Antifibrinolytics Reduce Blood Loss in Adult Spinal Deformity Surgery

         Perioperative blood loss is a major concern in surgery,  particularly in complex, high-risk surgical procedures such as adult spinal deformity correction. Although recent advances including autologous blood donation, erythropoietin, and cell saver have been employed to reduce perioperative bleeding and maintain blood volume, patients nevertheless have been known to lose their entire blood volumes or more during complex procedures. 1

          Blood loss–associated morbidities can be direct, including hypotension; organ damage, particularly cardiac, pulmonary, and renal;and coagulopathy. Indirect morbidities including acute lung injury, hypersensitivity reactions, infections, and immunosuppression also result from increased transfusions, with more transfusions leading to increased odds of morbidity. 1,2 Furthermore, the increased length of blood loss–associated intensive care unit stay results in signifi cantly higher healthcare costs. 1 Recently, there has been an increase in the use of antifi-brinolytics, including epsilon aminocaproic acid (EACA), aprotinin, and tranexamic acid (TXA), to reduce surgery-associated transfusion rates. Although aprotinin has been removed from the market, TXA and EACA have become widely used in several types of surgery, including cardiac and orthopedic. 3,4 Both are lysine analogs that bind select receptor sites on plasma and plasminogen, inhibiting there was a demonstrable but nonsignifi cant trend toward reduced intraoperative blood loss in both antifi brinolytic arms versus control. EACA had signifi cant reductions in postoperative blood transfusions versus TXA.

          Conclusion. The fi ndings in this study support the use of antifi brinolytics to reduce blood loss in posterior adult spinal deformity surgery. Key words: tranexamic acid , epsilon aminocaproic acid , antifi brinolytic , posterior spinal fusion , adult spinal deformity , blood loss , transfusion , randomized control , MAP , spine surgery , scoliosis. Level of Evidence: 1 Spine 2015;40:E443–E449 Antifi brinolytics Reduce Blood Loss in Adult Spinal Deformity Surgery A Prospective, Randomized Controlled TrialAustin Peters , MD ,* † Kushagra Verma , MD, MS, * ‡ Kseniya Slobodyanyuk , MD ,*Thomas Cheriyan , MD, * Christian Hoelscher , MD ,* Frank Schwab , MD, * Baron Lonner , MD ,* Tessa Huncke , MD, * Virginie Lafage , PhD, * and Thomas Errico , MD *Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SPINE141156_LR E443 PINE141156_LR E443 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al E444 www.spinejournal.com April 2015 plasminogen activation. TXA is up to 10 times more potent than EACA and binds more strongly to the plasminogen molecule. 2,5 Both are considered relatively safe although there is some question of thrombotic events, seizures, and renal failure. 6–11 As previously mentioned, TXA and EACA have a well-documented role in several types of surgery. However, their effi cacy in spine surgery is still unclear. This was a prospective, randomized, double-blind placebo-controlled study intended to provide high-quality evidence regarding relative effi cacies of TXA and EACA versus placebo in adult patients undergoing posterior spinal fusion of at least 5 levels. Primary outcomes were intraoperative blood loss and total blood transfusion rate. Secondary outcomes were postoperative drain output, total blood loss (estimated blood loss [EBL] + wound drainage), and the change in hematocrit (Hct). The hypothesis is that patients receiving either TXA or EACA will have reduced blood loss (intra- and postoperative) compared with control, with TXA having superior effi cacy to EACA.

MATERIALS AND METHODS

Study Design

         The study is a prospective, randomized, double blind placebo controlled trial conducted at a single institution and approved by the institutional review board. This clinical trial was registered at ClinicalTrials.gov (“Tranexamic Acid (TXA) Versus Epsilon Aminocaproic Acid (EACA) Versus Placebo for Spine Surgery,” NCT00958581).

