Clinical trial NCT02053363
Conditions: Adult Spinal Deformity
Keywords: tranexamic acid, reconstructive spine surgery
Sponsor: Washington University School of Medicine
Start date: 2014-03-01; Completion date: 2020-06-26
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate two dosing protocols for tranexamic acid (TXA), an anti-fibrinolytic used to decrease blood loss in adult patients undergoing complex, reconstructive spinal fusion surgeries.

Detailed description:
After consent is obtained and the patient is enrolled in the trial, patients will be assigned de-identified, unique identification (ID) numbers. Randomization of these IDs to either low or high dose TXA will occur via a computer generated random assignment. Given the variations that may exist in surgical technique (e.g. performance of osteotomies), stratified randomization will be performed by attending surgeon. Based upon the randomization, the pharmacy will prepare TXA for one of two intravenous dosing protocols:

1. Low Dose (Standard of Care/Control): Loading Dose 10mg/kg given over 15 minutes, followed by 1mg/kg/hr via continuous infusion
2. High Dose (Study Group): Loading Dose 50mg/kg given over 15 minutes, followed by 5mg/kg/hr via continuous infusion.

The surgeon, anesthesia team, and operating room staff will be blind to the concentration of TXA in the medications received. Treatments may be "unblinded" at the discretion of the surgeon and anesthesiologist, in cases of extreme blood loss. If additional anti-fibrinolytics are given, the change in dose will be recorded.

Post-operative care will be the same as any other patient and data collection will be information contained in the patient's medical record that is part of routine, standard of care.

Arms: arm 1: Tranexamic Acid (Cyklokapron) Loading Dose 50mg/kg given over 15 minutes, followed by 5mg/kg/hr via continuous infusion. The loading dose will be given to coincide with incision. The continuous infusion will be stopped at the conclusion of fascial layer closure. arm 2: Tranexamic Acid (Cyklokapron) Loading Dose 10mg/kg given over 15 minutes, followed by 1mg/kg/hr via continuous infusion. The loading dose will be given to coincide with incision. The continuous infusion will be stopped at the conclusion of fascial layer closure.
Interventions: intervention 1: Tranexamic Acid (Cyklokapron)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Low versus High Dose Tranexamic Acid in Adult Spinal Deformity Surgery: A Randomized, Blinded, 
Controlled Trial 
NCT 02053363 
08/01/2018 
 
 


Study Protocol 
Background and Significance 
 
Complex, reconstructive, spinal fusion surgeries are associated with large amounts of blood 
loss1-3. Antifibrinolytics, such as epsilon-aminocaproic acid, tranexamic acid(TXA), and aprotinin have 
been shown to reduce the blood loss and allogeneic, red cell transfusion requirements associated with 
these surgeries2-9. Aprotinin has been withdrawn from the market, due to an association with renal 
toxicity3. TXA is a lysine derivative that inhibits the formation of plasmin, thus inhibiting fibrinolysis, and 
is estimated to be 10 times more potent than epsilon-aminocaproic acid10. 
 
A meta-analysis of antifibrinolytic use in spine surgery found that TXA is effective in reducing 
blood loss, without an increase in medication related complications6. Elwatidy et al5 performed a 
randomized, placebo-controlled study of a high dose TXA (2gm load,  100mg/hr infusion) for patients 
undergoing a variety of spinal surgeries. This study showed both the safety and efficacy of this regimen. 
The patients randomized to TXA suffered less blood loss (p = 0.007) and required fewer PRBC transfusion 
(p = 0.008). They note, however, that the small numbers (N=64) limit the conclusions and that a larger 
study of TXA in this patient population is needed. 
 
In a retrospective analysis of patients undergoing complex spine reconstructions, Baldus et al1 
were unable to show a significant difference in blood loss or transfusions requirements between 
patients receiving low dose TXA (10mg/kg load, 0.5mg/kg/hr infusion) and controls. These authors 
postulate that a higher dose may be more effective in reducing blood loss and transfusion requirements. 
This same group has presented data for complex pediatric spinal reconstructions, showing a high dose 
TXA regimen (100mg/kg load, 10mg/kg/hr) results in significantly less blood loss that control and similar 
results to aprotinin11. No complications related to TXA were reported in either series. 
 
