.2.1. Total .......................................................................................................................................................................................................... 2.2.2. Intra-operative ..................................................................................................................................................................................... 2.2.3. Post-operative ....................................................................................................................................................................................... 2.3. Transfusion requirements .................................................................................................................................................................................. 2.4. Number of transfusions per patient .............................................................................................................................................................. 2.5. DVT complications ............................................................................................................................................................................................... 2.6. Subgroup analysis ................................................................................................................................................................................................ Discussion ............................................................................................................................................................................................................................. References .............................................................................................................................................................................................................................
Major orthopedic procedures may be associated with significant blood loss requiring transfusion of several units of blood [1]. However, blood transfusion carries the risk of immunological and non-immunological adverse effects, such as a higher rate of post-operative infections, intravascular haemolysis, transfusion induced coagulopathy, renal impairment or failure, and even increased mortality [2]. Numerous strategies, including autologous blood donation, autologous drain transfusion, regional anesthesia and acute normovolaemic haemodilution, have been used to reduce allogenic blood transfusion rates. However, their application is limited by their clinical and financial efficacy [3]. Antifibrinolytic therapy constitutes an effective method to control or reduce bleeding and to limit or avoid blood transfusion in current medical practice [4,5]. Aprotinin, a naturally occurring single-chain 58 amino acid polypeptide with a molecular weight of 6512 Da, is a proteinase inhibitor with antifibrinolytic properties that has found widespread application during cardiac surgical procedures due to its ability to decrease blood loss and transfusion requirements [6,7]. Numerous studies have investigated its efficacy in reducing blood loss and transfusion requirements in patients undergoing orthopedic surgery with various results. Thus, we conducted a meta-analysis of randomized controlled trials to assess the effectiveness and safety of aprotinin in reducing blood loss and transfusion in major orthopedic surgery. 1. Methods 1.1. Study design This review was based on Cochrane methodology for conducting meta-analysis. All data were reported according to the Quality of Reporting for Meta-analyses provided by the Handbook for Systematic Reviews of Interventions Version 5.0.0 [8].
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included “antifibrinolytics”, “cyklokapron”, “aprotinin”, “orthopedic surgery”, “hip surgery”, “knee surgery”, “spine surgery” and “randomized controlled trials”. Manufacturers were contacted for additional unpublished trials. Reference lists of included studies and relevant reviews were checked for additional trials. 1.3. Inclusion and exclusion criteria Studies were included if they met the following criteria: (i) participants undergoing orthopedic surgery; (ii) randomly assigned patients to the treatment group who received aprotinin and the control group who received a placebo or no treatment; (iii) neither the aprotinin-treated group nor the control group used anticoagulant drugs; (iv) both groups reported one of the following outcomes: the amount of blood loss, the number of patients receiving allogeneic transfusion, the number of blood transfusion units per patient and the number of patients with deep-vein thrombosis. Studies were excluded if they were non-English language, or if there were nonrandomized controlled trials or randomized controlled trials that did not contain any of the above outcomes. 1.4. Study selection The initial electronic databases searches to identify potential studies for inclusion based on title and abstract information were performed by two independent authors (H.F, Z.Q.C). When there was a dispute, the full article was retrieved for further scrutiny. Completely study reports were assessed for inclusion independently by both authors, and authors were contacted for more information and clarification of data as necessary. Any disagreement was resolved by consensus or consultation with the senior authors (M.G.W). References and data for each included study were carefully cross-checked to ensure no overlapping data was presented.