Patient Population

          Between December 2008 and September 2012, patients between 18 and 80 years of age undergoing posterior spinal fusion of at least 5 levels for adult spinal deformity at a single institution were enrolled in the study. Patients were excluded if they had renal dysfunction identifi ed by elevated blood urea nitrogen and creatinine (Cr) or blood urea nitrogen to Cr ratio greater than 20:1, had religious and/or other beliefs limiting blood transfusion, were using anticoagulant medications, had medical history leading to an abnormal coagulation profi le preoperatively, or had signifi cant medical history preventing the use of TXA or EACA described in the protocol or any history of coronary artery disease with stent placement. After obtaining written consent, 52 patients (40 females and 12 males) were enrolled in the study ( Figure 1 ).

Randomization

         Prior to the operation, patient de-identifi ed ID numbers were randomly assigned to the TXA, EACA, or placebo using computer-generated random assignment. Patients were each assigned a sequential de-identifi ed ID randomly assigned to TXA, EACA or saline. Allocation assignments were blinded from all persons except the pharmacist and remained unchanged for the duration of the study. “Unblinding” from the study was allowed at any time for medical necessity. These patients continued to be followed as per the protocol. Prospective patients who were approached for inclusion in the study but declined participation had their de-identifi ed ID passed over and their randomization allotment was not reviewed or reused so as to prevent potential bias. Allocation assignments favored the treatment groups over the saline group when the allocation assignments were revealed.

Study Intervention

         The treatment regimen for each group included a loading dose for more than 15 minutes before skin incision, followed by a maintenance dose for the duration of the surgery. Dosages of TXA and EACA groups were as follows: TXA: Loading dose of 10 mg/kg, followed by a maintenance dose of 1/mg/kg/hr. EACA: Loading dose of 100 mg/kg, followed by a maintenance dose of 10 mg/kg/hr. TXA has been shown to be 7 to 10 times more potent than EACA. 12 This provided the rationale for the higher EACA dose administered. The net volume of medication administered during the loading and maintenance phases was identical for all treatment groups.

Surgical Procedure

         Posterior skin incision along the midline was used to access the spine. Paravertebral muscles were dissected away from bony structures, taking care to achieve adequate hemostasis. Multilevel posterior releases of bony and ligamentous structures were performed to increase mobility of the spinal column. Bone grafts for fusion consisting of local autologous rib bone, or allograft were used. Pedicle screw fixation was performed in all cases. Subfascial hemovac drains were routinely placed at the wound site during closure to allow for adequate wound drainage. Hemovac drains were removed when drainage was less than 40 mL per 8-hour shift. To minimize intraoperative blood loss, the mean arterial pressure (MAP) was maintained at 60 to 80 mm Hg during surgical exposure and anchor placement and at 70 to 90 mm Hg during surgical correction. 13,14

Evaluation

         Dependent variables included intraoperative blood loss (EBL), total losses (TL), change in Hct, transfusion rates, and complications. The independent variables were demographic data (age, sex, body weight), estimated blood volume, number of levels fused, surgical invasiveness index, and perioperative factors such as hemoglobin and Hct, treatment groups, and duration of surgery. Intraoperative EBL was calculated to be 3 times the cell saver volume and was employed for all cases in the study with EBL of 300 mL or greater. For cases with EBL of 300 mL or less, cell saver could not be used and anesthesiologist and surgeon estimates of blood loss were used. Estimates were based on surgical sponges soaked and volume in suction canisters Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SPINE141156_LR E444 PINE141156_LR E444 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al Spine www.spinejournal.com E445 subtracting irrigation fl uid added to the surgical fi eld, as described by Tsutsumimoto et al. 15 Postoperative drainage was calculated using the volume of blood in hemovac drains.