Similar, effective results have been published in paediatric spinal deformity surgery8,12. Grant et 
al12, in a retrospective case-control series, showed a high dose TXA regimen (20mg/kg load, 10mg/kg/hr 
infusion) reduced blood loss and transfusion requirements when compared with a low dose TXA 
regimen (10mg/kg load, 1mg/kg/hr infusion). Unfortunately, the study was underpowered (High Dose 
TXA: 15, Low Dose TXA: 11) to detect a significant difference. Sethna et al8 showed a significant 
reduction in blood loss (p<0.01) in paediatric patients undergoing spinal fusion for scoliosis. In both 
series, no complications were reported related to TXA use. 
 
There is no appropriately powered study comparing two TXA dosing regimens in a homogenous 
patient population. This study will provide high quality evidence for or against the use of a high dose 
TXA regimen in adult spinal deformity patients, in addition to supporting the safety profile of TXA in this 
patient population. 
Research Design and Methods 
Study Design: Randomized, double blind, controlled Trial at a single institution.  The study will be 
registered at www.ClinicalTrials.gov .  


Power Analysis: We anticipated an intraoperative estimated blood loss (EBL) of 2,000mL with a standard 
deviation of 500mL in the control group. A difference of 400mL was estimated to be a clinically relevant 
difference, as differences in excess of 400mL may result in additional units of allogeneic packed red 
blood cell transfusion during and after surgery. A sample size of 26 patients per group (52 total) was 
needed to find a difference of 400mL with a power of 80% and alpha defined as 0.05. In anticipation of 
nonadherence and loss to follow up, target enrollment was 60 patients. 
Selection Protocol: Following Institutional Review Board (IRB) approval, adult patients (ages 18-75) 
scheduled to undergo long segment (Upper Instrumented Vertebra (UIV) T5 or proximal and Lower 
Instrumented Vertebra (LIV) L3 or distal)  posterior spinal fusion with instrumentation (PSF) for adult 
scoliosis without a current deep venous thrombosis (DVT), TXA related contraindications, or other 
distinct contraindications are eligible and consent for participation will be sought.  
 
Contraindications to Tranexamic Acid 
1. Patients with an acquired defective color vision 
2. Patients with subarachnoid hemorrhage 
3. Patients with active intravascular clotting 
4. Patients with hypersensitivity to tranexamic acid or any of the ingredients 
Contraindications to Enrollment 
1. Any patient who pre-donates autologous blood for intra- or postoperative use.  
(Directed donor units are acceptable). 
2. Any patient with history of suspected blood disorders or abnormal coagulation 
laboratory results. 
3. Any patient on anticoagulation therapy that cannot be interrupted. 
4. Any patient with history of deep vein thrombosis (DVT). 
5. Any patient with impaired renal function or serum creatinine > 1.5. 
 
All eligible patients will be provided with a detailed explanation of the study as well as a copy of an 
Investigational Review Board (IRB) approved informed consent form to take home and review.  Only 
after all patient questions have been answered and the patient is agreeable to participation, will an 
informed consent be obtained.  A study coordinator will obtain and complete baseline data forms.   
Patient Randomization:  After consent is obtained and the patient is enrolled in the trial, patients will be 
assigned deidentified, unique ID numbers. Randomization of these IDs to either low or high dose 
tranexamic acid will occur via a computer generated random assignment. Given the variations that may 
exist in surgical technique (e.g. performance of osteotomies), stratified randomization will be performed 
by attending surgeon. Based upon the randomization, the pharmacy will prepare tranexamic acid (TXA) 
for one of two intravenous dosing protocols(independent variable): (1) Low Dose(Standard of 
Care/Control): Loading Dose 10mg/kg given over 15 minutes, followed by 1mg/kg/hr via continuous 
infusion (2) High Dose(Study Group): Loading Dose 100mg/kg given over  15 minutes, followed by 


