Background: Antifibrinolytic agents have been shown to decrease the blood loss associated with major orthopaedic surgical procedures. Spine surgery, particularly procedures performed for deformity correction and procedures involving long arthrodesis constructs, can be associated with a large amount of blood loss requiring blood transfusions. The purpose of the present study was to determine if antifibrinolytic agents reduced blood transfusions in patients managed with spine surgery and to see if one agent had a greater effect than another.
Methods: A systematic review and meta-analysis of the available literature were performed to investigate the efficacy of aprotinin, tranexamic acid, and epsilon-aminocaproic acid in terms of reducing blood loss and blood transfusions in patients undergoing spine surgery. This meta-analysis was focused on the role of these agents in major spine operations as reported in eighteen clinical trials that included information on the drug dosage, the age of the patient, blood loss, blood transfusions, surgery complexity, and complications.
Results: Compared with control groups, the treatment groups for all three antifibrinolytic agents maintained lower levels of total blood loss and transfusions associated with spine surgery. The effect size (d) of the differences in total blood loss between the treatment and control groups ranged from −0.668 (95% confidence interval, −0.971 to −0.365) to −0.936 (95% confidence interval, −1.240 to −0.632) across all three agents. The effect size (d) of the differences in total blood transfusions between the treatment and control groups ranged from −0.466 (95% confidence interval, −0.764 to −0.167) to −0.749 (95% confidence interval, −1.046 to −0.453) across all three agents.
Conclusions: Aprotinin, tranexamic acid, and epsilon-aminocaproic acid are effective for reducing blood loss and transfusions in patients managed with spine surgery. With the exception of aprotinin, the side-effect profiles of these agents have not been shown to cause any substantial morbidity or to increase the rate of thromboembolic events. Epsilon-aminocaproic acid had a greater effect on reducing blood transfusions as the complexity of surgery increased. The surgeon and/or the anesthesiologist should consider the use of antifibrinolytic agents for patients undergoing spinal procedures in which a large amount of blood loss can be expected; however, at the present time, this is not a United States Food and Drug Administration-approved indication for these agents.
Level of Evidence: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.
1Department of Orthopaedic Surgery and Rehabilitation, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9436, Lubbock, TX 79430. E-mail address for J.B. Gill: firstname.lastname@example.org
2Department of Human Development and Family Studies, Texas Tech University, 2500 Broadway, MS 1162, Lubbock, TX 79409
Spine surgery may be associated with substantial blood loss; this is particularly true for procedures performed for deformity correction, procedures involving long arthrodesis constructs, and combined anterior and posterior procedures, which typically require allogeneic blood transfusions. Factors influencing the blood loss include the surgical technique, the operative time, the number of vertebral levels arthrodesed, the mean arterial blood pressure, the type of anesthesia, platelet abnormalities, dilutional coagulopathy, and primary fibrinolysis1,2. Large-vein bleeding is the source of the majority of the blood loss, often resulting in persistent blood loss after the operation3,4.
Aprotinin, tranexamic acid, and epsilon-aminocaproic acid are three commonly used antifibrinolytics. Aprotinin is a polypeptide serine protease inhibitor from bovine lung that inhibits kallikrein, plasmin, and platelet-activation factors. Tranexamic acid is a derivative of lysine and blocks lysine-binding sites on plasminogen molecules, causing the formation of a complex that removes plasminogen from fibrin, thus inhibiting fibrinolysis and plasmin activity5. Epsilon-aminocaproic acid is a lysine analogue; it binds reversibly to the kringle domain of the enzyme plasminogen and blocks binding of fibrin, which is normally activated to plasmin.
We studied the role of aprotinin, tranexamic acid, and epsilon-aminocaproic acid in spine surgery as reported in clinical series, focusing on the drug dosage, the age of the patient at the time of surgery, blood loss, transfusions, the complexity of surgery, and the complication profile of the drugs. We hypothesized that aprotinin, tranexamic acid, and epsilon-aminocaproic acid would significantly reduce blood transfusions in patients undergoing spine surgery and that the drugs would have a greater effect with increasing surgery complexity. The purpose of the present study was to determine if antifibrinolytic agents reduced blood transfusions in patients undergoing spine surgery and to see if one agent had a greater effect in doing so than another.