1.2. Search methodology 1.5. Data abstraction We sought published randomized controlled trials that evaluated aprotinin in patients undergoing orthopedic surgery. The published literature was searched by a literature search from 1966 to April 2013 using the electronic databases including the MEDLINE, PubMed, EMBASE and Cochrane Database of Systematic Reviews. The search terms
Data extracted from the included studies were entered by two independent authors (H.F, Z.Q.C). Any disagreement was resolved by consensus or consultation with the senior authors (M.G.W). Data extracted included: sample size, study design, subject age, type of surgery, dose and
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timing of aprotinin and outcome data. In addition, adverse outcomes were recorded. For studies without adverse outcomes, author(s) were contacted for confirmation or more information regarding adverse events, if necessary. 1.6. Quality assessment Assessment of the methodological quality of the included studies was performed by two independent investigators (H.F, Z.Q.C). Disagreements were resolved by consensus or consultation with the senior authors (M.G.W). Each study was assessed according to the 5-point scale introduced by Jadad et al. [9]. The maximum quality score given to a study by this instrument is five points (up to two points for random assignment, up to two points for blinding investigators and patients, and one point if all enrolled patients are accounted for at the conclusion of the study, with reasons given for all dropouts and withdrawals). A score of ≤2 indicates “low” quality, while ≥3 indicates “high” quality.
Fig. 1. Selection of studies for meta-analysis. RCTs = randomized controlled trials; n = number of papers.
1.7. Statistical analysis The Review Manager software (RevMan version 5.0, Cochrane Collaboration, Freiburg, Germany) was used to analyze elected studies. For continuous data, such as blood loss, mean ± standard deviation (mean ± SD) was used to calculate the weighted mean difference (WMD) and 95% confidence interval. For dichotomous data, relative risk (RR) and 95% CI were applied. Statistical heterogeneity was assessed using the value of I 2 and the result of the chisquared test. A P-value < 0.1 and an I2 value >50% were considered suggestive of statistical heterogeneity, prompting a random effects modeling estimate. Otherwise, a fixed effects approach was used. However, a non-significant chisquared test result (a P-value ≥ 0.1 and an I2 value ≤ 50%) only indicated a lack of evidence for heterogeneity, but not implied necessarily homogeneity, as there may have been insufficient power to be able to detect heterogeneity [10]. When the data allowed, we performed subgroup analysis of the trials according to the type of surgery, general anesthesia and administration of heparin. 2. Results 2.1. Characteristics of the included studies A total of 157 abstracts and titles were reviewed. According to the inclusion and exclusion criteria, we identified 18 randomized controlled trials associated with orthopedic surgery (Fig. 1) [11–28]. A total of 1276 patients were enrolled in the randomized controlled trials. Nine studies involved hip surgery [11–19], three studies involved spinal surgery [20–22], two studies involved knee surgery [23,24] and four studies involved other surgery [25–28]. The number of patients included in these randomized controlled trials ranged from 17 to 352. A systematic clinical and (or) duplex ultrasound screening for thrombosis was undertaken during the post-operative period, and patients received standard thromboprophylaxis in the majority of included trials. The median Jadad score was 3 (range, 2–5). Details of the se-
lected trials are shown in Table 1. DVT complications, the most frequently cited outcome, were used to generate the funnel plot analysis of publication bias. The asymmetric characteristic of the funnel plot indicated the presence of publication bias (Fig. 2). 2.2. Blood loss 2.2.1. Total Total blood loss was examined in 11 trials with 436 patients. The use of aprotinin significantly reduced total blood loss by a mean of 498.88 ml (95% CI; −735.03 to −262.72; P < 0.0001). However, there was significant heterogeneity (I2 = 85%) among included studies (Fig. 3). 2.2.2. Intra-operative Thirteen studies with a total of 839 patients were eligible for this outcome. These trials randomized 420 patients to receive aprotinin and 419 patients as controls. The use of aprotinin significantly reduced intra-operative blood loss by a mean of 246.11 ml (95% CI; −352.11 to −140.11; P < 0.00001) (Fig. 4). 2.2.3. Post-operative Thirteen studies with a total of 844 patients were eligible for this outcome. The effect of aprotinin was similar, significantly reduced post-operative blood loss by a mean of 169.81 ml (95% CI; −234.06 to −105.55; P < 0.00001) (Fig. 5). 2.3. Transfusion requirements Data on transfusion requirements were examined in 11 trials, including a total of 1172 patients. Aprotinin reduced the probability of receiving a blood transfusion by 41% (RR 0.59; 95% CI; 0.51 to 0.69; P < 0.00001) (Fig. 6).