10mg/kg/hr via continuous infusion. The medications will be delivered  to the operating room in 
identical packaging for both treatment groups, and labeled “TXA Study Drug.” All patients will receive a 
test dose prior to the induction of general anesthesia. The surgeon, anesthesia team, and operating 
room staff will be blind to the concentration of TXA in the medications received. Treatments may be 
“unblinded” at the discretion of the surgeon and anesthesiologist, in cases of extreme blood loss. If 
additional anti-fibrinolytics are given, the change in dose will be recorded.  The loading dose will be 
given to coincide with incision. The continuous infusion will be stopped at the conclusion of fascial layer 
closure. 
Surgical Technique: A standard, midline, subperiosteal approach will be taken to the spine. Hemostasis 
will be achieved with electrocautery. Mean arterial pressures (MAP) will be maintained between 60-
80mmHg in an effort to minimize blood loss. At the discretion of the surgeon, posterior column 
osteotomies and three column osteotomies/vertebral column resections will be performed. When 
performed, the number and location will be recorded. Pedicle screw instrumentation will be used 
preferentially. Extension to the ilium will accompany any lumbosacral fusion. Standard reduction 
techniques will be used. The dorsal elements will be decorticated, as a last measure. Iliac crest will not 
be harvested, unless specifically requested by the patient, or if a contraindication to the use of bone 
morphogenetic protein-2 (rhBMP-2) exists. Intraoperative red blood cell salvage will be used. Subfascial 
and suprafasical drains will be placed routinely. All wounds will be closed routinely, in layers. Drains will 
be removed on postoperative day #3 or when output is 30cc or less over an 8 hour shift. 
Postoperative Protocol: All patients are mobilized on postoperative day #1. Complete blood counts 
(CBC) are obtained on postoperative days #1-3. A transfusion trigger for all patients will exist at a 
Hemoglobin level of 8.0 g/dL. Patients with a higher hemoglobin level, with symptomatic anemia, who 
are refractory to fluid repletion will receive allogeneic red cell transfusions. All patients are kept nothing 
by mouth until a return of bowel function. Until diets are advanced, patients will receive intravenous 
maintenance fluids. All patients receive respiratory therapy postoperatively, to include incentive 
spirometry and intermittent positive pressure breathing.  
Data Collection: Routine demographic data will be collected at enrollment: 
1. Age 
2. Weight (kg) 
3. Height (cm) 
4. Gender 
5. Race 
6. Primary Diagnosis 
7. Standard Scoliosis Research Society Radiographic Measurements 
a. Coronal / Sagittal Cobb Measurements 
b. Coronal / Sagittal Alignment by C7 Plumb Lines 
8. Charlson Comorbidity Index13 
9. American Society of Anesthesiologists’ (ASA) Score13 
10. Nicotine Status 


11. Complete Blood Count 
12. Coagulation Profile (PT/PTT/INR) 
13. Narcotic Use (None / Mild Narcotic / Strong Narcotic / Quantities) 
14. Allergies 
15. Preoperative Neurologic Exam 
16. Scoliosis Research Society – 22 Score 
17. Oswestry Disability Index Score 
18. Visual Analog Pain Score 
Intraoperative data collected will include: 
1. Procedure Length (Incision to Skin Closure, minutes) 
2. Levels Fused 
3. Levels of Instrumentation and Type 
4. Osteotomies Performed (Yes / No / Type) 
5. Hemoglobin Concentration at Incision, Closure (by Arterial Blood Gas) 
6. Estimated Blood Loss (estimated as three times cell saver volume) 
7. Crystalloid / Colloid Volume Infused 
8. Allogeneic Packed, Red Blood Cells (PRBC) / Fresh Frozen Plasma (FFP) / 
Platelets (PLT) Transfused 
9. Urine Output 
10. Intraoperative Surgical Complications14 
Postoperative data collected will include: 
1. Drain Output (with Length of Drain Use) 
2. CBC on Postoperative Days #1,2, and 3 
3. Units of PRBC / FFP / PLT Transfused 
4. Length of Hospital Stay 
5. Disposition at Discharge 
6. Acute Perioperative Complications14 
7. Duplex Ultrasound Scan of Lower Extremities Result 
Followup visits will be six weeks and three months to capture complications potentially related to TXA at 
up to three months after surgery. At these visits, SRS-22 and ODI scores will be obtained. The dependent 
variables of interest are: 
1. Intraoperative and Total Estimated Blood Loss 
2. Number of PRBC Units Transfused 
3. Intraoperative and Acute Complications (up to three months) 
All findings will be reported using CONSORT guidelines.    
Human Subjects 