Materials and Methods
Prospective clinical trials that met certain inclusion criteria were considered for this meta-analysis. The inclusion criteria were the performance of spine surgery and the perioperative administration of aprotinin, tranexamic acid, or epsilon-aminocaproic acid. The antifibrinolytics were given mainly as a single bolus followed by constant intraoperative infusion. If the trial did not include data on blood transfusions or other necessary data such as the number of patients, the study was excluded from the analysis. Demographic characteristics such as age and sex were also included in the data analysis.
All identified studies were reviewed by all of the authors. On the basis of the preestablished inclusion criteria, each article was evaluated for inclusion in or exclusion from the meta-analysis. Any disagreements between the authors were resolved by means of discussion to reach a consensus. If an article did not indicate the mean number of units of blood transfused and/or the standard deviation, then the authors of that article were contacted to obtain the correct data. The outcome measures were recorded in a spreadsheet and were checked by the authors to ensure that they were accurate and correct.
An extensive literature search of the National Institutes of Health PubMed database was performed to identify studies on spine surgery in which aprotinin, tranexamic acid, or epsilon-aminocaproic acid was compared with a placebo from January 1990 to July 2007. Key words that were used in this search included “aprotinin,” “tranexamic acid,” “aminocaproic acid,” “spine surgery,” “orthopaedic surgery,” and “antifibrinolytic.” Additionally, a manual search of the scientific literature was performed by cross-checking the bibliographies of the selected articles. The data that were extracted from the selected articles included the number of patients, the total blood loss, the intraoperative blood loss, the number of blood transfusions, the mean age at the time of surgery, the sex of the patients, and the prevalence of complications attributable to the drugs.
The literature search yielded a total of eighteen articles that were eligible for analysis1,3,5-20. From those articles, twenty-one independent samples (including seven groups of patients managed with aprotinin, seven groups of patients managed with tranexamic acid, and seven groups of patients managed with epsilon-aminocaproic acid) qualified for inclusion, representing a total of 370, 288, and 308 patients, respectively. The discrepancy between the number of articles and the number of eligible samples is due to the fact that some studies involved the use of multiple antifibrinolytic agents in a single trial and one study presented data on two independent trials within the same article1,9,19. Lists of the included studies are presented in tables in the Appendix. The authors of all seven studies involving aprotinin elaborated on their protocol for estimating blood loss1,3,7-9,15,16. Four of those studies involved weighing the sponges at the time of surgery in addition to estimating blood loss through suction drainage systems and blood on the surgical drapes and gowns1,3,7,9. In the other three studies, blood loss was estimated in the same way, with the exception that the investigators did not weigh the sponges and instead just estimated how much blood was on the sponges8,15,16. The authors of three of the seven studies involving tranexamic acid elaborated on how blood loss was calculated. In two of those studies, the estimation of blood loss involved weighing the sponges in addition to estimating blood loss through suction drainage systems and estimating the amount of blood on the surgical drapes and gowns10,11. In the other study, blood loss was estimated in the same way, with the exception that the investigators did not weigh the sponges and instead just estimated how much blood was on the sponges14. The authors of all seven studies involving epsilon-aminocaproic acid specified the protocol for estimating blood loss, which involved weighing the sponges in addition to estimating blood loss through suction drainage systems and estimating the amount of blood on the surgical drapes and gowns1,9,17-20.
A meta-analysis of the mean differences between the treatment and control groups for aprotinin, tranexamic acid, and epsilon-aminocaproic acid was conducted to integrate the results of the eighteen articles. Three of the studies had two independent samples, yielding a total of twenty-one samples1,9,19. The effect size, Hedges' d, was computed for each study. Effect size is the standardized difference between two groups. The d statistic specifies, in standardized units, how much the control group mean is greater than the active group mean. The level of significance was set at p < 0.05.