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Fig. 2. Funnel plot of DVT to assess publication bias. SE = standard error. DVT = deep-vein thrombosis.
2.4. Number of transfusions per patient
2.6. Subgroup analysis
This outcome measure was available in 10 studies with 706 patients. The use of aprotinin significantly reduced the average number of blood transfusion per patient when compared with the control group (weighted mean difference; −0.93 units [95% CI −1.36 to −0.51 units]; P < 0.0001) (Fig. 7).
There was significant heterogeneity in the study outcomes. Subgroup analysis according to surgery type, anesthesia and DVT prophylaxis did not adequately explain the variation in outcomes (Table 2). 3. Discussion
2.5. DVT complications Twelve studies with 987 patients reported DVT complications. Patients receiving aprotinin (567 patients) had 21 episodes of DVT while 420 patients who did not receive aprotinin had a total of 19 episodes. The rate of DVT was not affected by the use of aprotinin when the aprotinin group was compared with the control group (RR 0.58; 95% CI; 0.31 to 1.08; P = 0.09) (Fig. 8).
The significant blood loss and risk for blood transfusion are important features that must be considered in orthopedic surgery. This is a result of several characteristics inherent to the surgery, such as extensive bone decortication, fluid therapy-induced dilutional coagulopathy, and the microthrombi present in transfusion blood. Several methods have been reported to reduce blood loss and blood transfusion after surgery. Techniques such as autologous
Fig. 3. Forest plot diagram showing the effect of aprotinin on total blood loss.
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Table 1 Characteristics of included studies. Number (Tx/C)
Mean age (year) (Tx/C)
Surgical methods
Intervention
DVT prophylaxis
DVT screen
Blood transfusion protocol
Anesthetic technique
Jadad score
Ray et al. (2005) [11]
15/15
72/69
THA
Aspirin
Ultrasound
3
69, 68, 75/68
(a) 63.7/63.2 (b) 65.5/63.2
THA
Warfarin
Ultrasound
Depending on patient’s condition Hct < 18% or clinical decision
General
Murkin et al. (2000) [12]
Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h for 3 h Control: saline Aprotinin: (a) 5 × 105 KIU after aneathesia (b) 1 × 106 KIU followed by 2.5 × 105 KIU/h during surgery (c) 2 × 106 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 1.5 × 106 KIU at the time fo aneathesia Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline Aprotinin: 2 × 106 KIU as a single dose Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline Aprotinin: 3.8 × 106 KIU total Control: saline Aprotinin: 5 × 105 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 2 × 104 KIU/kg at anesthesia followed by 5 × 104 KIU/hr Control: saline Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h over the next 2 h Control: —
NA
3
NA
NA
NA
Spinal
4
LMWH
Clinical
Hct < 30%
General
3
LMWH
NA
Clinical
Spinal
3
LMWH
Clinical
Hct < 18%
NA
4
Heparin
Ultrasound
Hb < 80 g/L
General
5
LMWH
Clinical
NA
General
3
Enoxaparin
NA
NA
NA
2
Heparin
Angiography
Depending on patient’s condition
General
3
(c) 63.4/63.2
Langdown et al. (2000) [13] Janssens et al. (1994) [14] Hayes et al. (1996) [15] Colwell et al. (2007) [16]
30/30
NA
THA
20/20
64.9/65.3
THA
20/20
70/72.9
THA
175/177
63.4/64.4
THA
Murkin et al. (1995) [17] D’Ambrosio et al. (1999) [18] Petsatodis et al. (2006) [19] Thorpe et al. (1994) [26]
29/24
66.9/65.5
THA
15/15
66.6/60.5
THA
25/25
58/59.6
THA
8/9
NA
TKA
(continued on next page)
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Author/s
Table 1 (continued) Number (Tx/C)
Mean age (year) (Tx/C)
Surgical methods
Intervention
DVT prophylaxis
DVT screen
Blood transfusion protocol
Anesthetic technique
Jadad score
Engel et al. (2001) [27]
12/12
68/66
TKA
LMWH
Clinical & venography
Hb < 100 g/L
Spinal
2
Capdevila et al. (1998) [28]
12/11
48.6/48.5
Surgery of the hip, femur, or plevis for sepsis, or malignant tumor
Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h for 4 h Control: — Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: saline