         The respective sum of the EBL and postoperative drainage was the TL for that patient. Patient Hcts were measured systematically throughout the procedure: preincision, at incision, at screw placement, at rod placement, at wound closure, postoperatively on arrival to postanesthesia care unit (PACU), postoperative day 1 (POD 1), and postoperative day 2 (POD 2). During surgery, patients were Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CONSORT 2010 Flow Diagram Allocated to intervention: Control (n=14) Received allocated intervention (n=13) Did not receive allocated intervention (n=1) Surgery was aborted Assessed for eligibility (n=90) Excluded (n=38) Not meeting inclusion criteria (n=8) Declined to participate (n=30) Other reasons (n=0) Analysed (n=19) Excluded from analysis (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Allocated to intervention: TXA (n=19) Received allocated intervention (n=19) Did not receive allocated intervention (n=0)

Allocation Analysis Follow-Up

         Randomized (n=52) Enrollment Lost to follow-up (n=0) Discontinued intervention(n=0) Analysed (n=19) Excluded from analysis (n=0) Analysed (n=13) Excluded from analysis (surgery was aborted pre-operatively) (n=1) Allocated to intervention: EACA (n=19) Received allocated intervention (n=19) Did not receive allocated intervention (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Figure 1. Consort diagram illustrating exclusion, enrollment, and randomization. TXA indicates tranexamic acid; EACA, epsilon aminocaproic acid. SPINE141156_LR E445 PINE141156_LR E445 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al E446 www.spinejournal.com April 2015 transfused if they had measured Hct of 25 or less with ongoing bleeding. Postoperatively, symptomatic patients with Hct of 22 or less were transfused. The number of patients receiving transfusions was reported as both proportion and percentage. Complexity of surgery was determined by the number of levels fused. Low-complexity procedures were defi ned as fusions of between 5 and 12 levels, whereas high-complexity fusions involved 13 or more levels. Surgical invasiveness index for each surgery was determined, as defi ned by Mirza et al, 16 which included the number of levels being fused, whether it was a revision, and so forth. Primary outcomes of this study were intraoperative EBL, TL (EBL + postoperative drainage), and transfusion rates. Secondary outcomes were changes in Hct (from various points of measure) and length of stay.

Statistical Analysis

         Sample size was determined on the basis of previous studies comparing effi cacies of aprotinin, EACA, and control in spine surgery. 13,17 Two-tailed analysis of variance was used to analyze data, and Fisher-protected least squares difference post hoc test was used to determine signifi cance of the difference between selected groups when variance between groups was equal; when unequal variance existed between groups, Games-Howell post hoc test was employed. All statistical analysis was performed using SPSS software (Version 22) and statistical signifi cance was set at P value of less than 0.05. Source of Funding and Confl icts This project was supported using departmental funds. The authors do not have any confl icts of interests related to the subject of this article.

RESULTS

           Patient Demographics Fifty-two enrolled patients were randomized to 1 of 3 treatment groups: TXA (19), EACA (19), and placebo (13);1 female randomized to the placebo arm had her surgery aborted prior to intervention and was excluded from all analysis ( Figure 1 ). Mean ages were 60, 47, and 43 years, respectively. There were statistically signifi cant differences between the ages of the TXA branch and both other arms of the study, as well as estimated blood volume between TXA and EACA ( Table 1 ). Intraoperative Blood Loss, Postoperative Drainage, and TL There were no statistically signifi cant differences in EBL between groups, although there was a trend toward reduced blood loss in the antifi brinolytic groups compared with control. Postoperative drainage was not signifi cant between all groups. EACA had signifi cantly reduced TL compared with control ( P = 0.007), and, when controlled for levels fused, was signifi cantly reduced compared with both control and TXA ( P = 0.021, P = 0.042, respectively) ( Table 2 ). Change in Hct Hct changes from incision-to-PACU ( P = 0.709), PACU-POD1 ( P = 0.070), POD1-POD2 ( P = 0.746), and PACU-POD2 ( P = 0.180) were similar between all groups: there was a trend toward decreased Hct change pre- to postoperatively with antifi brinolytics, but this did not reach statistical signifi cance ( Table 2 ). Transfusions Intraoperation There were no signifi cant differences in intraoperative transfusion rate or amount of blood transfused between groups. Postoperation Patients treated with EACA required fewer postoperative blood transfusions compared with TXA (11% [2/9] vs. 53% [10/19], P = 0.013) ( Table 3 ). Deviations From Protocol and Complications Four patients did not have total drain output recorded due to unfamiliarity with the study protocol and were excluded from this aspect of the analysis. One patient passed away on postoperative day 10 because of cardiopulmonary complications stemming from sleep apnea. Two patients, 1 each in the EACA and TXA treatment arms, were diagnosed with pulmonary embolism in the postoperative period.

