Clinical trial NCT02540226
Conditions: Osteoarthritis, Knee
Keywords: Tranexamic Acid Total Knee Arthroplasty Total Knee Replacement
Sponsor: Hospital for Special Surgery, New York
Start date: 2015-11-19; Completion date: 2019-12-01
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tranexamic acid (TXA) is a drug that is being used more frequently at the Hospital for Special Surgery to lessen the amount of blood loss after total knee replacement (TKR). It is an anti-fibrinolytic agent, which means that it promotes the formation of blood clots. TXA can be given either intravenously or topically (placed directly on the open wound) before wound closure. Patients with certain medical conditions have been found to have a high risk of thrombosis after being given intravenous TXA, which may lead to serious complications. However, to date, no high-risk patients have been identified for use of topical TXA. This study will look at thrombogenic markers (proteins found in blood that promote clot formation) after TXA is given either intravenously or topically. If the effect on these markers is similar between intravenous and topical use of TXA, then the safety of topical TXA should be questioned. Of note, these markers have never been measured after TXA has been given topically. As a result, this information would be important for the medical community.

Detailed description:

Arms: arm 1: Patients will receive 1g tranexamic acid in 100mL solution intravenously in the operating room before inflation of the tourniquet. They will again receive the same IV solution in the post-anesthesia care unit, approximately 3 hours after the first solution was given. They will also receive a 75cc topical saline solution approximately 5 minutes before the tourniquet is released. arm 2: Patients will receive 3g tranexamic acid in 75mL solution topically in the operating room, approximately 5 minutes before the tourniquet is released. It will sit for 5 minutes before the solution is suctioned off by the surgeon. They will also receive 2 intravenous saline solutions: one in the operating room before inflation of the tourniquet, and one in the post-anesthesia care unit 3 hours after the first solution was given.
Interventions: intervention 1: Intravenous tranexamic acid intervention 2: Topical tranexamic acid intervention 3: Intravenous saline intervention 4: Topical saline
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
Confidential 
Page 1 of 13 
 
 
 
 
 
 
 
 
 
The Effect of Topical and Intravenous Tranexamic 
Acid (TXA) on Thrombogenic Markers in Patients 
Undergoing Total Knee Replacement (TXA Knee) 
FUNDER: 
Research & Education Fund, Department of 
Anesthesiology, Critical Care & Pain 
Management 
PROTOCOL NO.: 
2015-210 
VERSION & DATE: 
12/3/19 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains the confidential information of the Hospital for Special Surgery.  It is provided to you and your company’s personnel for 
review.  Your acceptance of this document constitutes an agreement that you will not disclose the information contained herein to others without 


 
  
 
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the prior written consent of the Hospital for Special Surgery.  No other use or reproduction is authorized by Hospital for Special Surgery, nor does 
the Hospital for Special Surgery assume any responsibility for unauthorized use of this protocol 
PROTOCOL SYNOPSIS 
Protocol Title: 
The Effect of Topical and Intravenous Tranexamic Acid (TXA) 
on Thrombogenic Markers in Patients Undergoing Total Knee 
Replacement (TXA Knee) 
Protocol Number: 
2015-210 
Protocol Date: 
5/13/19 
Sponsor: 
N/A 
Principal 
Investigator: 
Kethy JulesElysee, MD 
Products: 
NA 
Objective: 
This study will investigate the effect of both topical and intravenous (IV) 
administration of tranexamic acid (TXA) on thrombogenic markers in 
patients undergoing total knee arthroplasty. 
Study Design: 
Randomized Controlled Trial 
Enrollment: 
76 
Subject Criteria: 
1. Patients undergoing primary unilateral total knee 
arthroplasty with a participating surgeon (Drs. 
Mayman, Sculco, Su, McLawhorn) 
2. Patients aged 18-80 
Study Duration: 
11/2016-12/2017 
Data Collection: 
 
Age 
 
Gender 
 
Race 
 
Ethnicity 
 
BMI 
 
History of systemic or pulmonary hypertension 
 
Anesthesia time –duration 
 
Surgery time – duration 
 
Tourniquet time – duration 
 
Time of TXA/Placebo administration(s) 
 
Time of blood collection - Before TQ onset (after time 
out), before final TQ release, 1-hour post-TQ release, 4-
hours post-release 
 
Color/condition of blood samples after centrifugation 
 
Amount of Constavac drainage 


 
  
 
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 
Blinding Assessment 
 
Amount of blood loss 
 
Number of intraoperative and postoperative blood 
transfusions 
 
Hcb and Hct levels 
 
Incidence of DVT/PE 
 
Range of Motion 
Outcome 
Parameters: 
 
Levels of plasmin anti-plasmin (PAP), a marker of 
fibrinolysis - measured from peripheral blood and wound 
drainage 4 hours after tourniquet (TQ) release.  
 