Heparin
Ultrasound
General
4
Jeserschek et al. (2003) [23]
9/9
67/72.7
Aprotinin: 1 × 106 KIU followed by 5 × 105 KIU/h Control: saline
LMWH
Clinical
NA
3
Samama et al. (2002) [24]
18, 22/ 18
(a) 44/44
Venography
Hct < 24%
General
4
23/24
48/55
Mechanical
Clinical
Hb < 80 g/L or Hct < 25%
General
5
Lentschener et al. (1999) [20] Cole et al. (2003) [21]
32/32
46/51
Heparin
Clinical
Hct < 26%
General
4
21/23
13/12.2
Posterior spinal fusion
NA
Ultrasound
Hb < 85 g/L or Hct ≤ 27%
General
4
Urban et al. (2001) [22]
20/18
20/18
Anteroposterior spine fusion
Aprotinin: (a) 4 × 106 KIU followed by 1 × 105 KIU/h during surgery (b) 2 × 106 KIU followed by 5 × 105 KIU/h during surgery Control: saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until the end of surgery Control: normal saline Aprotinin: 2 × 106 KIU followed by 5 × 105 KIU/h until skin closure Control: saline Aprotinin: 240 mg/m2 followed by 56 mg/m2/h continuing 4h after surgery Control: saline Aprotinin: 1 × 106 KIU followed by 2.5 × 105 KIU/h during surgery Control: —
LMWH
Amar et al. (2005) [25]
Revision of arthroplasty of the hip or knee, or for resection of a softtissue sarcoma Revision spine or hip surgery, trauma surgery, cancer surgery, or surgery for sepsis Malignancy for pelvis, extremity or spine surgery Lumbar spinal fusion
Maintaing intraoperative Hct > 25%, and postoperative Hct > 28% NA
NA
Clinical
Hb < 80 g/L or Hct < 25%
General
4
(b) 48/44
F. Huang et al./Transfusion and Apheresis Science 51 (2014) 152–161
Author/s
DVT deep-vein thrombosis, THA total hip arthroplasty, TKA total knee arthroplasty, KIU kallikrein inhibitor units, LMWH low-molecular-weight heparin, Hb hemoglobin, Hct hematocrit, Tx treatment group, C control group, NA not available, a, b, c indicate multiple treatment arms.
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Fig. 4. Forest plot diagram showing the effect of aprotinin on intra-operative blood loss.
blood transfusion, intra-operative hemodilution, hypotensive anesthesia and modified use of the drain increase costs pose additional logistical problems and may be immunomodulatory. Aprotinin is measured using kallikrein inhibitor units (KIU) and inhibits multiple mediators such as trypsin, chymotrypsin, cathepsin, elastase, kallikrein, plasmin, protein C, thrombin, and urokinase that result in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin has been used in cardiac surgery and noncardiac procedures including liver transplantation and major vascular reconstruction [29,30], and its efficacy in reducing blood loss and requirements is widely recognized. In 2006, the use and safety of aprotinin became controversial due to its association with postoperative renal failure, myocardial infarction (MI), cerebral vascular accident (CVA), and death in patients undergoing cardiac surgery. In 2007, distribution of aprotinin was temporarily suspended in the United States by the Food and Drug Administration (FDA)
based on preliminary safety results from a Canadian heart study. However, several studies have previously shown that aprotinin is effective in decreasing surgical blood loss in various fields of orthopaedic surgery [31–33]. In a systematic review of orthopaedic clinical trials, Shiga et al. analyzed blood loss, transfusion rates and rates of DVT with aprotinin in major orthopedic surgery [34]. His review demonstrated that the use of aprotinin decreased blood loss and allogeneic blood transfusion requirement, and did not increase the risk of DVT. However, their findings are limited because of the limited sample size of the pooled subjects, and blood loss was collectively defined as ‘peri-operative blood loss’, despite including the results of total blood loss as well as post-operative blood loss under this definition. The most significant result of our review was the use of aprotinin for patients undergoing major orthopedic surgery is effective and safe for the reduction of blood loss and blood transfusion, and it did not appear to increase the risk of DVT. These results are similar to those in other studies [35].