DISCUSSION

          TXA and EACA are antifi brinolytics currently offered as prophylactic agents to reduce surgery-associated blood loss. Although a number of previous studies have individually evaluated TXA and EACA in placebo-controlled trials, there remains no consensus regarding the relative effi cacy of these Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. TABLE 1. Patient Demographics

Characteristic

TXA (n = 19)

EACA (n = 19)

Control

(n = 13) Age (yr) 60* 47* 43*BMI (kg/m 2) 27 25 28

Number of levels fused 11 12 13

EBV (mL) 5500* 4400* 5300

Duration of surgery (min) 310 290 280

Length of stay (d) 8 10 8

Invasiveness index 22 25 27

          For all patients, those randomized to TXA were signifi cantly older than both EACA and control patients and had signifi cant greater EBV than those in the EACA group. Values in boldface signify signifi cance at P < 0.05. *Signifi cant comparison. TXA indicates tranexamic acid; EACA, epsilon aminocaproic acid; BMI, body mass index; EBV, estimated blood volume. SPINE141156_LR E446 PINE141156_LR E446 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al Spine www.spinejournal.com E447 2 treatment options. Furthermore, the direct costs of the 2 antifi brinolytics can vary with institution. The purpose of this study was to compare these 2 treatment options head-to-head in a prospective randomized clinical trial in a population of adult spinal deformity patients undergoing spinal fusion. This present study reports a lower blood transfusion rate for EACA as compared with TXA. Previous studies evaluating blood loss and transfusion outcomes for all adult spine surgery patients randomized to either TXA or EACA have yielded mixed results. 15,18–27 Regarding TXA, Wong et al, 26 in a placebo-controlled trial of adult spinal fusion surgery, which used a comparable dosage regimen to this study, similarly found that TXA signifi cantly reduced intraoperative, postoperative, and total losses but not transfusion outcomes. Regarding EACA, Florentino-Pineda et al19 found that EACA signifi cantly decreased total and postoperative, though not intraoperative, blood loss in patients undergoing posterior spinal fusion for idiopathic scoliosis, and no signifi cant reduction in blood transfusions.

         On the contrary, Urban et al21 compared EACA, aprotinin and placebo, fi nding that EACA did not signifi cantly affect either blood loss or transfusion outcomes in complex adult spinal reconstructive surgery. However, patients in that study were undergoing combined anterior/posterior fusion, a more complicated procedure involving greater blood loss. The present study found no differences in Hct between treatment arms. Previous studies evaluating effects on Hct have yielded varying results. Elwatidy et al22 found that postoperative Hct was signifi cantly higher after patients received TXA than placebo for spine surgical procedures. However, the study evaluated outcomes in all spine patients, irrespective of age or type of surgery. With regard to EACA, the aforementioned study by Urban et al21 found that postoperative Hct was similar in both randomization groups. The relationship between intraoperative hypotension and reduced surgical blood loss has been extensively documented. Several previous studies looking at antifi brinolytics have included the importance of lowering MAP to reducd blood loss (2, 13, 20–21, 26, 28). The adolescent branch of this study similarly showed improved effi cacy of antifi brinolytics when blood pressure was diligently controlled. 13 For the current study, less than half of the patients were maintained at an average MAP below 75 mm Hg throughout their surgery. This refl ects the increased concern in adults for hypoperfusion-related stroke, cardiac ischemia, and spinal cord and renal injury.