Serum and wound levels of prothrombin fragment 1.2 
(PF1.2), plasmin anti-plasmin (PAP), and IL-6 – prior to 
TQ release, and 1-hour after TQ release (serum only) 
and 4-hours post-TQ release 
 
Serum and wound levels of TXA – prior to TQ release, 
and 1-hour after TQ release (serum only) and 4-hours 
post-TQ release to determine whether IV TXA diffuses 
into tissue readily and to what extent topical TXA is 
absorbed. 
 
Blood loss – measured up until hospital discharge. Blood 
loss will be determined using an equation that calculates 
 
the patient's blood volume based on their height and 
weight, then multiples the patient's blood volume by the 
 
change in hematocrit after surgery compared to before 
surgery. 
 
Hemoglobin (Hgb) levels – measured up until hospital 
discharge 
 
Hematocrit (Hct) levels - measured up until hospital 
discharge 
 
Constavac drainage – measured 4-hours postoperatively 
 
Incidence of thrombosis (DVT/PE) – measured up until 2 
weeks after the date of surgery 
 
Units of intraoperative and postoperative blood 
transfusions administered – measured up until hospital 
discharge 
 
Time to PT Discharge – PT discharge during hospital 
stay 
 
Length of Stay – time of discharge 
Statistical Analysis: 
Proposed analysis (e.g., student’s t-test, ANOVA, chi-square, 
regression, etc.): Two-sample t-test 
Alpha level:  0.05 
Beta or power level: 0.80  


 
  
 
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Primary outcome variable estimate (mean +/- s.d. for continuous 
outcome, frequency/percentage for categorical variable): 
Based on results from the control group of a previous study (IRB 
#11007) the mean + standard deviation PAP level 4-hours post-
operatively in unilateral TKA patients = 1086.6 + 536.3 µg/mL 
Number of groups being compared (use 1 for paired analysis 
within the same subjects): 2 (IV TXA vs. topical TXA) 
Effect size or change expected between groups: 
There is no information in the literature regarding a clinically 
meaningful difference in PAP level. Based on clinical 
experience, a difference of 400 µg/mL in mean PAP level 
between IV and topical TXA groups was estimated to be 
clinically meaningful. 
Resulting number per group: 30 
Total sample size required:  After inclusion of 6 additional 
patients (+10%) to account for potential withdrawals and/or 
protocol violations, the total sample size 
 
It was determined that a sample size of 30 patients per group 
would achieve 80% power at alpha = 0.05 to detect a 400 µg/mL 
difference in mean PAP level 4-hours post-operatively between 
the IV and topical TXA groups assuming a common within-group 
standard deviation of 536.3 µg/mL using a two-sided two-sample 
t-test. After addition of 10% to the sample size to account for 
potential withdrawals and/or protocol violations, the total sample 
size required was 66 patients. 
 
The primary outcome (PAP level 4 hours postoperatively) will be 
compared between the IV and topical TXA groups using a two-
sample t-test or the Wilcoxon rank-sum test, depending upon 
the distribution of the data. 
 
Continuous secondary outcomes will be compared between 
groups using two-sample t-tests or Wilcoxon rank-sum tests, as 
appropriate. Differences between groups will be expressed as 
differences in means or Hodges-Lehmann estimate of location 
shift with 95% confidence intervals. Categorical secondary 
outcomes will be compared between groups using chi-square or 
Fisher’s exact tests, as appropriate. The magnitude of the 
effects will be expressed as odds ratios with 95% confidence 
intervals. 
 