Once each effect size was obtained, each study was weighted by the inverse of its variances and then the weighted mean effect sizes and their 95% confidence intervals were calculated. Also, the heterogeneity of effect sizes was tested with use of the homogeneity statistic, Q, and fail-safe numbers were examined with use of Rosenthal's method21.
For the meta-regression analysis, the age of the patient, the dosage of drug administered, and the type of surgery were weighted accordingly. The weighting of age was equal to the age of the patient. The weighting of dosage was determined according to the dosage that was administered to the patient. For aprotinin, tranexamic acid, and epsilon-aminocaproic acid, three different dosages were administered. The lowest dosage received a weight of 1, and the highest dosage received a weight of 3. If the dosage was between the high and low dosages, then a weight of 2 was given. The weighting of the type of surgery was determined according to the complexity of the procedure. Specifically, a decompressive procedure and/or posterior arthrodesis of fewer than six levels was assigned a weight of 1; an arthrodesis of six levels or more was assigned a weight of 2, as long as the arthrodesis was done through one approach (anterior or posterior); and any operation involving two approaches (anterior and posterior) was assigned a weight of 3, representing the most complex surgery.
Aprotinin, tranexamic acid, and epsilon-aminocaproic acid were found to reduce total blood loss and blood transfusions as shown in Figures 1 through 6. The average effect sizes for aprotinin, tranexamic acid, and epsilon-aminocaproic acid on total blood loss were −0.691, −0.668, and −0.936, respectively, and the average effect sizes on blood transfusions were −0.693, −0.466, and −0.0749, respectively (Table I). We found a medium to large effect size difference between the treatment and control groups on the basis of the absolute value of d, with 0.20 representing a small effect size, 0.50 representing a medium effect size, and 0.80 representing a large effect size. Negative d values indicate better outcomes (that is, a smaller amount of total blood loss and fewer units of blood transfused) in the treatment group. The Rosenthal's fail-safe number ranged from 26.4 to 131.2, indicating that approximately twenty-six to 131 future studies are required to change the statistical results found in the present study21.
Tests to reject the null hypothesis of homogeneous effect sizes were not significant (p > 0.05) for aprotinin and tranexamic acid. That is, for each comparison, the results from study to study were consistent. For epsilon-aminocaproic acid, the studies showed some variation in results (Q = 19.931, p < 0.01 for blood loss). These findings indicate that moderating variables should be taken into account. Therefore, an additional exploration was done to test whether the differences between the treatment and control groups were moderated by sample characteristics such as the dosage of medicine, the type of surgical procedure, and the average age of the patients at the time of surgery. A study feature that is negatively related with the effect size means that this feature is associated with finding a greater difference between the treatment and control groups, whereas a study feature that is positively related with the effect size means that the feature is associated with finding a lesser difference (that is, approaching zero) between the treatment and control groups.
As shown in Table II, for tranexamic acid, as the level of complexity of surgery increased, the treatment effects on blood transfusions decreased; that is, the more complex the surgery, the smaller the difference between the treatment group and the control group in terms of blood transfusions. Thus, our data supported the moderating effect of the type of surgery on blood transfusions for tranexamic acid. However, we found no support for the suggested impact of study features for aprotinin. This finding is consistent with the result of homogeneity of effect size for aprotinin. The effect size of epsilon-aminocaproic acid was heterogeneous when the dependent variable was blood loss. However, we found no support for the possible impact of the moderators, which included the dosage of the medicine, the surgical complexity, and the average age of the patients at the time of surgery. Observed differences in blood loss could be explained by other variables such as the sex of the patients and the techniques used to estimate blood loss. Because not all of the studies included these variables, we were unable to address the impact of these variables.
Demographic Characteristics and Dosing Regimens
The mean age of the patients at the time of surgery ranged from 12.2 to fifty-five years in the aprotinin group, from 13.6 to 60.8 years in the tranexamic acid group, and from 12.3 to fifty-five years in the epsilon-aminocaproic acid group. The majority of the trials included either posterior or anterior spinal arthrodesis, with the younger patients typically undergoing treatment for scoliosis. The older patients typically had various surgical procedures, including spinal arthrodesis for the treatment of fracture or deformity, spinal decompression for the treatment of spinal stenosis, and spinal reconstruction for the treatment of tumor.