         Analysis controlling for reduced MAP in this study showed similar effi cacy for the antifi brinolytics compared with that of the larger study group, but these were signifi cantly less reliable data due to low sample numbers. In this study, 2 patients treated with antifi brinolytics were diagnosed with pulmonary embolism: 1 occurred in the EACA branch in the immediate postoperative period and another in the TXA branch occurred several weeks later. Overall, there was no difference in complication rate between treatment groups. Although complications were judiciously collected and reported, this study is underpowered to report the relative frequency of uncommon complications. To date, several studies including a Cochrane meta-analysis have failed to show an association between antifi brinolytics and embolic phenomena. 2,19,22,23,26 The thromboembolic events occurring in this study are best attributed to patient comorbidities and chance; however, caution and vigilance in the use of these medications remains a necessity. In summary, this is the fi rst study to directly compare TXA and EACA head-to-head in adult spinal deformity surgery. Both medications were similar in effect with a few exceptions Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. TABLE 2. Blood Loss Characteristic TXA EACA Control

Intraoperative EBL (mL) 1400 1100 2200

Intraoperative EBL/level (mL) 130 90 180

Postoperative drainage (mL) 1600 1300 1800

Postoperative drainage/level (mL) 160 110 130

Total losses (mL) 3100 2400* 4100*

Total loss/level (mL) 290* 210* 310*

Hct change: Incision-PACU –1 0 –1

Hct change: PACU-POD1 –1 0 –3

Hct change: POD1-POD2 –1 –2 –2

Hct change: PACU-POD2 –3 –3 –5

         When comparing all blood loss parameters, there was a signifi cant reduction in total losses (intraoperative EBL + post-operative drainage) for EACA compared with control; when controlled for number of levels fused, there was signifi cant reduction compared with both TXA and control. Values in boldface signify statistical signifi cance at P < 0.05. Hct change refers to the difference in mean hematocrits between groups when compared at the different time periods. *Signifi cant comparison. TXA indicates tranexamic acid; EACA, epsilon aminocaproic acid; EBL, estimated blood loss; Hct, hematocrit; PACU, postanesthesia care unit; POD, postoperative day.

TABLE 3. Transfusions

Characteristic TXA EACA Control Intraoperative transfusion rate

74%

(14/19)

58%

(11/19)

46%

(6/13)

Intraoperative transfusion no. of units 1.8 1.6 1.6 Postoperative transfusion rate

53%

(10/19)*

11%

(2/19)*

46%

(6/13)

          Postoperative transfusion no. of units 1* 0.2* 0.7 For all patients, there was no difference in intraoperative transfusion rates or amounts between all groups; EACA had a signifi cantly lower transfusion rate and number of units transfused than TXA. Values in boldface signify statistical signifi cance at P < 0.05. *Signifi cant comparison. TXA indicates tranexamic acid; EACA, epsilon aminocaproic acid. SPINE141156_LR E447 PINE141156_LR E447 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al E448 www.spinejournal.com April 2015

➢ Key Points

         This was a prospective, randomized, double-blind placebo-controlled study that provided high-quality evidence regarding relative effi cacies of TXA and EACA versus placebo in adult patients undergoing posterior spinal fusion of at least 5 levels. EACA signifi cantly reduced perioperative bleeding compared with control; TXA had reduced bleeding compared with control but did not reach statistical signifi cance. No diff erences were seen in intraoperative transfusion rates between groups; however, EACA had signifi cant reduction in both postoperative transfusion rates and amount of blood transfused when compared with TXA. Overall hematocrit diff erences were not signifi cant between any of the treatment arms. The use of either TXA or EACA is strongly advocated and should be standard of care for adult patients undergoing posterior spinal fusion surgery. 