 
 
 


 
  
 
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1.0 INTRODUCTION 
Tranexamic acid (TXA), a lysine analog and antifibrinolytic agent, is being used more 
frequently at HSS in order to decrease blood loss associated with total knee replacement 
(TKR). It can be used intravenously or topically prior to tourniquet release. One of the 
concerns while using TXA is the possibility of deep vein thrombosis (DVT) or pulmonary 
embolism (PE). According to HSS medical guidelines, there are specific contraindications to 
use of IV TXA, but none for topical use of TXA. Interestingly, in a recent study done by one 
of the co-investigators (Dr. Mayman), 2 patients in a group of 320 patients who received 
topical TXA developed DVT while none of the IV group (320 patients) developed signs of 
thrombosis. This may be a coincidence since the total number of patients is small, but it 
raises concern about the safety of topical application. According to Wong et al, topical 
application of TXA at a dose of 3gm led to serum levels of 8.05 (7.2-9.9 mg/ml). The 
therapeutic level of TXA is considered to be 10 mg/ml. If topical and IV TXA have a similar 
effect on thrombotic markers, topical administration may have the same risk of thrombosis 
as the intravenous form. 
 
If we find that the IV form of TXA has mostly a local effect, should we give it only topically? 
These are some of the questions this study will help answer. 
 
This study will examine thrombotic markers when TXA is given both IV and topically. We will 
also measure levels of TXA as well and establish a correlation if possible from peripheral 
blood and Constavac drainage. 
2.0 PRODUCT DESCRIPTION 
N/A 
3.0 OBJECTIVE OF CLINICAL STUDY 
1) Similarly to IV TXA, does topical use of TXA also lead to systemic changes in fibrinolysis in blood after TKR, 
since it may get systemically absorbed? 
 
2) Is there a difference with thrombotic markers between topical and IV use of TXA? 
 
3) Does IV TXA exert its effects systemically and/or locally? 
4.0 STUDY HYPOTHESES 
Topical application of TXA is absorbed through tissue and may lead to the same effect on 
thrombogenic markers as when given intravenously. 
 
5.0 STUDY DESIGN 
 


 
  
 
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5.1 
Study Duration 
11/2016-12/2017 
5.2 
Endpoints 
 
5.2.1 
Primary Endpoint 
 
Levels of plasmin anti-plasmin (PAP), a marker of fibrinolysis - measured 
from peripheral blood and wound drainage 4 hours after tourniquet (TQ) 
release.  
5.2.2 
Secondary Endpoints 
 
Serum and wound levels of prothrombin fragment 1.2 (PF1.2), a marker of thrombin 
generation – measured at pre-incision (serum only), prior to TQ release, and 1-hour 
after TQ release (serum only) and 4-hours post-TQ release 
 
Serum and wound levels of TXA – measured prior to TQ release and 1-hour post-TQ 
release (serum only) to determine whether IV TXA diffuses into tissue readily and to 
what extent topical TXA is absorbed. 
 
Blood loss – measured up until hospital discharge. Blood loss will be determined 
using an equation that calculates the patient's blood volume based on their height 
and weight, then multiples the patient's blood volume by the change in hematocrit 
after surgery compared to before surgery. 
 
Hemoglobin (Hgb) levels – measured up until hospital discharge 
 
Hematocrit (Hct) levels - measured up until hospital discharge 
 
Constavac drainage – measured 4-hours postoperatively 
 
Incidence of thrombosis (DVT/PE) – measured up until 2 weeks after the date of 
surgery 
 
Units of intraoperative and postoperative blood transfusions administered – 
measured up until hospital discharge 
5.3 
Study Sites 
Hospital for Special Surgery – Main Campus 
6.0 STUDY POPULATION 
6.1 
Number of Subjects 
 
76 
6.2 
Inclusion Criteria 
Subjects of either gender will be included if they: 
 
1. Patients undergoing primary unilateral total knee arthroplasty with a 
participating surgeon (Drs. Mayman, Sculco, Su, McLawhorn) 
2. Patients aged 18-80 


 
  
 
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6.3 
Exclusion Criteria 
Subjects will be excluded from the study if they: 
 