Fig. 5. Forest plot diagram showing the effect of aprotinin on post-operative blood loss.
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Fig. 6. Forest plot diagram showing the effect of aprotinin on blood transfusion.
Significant difference was observed in blood loss, transfusion requirements and number of transfusions between the aprotinin-treated group and the control group. Our results showed that aprotinin reduced intra-operative blood loss by a mean volume of 246.11 ml, post-operative blood loss by a mean volume of 169.11 ml, total blood loss by a mean volume of 498.88 ml and number of transfusions by a mean of 0.93 U. Aprotinin also reduced the probability of receiving a blood transfusion by 41%. Furthermore, subgroup analysis showed that this positive effect persisted regardless of whether the patient had heparin and general anesthesia, and the surgery type. The evidence that aprotinin reduces the need for blood transfusion is strong but the increased risk of thrombosis with aprotinin is another concern in orthopedic surgery because of its mechanism of action. A modest increase in the risk of thrombosis could outweigh the benefits of reduced blood loss and transfusion requirements. However, in our meta-analysis of use of aprotinin in major orthopedic surgery, we did not observe
any statistically significant increases thromboembolic event risk. The rates of DVT in the aprotinin and control groups were 21 of 567 patients and 19 of 420 patients, respectively. The effective dosage of aprotinin remains a topic of controversy. We did not analyze the relation between dose and the amount of blood loss because of the small number of trials. Nevertheless, a dose-related reduction in blood loss has been suggested in some studies [12,24]. Further large randomized trials are needed. The quality assessment score for most of the included studies was high, which contributes to the strength of point estimates and conclusions drawn from the meta-analysis. Most included studies were of good methodological quality and well designed. However, it is inevitable to acknowledge several potential limitations in our meta-analysis. Firstly, we systematically searched a range of databases for published and unpublished trials. However, we can not exclude the possibility that some were missed. If many
Fig. 7. Forest plot diagram showing mean units of transfusion per patient.
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Fig. 8. Forest plot diagram showing the effect of aprotinin on DVT.
unpublished trials show little or no effect of aprotinin on the reduction of blood loss and transfusion requirements, then the treatment effect of aprotinin could be overestimated in this meta-analysis. Secondly, the funnel plot indicated the presence of publication bias in this metaanalysis. Publication bias is a well-know problem affecting the accuracy of the results of meta-analysis because positive results tend to be accepted by journals, and negative results is often subjected to rejection and be unpublished. Thirdly, there was significant heterogeneity among the studies when intra-operative, post-operative and total blood
loss, and blood units transfused per patient were evaluated. Estimating blood loss was variable, since blood due to hematomas or tissue extravasation were rarely measured, and this can cause inaccurate results. In the most of included study, intra-operative blood loss was simply measured by adding the volume of blood in suction bottles and the weight of sponges, and total blood volume in the reservoir could be misleading, since patient’s blood could be highly diluted by saline washing of the operatory field. Intraand post-operative blood transfusion threshold may largely vary among different institutions, as reported in Table 1:
Table 2 Subgroup analysis of outcome. Outcome or subgroup Total blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Intra-operative blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Post-operative blood loss Knee surgery Hip surgery Spine surgery General anesthesia Heparin Number of transfusions per patient Knee surgery Hip surgery Spine surgery General anesthesia Heparin
Studies
Number
Statistical method
Effect estimate
2 3 2 9 8
41 133 116 386 345
Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
−133.63 (−433.86, 166.6) −471.7 (−650.94, −294.4) −627.21 (−1134.79, −119.62) −521.33 (−788.62, −254.04) −569.93 (−839.16, −300.7)
P = 0.38 P < 0.00001 P = 0.02 P = 0.001 P < 0.0001
1 8 1 9 7
24 655 72 630 295
Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
10.00 (−199.08, 219.08) −181.19 (−287.16, −75.22) −443.00 (−831.00, −55.00) −279.80 (−410.54, −149.07) −279.08 (−412.42, −145.74)
P = 0.93 P = 0.0008 P = 0.03 P < 0.0001 P < 0.001
0 8 1 7 9
0 655 72 324 682
0 Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
0 −103.58 (−165.22, −41.94) −483.00 (−751.72, −241.28) −366.66 (−540.22, −193.01) −247.36 (−352.57, −142.15)
P = 0.001 P = 0.0004 P < 0.0001 P < 0.00001
1 5 2 5 6
24 535 82 222 553
Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, fixed, 95%CI) Mean difference (IV, random, 95%CI) Mean difference (IV, random, 95%CI)
CI, confidence interval; IV, inverse variance.