For the aprotinin trials in adults, the drug was administered mainly in its so-called Regimen-A dosage of a 2-million-KIU (Kallikrein inhibitor units)/mL loading dose and a constant infusion dose of 500,000 KIU/hr3,8,9. The so-called Regimen-B dosage of a 1-million-KIU loading dose and constant infusion dose of 250,000 KIU/hr was only used in the study by Urban et al.1. The clinical trial by Cole et al. on posterior spinal arthrodesis for the treatment of scoliosis was the only trial involving young patients (mean age, thirteen years) in which the dosage was less than Regimen A but greater than Regimen B, with a loading dose of 240 mg and a continuous infusion dose of 56 mg/hr during surgery7.
In three clinical trials of tranexamic acid (one of which involved spinal arthrodesis for the treatment of idiopathic and secondary scoliosis7 and two of which involved tumor treatment and posterior spinal arthrodesis4,11), the drug was administered with a loading dose of 10 mg/kg and a constant infusion dose of 1 mg/kg/hr during surgery. The clinical trial by Krohn et al., which involved screw fixation of the lower back, differed from the other trials in that tranexamic acid was only infused at the conclusion of surgery14. That trial was excluded from the meta-regression because, in the other trials, tranexamic acid was administered throughout surgery and not just at the conclusion of the procedure. As that was the only study in which tranexamic acid was administered in that way, a meta-regression involving that trial was not feasible. The two other trials involving posterior spinal arthrodesis for the treatment of idiopathic and secondary scoliosis involved an increased loading dose of 100 mg/kg and a continuous infusion dose of 10 mg/kg/hr during surgery6,13. Previous studies have shown that a loading dose of 100 mg/kg was more effective than either a 10 mg/kg or 50 mg/kg dose and was equally as effective as a 150 mg/kg dose13.
Epsilon-aminocaproic acid was administered with use of three different dosages as well. One trial involved the highest dosage regimen, consisting of a bolus of 150 mg/kg/30 minutes followed by continuous infusion of 15 mg/kg/hr until the completion of surgery9. Another study used half of that dosage, with a 5-g bolus followed by 15 mg/kg/hr infusion1,9. The remaining five studies involved the same regimen of a 100 mg/kg bolus followed by a 10 mg/kg/hr infusion17-20.
None of the studies demonstrated any complications that were attributable to the administration of any of the antifibrinolytic agents, and none of the studies demonstrated any increase in the rate of deep venous thrombosis or pulmonary embolus when the groups receiving antifibrinolytic agents were compared with the control group. However, none of the studies that were included in the present analysis were adequately powered to demonstrate differences in the complication rate between an antifibrinolytic agent and a placebo.
Aprotinin, tranexamic acid, and epsilon-aminocaproic acid are antifibrinolytic drugs that have shown highly encouraging results for decreasing blood loss and the number of transfusions in clinical trials involving patients managed with cardiac and orthopaedic surgery. The results of the present study showed that all three antifibrinolytic agents notably reduced total blood loss and transfusions in patients managed with spine surgery. Previous meta-analyses have created a better understanding of the overall effect of aprotinin, tranexamic acid, and epsilon-aminocaproic acid in various clinical trials. The meta-analysis on antifibrinolytics by Henry et al. focused on sixty-one trials involving aprotinin, eighteen trials involving tranexamic acid, and four trials involving epsilon-aminocaproic acid22. The majority of those trials involved cardiac surgery, and aprotinin, tranexamic acid, and epsilon-aminocaproic acid were found to significantly decrease blood loss and transfusions. While the meta-analysis by Henry et al. did provide a large number of clinical trials to give it sufficient power, it was biased by the fact that 88% of the studies involved cardiac surgery. More recently, aprotinin has been shown to be associated with an increased risk of long-term mortality following coronary bypass surgery in comparison with epsilon-aminocaproic acid or no agent23,24.