1. All patients on steroid therapy regardless of dose, duration, or treatment or those 
requiring stress-dose steroids preoperatively 
2. Patients who will require postoperative use of Coumadin, Xarelto, or Plavix 
3. Use of non-steroidal anti-inflammatory drugs (NSAIDs) within 1 week of surgery 
4. Hypersensitivity to tranexamic acid 
5. Contraindication to use of IV tranexamic acid as per HSS guidelines, which includes: 
a.  Renal dysfunction (Creatinine clearance <40 ml/min) 
b. Hepatic dysfunction (AST or ALT 2x upper limit of normal) 
c. Cardiac exclusions: coronary stent, history of MI, positive stress test or atrial 
fibrillation, advanced CAD 
d. Advanced COPD or advanced interstitial lung disease 
e. History of venous thromboembolism (VTE) 
f. Hypercoagulability (e.g. antiphospholipid syndrome, genetic 
hypercoagulability with or without prior VTE) 
g. History of stroke or TIA 
6.4 
Randomization 
 This is a double-blinded study; group assignment will be concealed from both patients and 
the treating physicians/researchers. A computer-generated randomization table will be 
generated by a statistician. After a patient is enrolled in the study, the pharmacist will 
provide 2 vials of study medication (TXA or placebo) to be given intravenously (one 
intraoperatively, one postoperatively), as well as a syringe containing study medication (TXA 
or placebo) to given topically. 
 
 Randomization was performed prior to enrollment start. Due to methodological and sample 
collection issues, the first 10 patients enrolled using this randomization scheme are 
excluded from data analysis. In order to meet the required sample size, the target 
enrollment number will be increased by 10 patients and a new randomization scheme will be 
created for the required sample size (66 patients) prior to enrolling the 11th patient. 
7.0 PROCEDURES 
7.1 
Surgical Procedure 
Total knee arthroplasty 
7.1.1 
Investigational Product Application 
N/A 
 


 
  
 
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7.2 
Data Collection 
 
Data will be collected by an investigator or research assistant. Sources of data 
include medical records and patient physical assessments conducted by study 
personnel. Data will be recorded and managed using REDCap electronic data 
capture tools hosted at the Clinical and Translational Science Center (CTSC) at 
Weill Cornell Medical College. REDCap (Research Electronic Data Capture) is a 
secure, web-based application designed to support data capture for research 
studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) automated export procedures 
for seamless data downloads to common statistical packages; and 4) procedures for 
importing data from external sources. Connection to REDCap occurs via the 
hospital’s encrypted cable and wireless networks, and data will be entered through a 
password-protected computer terminal or iPad.   


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7.3 
Schedule of Assessments 
 
Study Visit # 
Randomization 
Surgery 
Administration of IV 
Study Medication 
Administration of 
Topical Study 
Medication 
Blood Draw 
(from existing 
catheter) 
Collection of 
Drained Blood from 
Wound 
#1  
OR, Before 
TQ onset 
X 
SOC 
X 
 
X 
 
#2  
OR, Before 
final TQ 
release 
 
 
 
X 
X 
X (Surgeon collects 
pooled blood 
around wound) 
#3 PACU, 1 
hour after 
TQ release  
 
 
X 
 
X 
 
#4 PACU, 4 
hours after 
TQ release 
 
 
 
 
X 
X  
(Taken from 
surgical drain) 
 
X= Research Procedures 
SOC= Standard of care (care you would receive if you were not participating in this study) 
OR = Operating Room; PACU = Post-Anesthesia Care Unit; TQ = Tourniquet; IV = Intravenous 


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8.0 STATISTICAL ANALYSIS 
 
Proposed analysis (e.g., student’s t-test, ANOVA, chi-square, regression, etc.): Two-sample 
t-test 
Alpha level:  0.05 
Beta or power level: 0.80  
Primary outcome variable estimate (mean +/- s.d. for continuous outcome, 
frequency/percentage for categorical variable): 
Based on results from the control group of a previous study (IRB #11007) the mean + 
standard deviation PAP level 4-hours post-operatively in unilateral TKA patients = 1086.6 + 
536.3 µg/mL 
Number of groups being compared (use 1 for paired analysis within the same subjects): 2 
(IV TXA vs. topical TXA) 
Effect size or change expected between groups: 
There is no information in the literature regarding a clinically meaningful difference in PAP 
level. Based on clinical experience, a difference of 400 µg/mL in mean PAP level between 
IV and topical TXA groups was estimated to be clinically meaningful. 
Resulting number per group: 30 
Total sample size required:  After inclusion of 6 additional patients (+10%) to account for 
potential withdrawals and/or protocol violations, the total sample size 
 
It was determined that a sample size of 30 patients per group would achieve 80% power at 
alpha = 0.05 to detect a 400 µg/mL difference in mean PAP level 4-hours post-operatively 
between the IV and topical TXA groups assuming a common within-group standard 
deviation of 536.3 µg/mL using a two-sided two-sample t-test. After addition of 10% to the 
sample size to account for potential withdrawals and/or protocol violations, the total sample 
size required was 66 patients. 
 