         ( Figure 2 ). EACA offered less TL than control and perhaps TXA. In addition, postoperative t ransfusion rate was lower for EACA than that for TXA. Finally, there was a trend toward decreased intraoperative blood loss with either TXA or EACA. Aforementioned spine studies may have differing results due to variability in treatment and dosing regimens, outcomes measured, transfusion triggers, and patient profi le. In joint replacement and cardiac surgery, these variables may be better controlled. 28,29 Camarasa et al28 randomized total knee patients to 3 groups as well: TXA, EACA, and placebo. Although their dosing regimen was different from this study, the authors concluded that TXA and EACA were equivocal in terms of total blood loss, transfusions, and change in Hct. Similarly, Chauhan et al30 compared TXA, EACA, and placebo head- to-head in 120 adults undergoing coronary artery bypass surgery. Here again, both treatments equivocally reduced blood losses. Finally, using the same dosing regimen in the adolescent idiopathic scoliosis (AIS) population, Verma et al13 reported that TXA and EACA equivocally reduced operative blood loss but not transfusion rate as compared with control. Compared with saline, both medications had a smaller decrease in post operative Hct. In addition, TXA reduced postoperative drainage and total blood losses as compared with EACA or control.

          The conclusions from this study should be drawn with con-sideration to the previous study in the AIS population. The AIS population, although homogenous in terms of medical history and surgical treatment, had relatively low blood losses and transfusion requirements. In contrast, adult deformity patients are medically complex and have variable surgical treatment(osteotomies performed, etc.), larger blood losses, and higherblood transfusion requirements. This patient and surgical variability is a study limitation and led to 2 notable biases that favored EACA over TXA: fi rst, patients in the TXA group were signifi cantly older; second, TXA patients had a larger estimated blood volume at baseline. This has the tendency to underestimate blood losses and reducing transfusion requirements in the TXA group, possibly leading to a type II error favoring the control group. A secondary analysis was performed controlling for the age differences between groups, but this did not alter the result (omitted for clarity). The statistical differences between EACA and TXA are not likely clinically signifi cant. Other limitations of this study include the relatively small sample size, which was unequal between treatment arms. Another possible limitation is the selection of dosage regimens for TXA and EACA.

           Dosages were determined from previous studies and after achieving a consensus between the orthopedic and anesthesia departments. However, TXA is thought to 10 times more potent than EACA, and higher doses of TXA have been used safely in numerous studies. 7,11,22,23 This is a direction for future study. Finally, although treatment with either TXA or EACA tended to decrease intraoperative blood loss compared with controls, this difference did not reach statistical significance. Given the fi ndings from the AIS study and the clinical judgment that adult patients benefi tted from antifi brinolytics, it was decided to prematurely terminate the study and eliminate the control arm. 17 Although somewhat detrimental to the study, these medications are now offered to all adult deformity patients as the standard of care at the host institution. In conclusion, adult deformity patients undergoing spinal fusion are well suited for either TXA or EACA. The results from this study in adults and previous work on patients with AIS support the routine use of either TXA or EACA to reduce perioperative blood loss associated with spinal deformity surgery. At this dosing regimen, differences between TXA and EACA in terms of blood loss and drain output are relatively small. Future studies may investigate alternate dosing regimens, patients with neuromuscular scoliosis, and complications associated with antifi brinolytic use ( Figure 2 ). Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

-500, 500, 1500, 2500, 3500, 4500, 5500, 6500, 7500

Volume (mL)

TXA EACA Control

Peri-Operave Blood Loss

Intra-operave EBL

Post-operave drainage

Total losses

p=0.007

         Figure 2. Comparison of perioperative blood loss. Illustration of blood loss for all groups. Statistical signifi cance was reached for total losses between epsilon aminocaproic acid and control. Intraoperative EBL and postoperative drainage were not statistically signifi cant between any groups. EBL indicates estimated blood loss. SPINE141156_LR E448 PINE141156_LR E448 16/03/15 2:16 PM 6/03/15 2:16 PM RANDOMIZED TRIAL Antifi brinolytics in Adult Spinal Deformity • Peters et al Spine www.spinejournal.com E449 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

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