In November 2007, the United States Food and Drug Administration announced that the manufacturer of aprotinin had halted its production because the preliminary results of a clinical trial demonstrated that patients receiving aprotinin had a higher mortality rate following cardiac surgery. The exact reason for this higher mortality rate is unknown at the present time. One important difference between aprotinin and the other two agents is that it is not synthetic and perhaps induces an immunological response or is excreted from the kidney abnormally. Additional research is needed to delineate the exact mechanism by which this adverse event occurs. However, none of the studies in the analysis demonstrated any mortalities or adverse events in association with the antifibrinolytic agent. The side-effect profiles of these drugs are listed in a table in the Appendix25-27.
Zufferey et al. performed a meta-analysis in which they reviewed the role of antifibrinolytics in major orthopaedic surgical procedures (total knee arthroplasty, total hip arthroplasty, and spine surgery)28. Their analysis was largely weighted toward total hip arthroplasty trials, and thus the results were too general to be applied to each specific type of surgery. Thus, while the current meta-analysis on spine surgery does not contain as many trials as the studies by Zufferey et al.28 or Henry et al.22, specific conclusions can be drawn regarding the role of aprotinin, tranexamic acid, and epsilon-aminocaproic acid in spine surgery.
The present meta-analysis demonstrated that aprotinin, tranexamic acid, and epsilon-aminocaproic acid consistently reduced blood loss and blood transfusions in patients managed with spine surgery. Epsilon-aminocaproic acid had a greater effect on blood loss and transfusions when compared with the other two agents, although the difference was not significant. When controlling for the moderating variables, epsilon-aminocaproic acid was found to be more effective for reducing blood transfusions as the complexity of surgery increased. In contrast, tranexamic acid had a significantly smaller overall benefit in terms of reducing blood transfusions as the complexity of surgery increased. For aprotinin, none of the moderating variables had an effect on blood transfusions.
The main limitation of a meta-analysis is the quality of the studies included in the analysis and the ability to control for any extraneous variables. The present study only included prospective studies, so any case reports or case series, which are considered to be of lesser quality, were omitted. At the time of our analysis, we were aware of no randomized controlled trials, which offer the highest level of quality. The present analysis identified the type of surgical procedure, the dosage of the medicine, the age of the patient at the time of surgery, and sex as variables that may affect blood loss and, ultimately, blood transfusions. Thus, we performed a meta-regression to determine the effect size that each of these variables may have on blood loss and transfusions. It is also important to note that these agents are used in an off-label manner for spine surgery as they are only indicated for use in cardiac surgery (aprotinin), for dental extraction procedures in hemophiliacs (tranexamic acid), and in cases in which fibrinolysis contributes to bleeding (epsilon-aminocaproic acid).
Another limitation of the present study is the way in which blood loss was estimated in the included studies. The majority of studies that provided detailed information on the methods that were used to estimate blood loss involved a combination of the gravimetric method, in which the blood is converted into milliliters on a mL/gram basis, and visual estimation. The authors of several studies have tried to correlate the gravimetric method with the standard spectrophotometry method, with mixed results29,30. The spectrophotometry method is a laboratory-based method that is time-consuming, expensive, and impractical in clinical medicine. In a clinical setting, the gravimetric method is preferred over visual estimation30,31.
In conclusion, aprotinin, tranexamic acid, or epsilon-aminocaproic acid can reduce blood loss and blood transfusions in patients managed with spine surgery. The surgeon and the anesthesiologist should familiarize themselves with these agents and should make a collaborative decision on whether and when these agents should be used. Finally, appropriate disclosure to the patients should be made if these agents are to be used during surgery. The patient should understand the potential side effects of these agents and should also understand that these agents would be used in an off-label manner. Additional studies should critically evaluate the cost-effectiveness and safety of these agents.
Tables listing the studies analyzed and the side-effect profiles of the three agents are available with the electronic versions of this article, on our web site at jbjs.org (go to the article citation and click on “Supplementary Material”) and on our quarterly CD/DVD (call our subscription department, at 781-449-9780, to order the CD or DVD).
Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at Texas Tech University Health Sciences Center and Texas Tech University, Lubbock, Texas
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