−0.08 (−0.60, 0.76) −0.92 (−1.46, −0.38) −1.45 (−2.09, −0.81) −1.12 (−1.61, −0.63) −1.04 (−1.56, −0.52)
P = 0.32 P = 0.0009 P < 0.00001 P < 0.0001 P < 0.0001
F. Huang et al./Transfusion and Apheresis Science 51 (2014) 152–161
threshold Hct vary from 18% to 30%, and in 7 out of 18 studies the transfusion strategy is not reported. It is likely that these inconsistencies across all studies contributed to the high I2 values seen in statistical analyses. Thus, more accurate results could be obtained if the total red blood cell loss could be calculated by using reservoir’s blood hematocrit, and adopt a unified standard blood transfusion protocol. The other variations that may have accounted for such heterogeneity include the difference in surgery type, surgical techniques, sample sizes, the variations in patient characteristics. In summary, we conclude that aprotinin significantly reduced intra-operative, post-operative and total blood loss and transfusion requirements in patients undergoing major orthopedic surgery. At the same time, the application of aprotinin does not increase the prevalence of DVT. However, given the heterogeneity of the pooled estimates and relatively low number of studies included, further larger studies are needed to examine blood loss, transfusion and thromboembolic complications using aprotinin in orthopedic procedures. References [1] Sculco TP. Global blood management in orthopaedic surgery. Clin Orthop Relat Res 1998;357:43–9. [2] Cardone D, Klein AA. Perioperative blood conservation. Eur J Anaesthesiol 2009;26:722–9. [3] Etchason J, Petz L, Keeler E, Calhoun L, Kleinman S, Snider C, et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med 1995;332:719–24. [4] Schulman S. Pharmacologic tools to reduce bleeding in surgery. Hematology Am Soc Hematol Educ Program 2012;2012:517–21. [5] Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg 2010;18:132–8. [6] Dhir A. Antifibrinolytics in cardiac surgery. Ann Card Anaesth 2013;16:117–25. [7] Pasquali SK, Hall M, Li JS, Peterson ED, Jaggers J, Lodge AJ, et al. Safety of aprotinin in congenital heart operations: results from a large multicenter database. Ann Thorac Surg 2010;90:14–21. [8] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;354:1896–900. [9] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. [10] Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539–58. [11] Ray M, Hatcher S, Whitehouse SL, Crawford S, Crawford R. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty-a prospective randomized double-blind placebo-controlled study. J Thromb Haemost 2005;3:1421–7. [12] Murkin JM, Haig GM, Beer KJ, Cicutti N, McCutchen J, Comunale ME, et al. Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement. J Bone Joint Surg Am 2000;82:675– 84. [13] Langdown AJ, Field J, Grote J, Himayat H. Aprotinin (Trasylol) does not reduce bleeding in primary total hip arthroplasty. J Arthroplasty 2000;15:1009–12. [14] Janssens M, Joris J, David JL, Lemaire R, Lamy M. High-dose aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Anesthesiology 1994;80:23–9.
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