The primary outcome (PAP level 4 hours postoperatively) will be compared between the IV 
and topical TXA groups using a two-sample t-test or the Wilcoxon rank-sum test, depending 
upon the distribution of the data. 
 
Continuous secondary outcomes will be compared between groups using two-sample t-tests 
or Wilcoxon rank-sum tests, as appropriate. Differences between groups will be expressed 
as differences in means or Hodges-Lehmann estimate of location shift with 95% confidence 
intervals. Categorical secondary outcomes will be compared between groups using chi-
square or Fisher’s exact tests, as appropriate. The magnitude of the effects will be 
expressed as odds ratios with 95% confidence intervals. 
 
Outcomes measured at multiple timepoints will be analyzed using the generalized 
estimating equations (GEE) method. 
9.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report. Definitions for Adverse 
Event (AE) used in this study are listed below and are based on FDA and international 
guidelines: 
 


 
  
 
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9.1 
Adverse Event (AE) 
Tranexamic acid (TXA) is routinely used at HSS to reduce postoperative blood loss 
after total knee arthroplasty and potentially reduce the need for transfusion. Risks 
associated with TXA administration are rare.  
One risk of participating is this study is having blood drawn. The risks of blood 
drawing include mild pain, bruising, and very rarely infection at the place of the 
needle insertion. However, the likelihood of these risks occuring is rare, as an arterial 
line catheter is routinely placed in TKA patients. The purpose of this catheter is to 
continuously monitor blood pressure during and after surgery. We expect to draw 
blood using the pre-existing catheter. 
9.2 
Serious Adverse Events (SAE) 
Due to the pro-clotting nature of TXA, there have been long-standing concerns about 
the potential for thromboembolic events, including: deep vein thrombosis (DVT), 
pulmonary embolism (PE), myocardial infarction (MI), transient ischemic attack (TIA), 
and stroke. However, intravenous administration of TXA has been widely studied and 
has been shown to reduce the need of blood transfusions without an increase in risk 
of complications (Poeran et al, 2014). Moreover, TXA is contraindicated in patients 
with a history or high risk of thromboembolism. It is currently unknown whether 
topical TXA administration has similar risks in regards to thromboembolism. 
 
9.3 
Subsequent Surgical Interventions Definitions 
If a patient is found to have an allergy/hypersensitivity to TXA, they will immediately be 
withdrawn from the study and kept at HSS for observation and treatment. Based on the 
current literature, the doses that are used in this study have not been found to result in any 
toxicity level in patients. However, if this occurs, patients will immediately be withdrawn from 
the study. If any mortality is seen, or if there is any increase in DVT or PE rates from the 
established incidence in the literature, the DSMB will recommend termination of the study. 
 
9.4 
Adverse Event Reporting 
All adverse events will be reported to the DSMB and IRB within five working days of the 
event. 
10.0 INVESTIGATOR RESPONSIBILITIES, RECORD AND REPORTS 
 
10.1 Subject Consent and Information 
Written/signed consent will be collected from participants in the holding area before surgery. 
 
10.2 Subject Data Protection 
o HSS tries to minimize those risks by (i) removing some direct identifiers from information 
stored [(i.e., names, social security numbers, medical record numbers)]; (ii) securing, in a 
separate location, and limiting access to information linking codes (i.e., linkage codes) 


 
  
 
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assigned to the registry information with direct participant identifiers; and (iii) limiting 
access to information stored to HSS investigators.  
o Access to the REDCap program is password-protected, and access to a specific study's 
information within the program is limited to the research assistant and other IRB-approved 
study personnel who have been given permission to view and/or enter study data. 
REDCap program access is authorized by the CTSC; particular study access is granted by 
the research assistant. For data exports, fields marked as protected health information 
(PHI) in REDCap will be de-identified, if feasible. 
o All transmission of data will occur via encrypted networks in password-protected files. Any 
paper-based data sheets utilized for the study will have personal identifiers removed 
whenever possible and will be stored in the department's locked office. Each subject will 
be assigned a unique study number for identification, and that number will not be derived 
from or related to information about the individual. Presentations and publications that 
result from this study will not contain any individual identifiers (at most the unique study 
numbers may be referred to). Thus our research presents a minimal risk of harm to 
subjects' privacy. 
 
 


 
  
 
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