All protocol violations will be reported to the Washington University IRB.  All serious adverse events 
(SAE’s) will be reported to the Washington University IRB within 15 days of occurrence.  SAE will be 
tracked and potential association with TXA administration will be determined site PI.   Any frequently 
occurring SAE felt to be associated with TXA administration will be reported to all participating centers 
as well as Med Watch. 
Literature Cited 
1. 
Baldus CR, Bridwell KH, Lenke LG, Okubadejo GO. Can we safely reduce blood loss during lumbar 
pedicle subtraction osteotomy procedures using tranexamic acid or aprotinin? A comparative study with 
controls. Spine 2010;35:235-9. 
2. 
Neilipovitz DT. Tranexamic acid for major spinal surgery. European spine journal : official 
publication of the European Spine Society, the European Spinal Deformity Society, and the European 
Section of the Cervical Spine Research Society 2004;13 Suppl 1:S62-5. 
3. 
Okubadejo GO, Bridwell KH, Lenke LG, et al. Aprotinin may decrease blood loss in complex adult 
spinal deformity surgery, but it may also increase the risk of acute renal failure. Spine 2007;32:2265-71. 
4. 
Berenholtz SM, Pham JC, Garrett-Mayer E, et al. Effect of epsilon aminocaproic acid on red-cell 
transfusion requirements in major spinal surgery. Spine 2009;34:2096-103. 
5. 
Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of 
prophylactic large dose of tranexamic acid in spine surgery: a prospective, randomized, double-blind, 
placebo-controlled study. Spine 2008;33:2577-80. 
6. 
Gill JB, Chin Y, Levin A, Feng D. The use of antifibrinolytic agents in spine surgery. A meta-
analysis. The Journal of bone and joint surgery American volume 2008;90:2399-407. 
7. 
Neilipovitz DT, Murto K, Hall L, Barrowman NJ, Splinter WM. A randomized trial of tranexamic 
acid to reduce blood transfusion for scoliosis surgery. Anesthesia and analgesia 2001;93:82-7. 
8. 
Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic acid 
reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. Anesthesiology 
2005;102:727-32. 
9. 
Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes intraoperative blood loss and 
transfusion in spinal fusions for duchenne muscular dystrophy scoliosis. Spine 2007;32:2278-83. 
10. 
Cyklokapron (tranexamic acid tablets and tranexamic acid injection). 2008. (Accessed March 5, 
2012, at http://media.pfizer.com/products/rx/rx_product_cyklokapron.jsp.) 
11. 
Rahman R, Min, WK, Nakamura, Y, Zebala, LP, Sides, BA, Bridwell, KH, Lenke, LG. High Dose 
Tranexamic Acid Reduces Blood Loss in Complex Pediatric Spinal Deformity Surgery. In: Scoliosis 
Research Society 46th Annual Meeting. Louisville, KY; 2011. 


12. 
Grant JA, Howard J, Luntley J, Harder J, Aleissa S, Parsons D. Perioperative blood transfusion 
requirements in pediatric scoliosis surgery: the efficacy of tranexamic acid. Journal of pediatric 
orthopedics 2009;29:300-4. 
13. 
Howe CR, Agel J, Lee MJ, et al. The morbidity and mortality of fusions from the thoracic spine to 
the pelvis in the adult population. Spine 2011;36:1397-401. 
14. 
Glassman SD, Hamill CL, Bridwell KH, Schwab FJ, Dimar JR, Lowe TG. The impact of perioperative 
complications on clinical outcome in adult deformity surgery. Spine 2007;32:2764-70. 
 

SAP_001.pdf: 
Low versus High Dose Tranexamic Acid in Adult Spinal Deformity Surgery: A Randomized, Controlled 
Trial  
NCT 02053363  
08/01/2018 
 


Statistical Analysis Plan 
 
Parametric data were expressed as mean ± standard deviation and compared using the Student t test 
and Chi-square. Nonparametric data were expressed as median (interquartile range) and compared via 
the Mann-Whitney U test. Prior to analysis, outlier values were examined to determine their origin and 
ensure they did not represent data entry errors. Enrollment and surgical data were compared to ensure 
successful randomization. Data were analyzed on an intention-to-treat basis. Only patients who enrolled 
and underwent surgery were considered completed. Randomization failures were patients who enrolled 
but failed to undergo surgery as scheduled and were not randomized. Mean EBL was the primary 
outcome measure, while number of PRBC transfused, mean number of intraoperative complications and 
90-day complications were secondary outcomes. All tests were 2 sided and were considered statistically 
significant if the P value was less than 0.05. Statistical analysis was performed using JMP, version 13 (SAS 
Institute Inc., Cary, North Carolina, USA).