Determining the Optimal Dose of Tranexamic Acid in Decreasing Blood Loss During Lower Extremity Total Joint Arthroplasty
Phase: PHASE4
Conditions: Arthropathy of Hip, Arthropathy of Knee
Sponsor: Columbia University

 
1 
 
 
 
 
 
 
 
 
 
 
 
NCT02584725 
Official Title:  
Determining the Optimal Dose of Tranexamic Acid in Decreasing Blood Loss During Lower 
Extremity Total Joint Arthroplasty 
 
Version: 07/23/2014 
 
Robert Maniker, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
Study Description 
 
1. Study Purpose and Rationale: The purpose of this study is to determine the dose response of 
increasing doses of tranexamic acid (TXA) on limiting blood loss during total knee and total hip 
arthroplasty as defined by a change in hemoglobin from pre-operative baseline to the first post-
operative day. 
 
2. Study Design and Statistical Procedures: The study is a prospective, randomized, double-
blinded trial involving 3 groups, comparing three different doses of TXA (5mg/kg, 10mg/kg, 
15mg/kg) in decreasing blood loss during and after total knee and total hip arthroplasty. 
Patients undergoing total knee arthroplasty and total hip arthroplasty will be analyzed 
separately, in sub-group analysis. 
 
The primary endpoint will be the change in hemoglobin from baseline to the first post-
operative day (POD#1). Preoperative blood work for total hip and total knee arthroplasty 
always includes a baseline complete blood count, which includes a hemoglobin value. All 
patients undergoing total hip and total knee arthroplasty also have a blood sample drawn in the 
pre-operative holding area on the day of surgery for obtaining a type and screen. A baseline 
complete blood count will be sent along with this blood sample for use as a pre-operative 
baseline hemoglobin value. 
Similarly, at least three complete blood counts (CBCs) are routinely obtained in patients who 
have undergone total hip and total knee arthroplasty; the first CBC is obtained in the recovery 
room on POD#0, the second on POD#1, and the third on POD#2. The proposed primary 
endpoint of this study should thus create no additional burden to the patient, the primary 
team, or to hospital costs. 
 
Secondary endpoints will include change in hemoglobin from baseline to POD#0, change in 
hemoglobin from baseline to POD#2, and the number of units of blood given from the intra-
operative period into the end of POD#2 using a transfusion threshold of a hemoglobin value 
equal to or less than 8. Secondary endpoints will also include total estimated intra-operative 
blood loss, and volume of blood in the surgical suction canister at the end of surgery. 
 
Secondary endpoints will also include the ability to sit, stand, and walk during participation in 
physical therapy on POD#1 and POD#2 (yes/no), visual analog scale (VAS) pain scores (a 0-10 
scale, with 0 being no pain, and 10 being severe pain) on POD#1 and POD#2, and patients’ self-
reported scores on a scale of overall feeling of wellbeing on POD#1 and POD#2 (a 0-10 scale, 
with 0 being the worst they have ever felt and 10 representing feeling at baseline). Finally, 
secondary end points will also include the incidence of seizure, transient ischemic attack, 
stroke, myocardial infarction, deep venous thrombosis, and pulmonary embolus via clinical 
exam in the first 48 hours post-operatively. 
 
 
 

 
3 
 
 
 
 
Statistical procedures: 
As above, the primary outcome will be the change in hemoglobin from baseline to the first 
post-operative day (POD#1). A linear regression model will be used for analysis of the change in 
hemoglobin as a function of the TXA dose. The expectation is that as the dose of TXA increases 
(from 5mg to 10mg to 15mg), the difference in hemoglobin (baseline minus post-operative) will 
decrease. We have chosen the difference in hemoglobin as our primary outcome, rather than 
total blood loss, because change in hemoglobin values more accurately reflect total blood loss 
than visual estimation by a practitioner. 
 
Literature on the use of TXA in orthopedic surgery has shown that in the absence of TXA, the 
average drop in hemoglobin with total knee arthroplasty is roughly 3g/dl, while the average 
drop in hemoglobin in total knee arthroplasty with the addition of TXA is reduced to 1.9g/dl, 
which is a 33% reduction, or a moderate effect (5,8,13,15). 
 
Clinical experience at this institution has produced similar results with regard to decreases in 
hemoglobin, which we consider to be reflective of total blood loss, in total hip and knee 
replacement surgeries. Prior to this institution's addition of TXA as standard of care for total 
joint arthroplasty, the average drop in hemoglobin in total knee arthroplasty cases was 2.3g/dl, 
while the average drop in hemoglobin in total hip arthroplasty cases was 2.8g/dl. Since 
these changes in hemoglobin, which are reflective of blood loss for total joint arthroplasty 
without the use of TXA, are similar to those changes in hemoglobin published in the literature, 
we anticipate that the addition of TXA at our institution has produced a similar moderate effect 
on decreasing the change in hemoglobin post-operatively. Because this study is not comparing 
change in hemoglobin between placebo versus TXA groups, but instead is comparing 
change in hemoglobin between three different doses of TXA, we expect the effect to be slightly 
smaller: we estimate a 15-20% decrease in change in hemoglobin between each TXA group. 
 
Assuming a starting hemoglobin level of 12.5g/dl, we anticipate a drop in hemoglobin of 1.75 in 
the lower-dose TXA group (5mg/kg), a drop in hemoglobin of 1.5 with the intermediate-dose 
TXA group (10mg/kg), and a smaller drop in hemoglobin of 1.25 with the higher-dose TXA group 
(15mg/kg). We would therefore like to detect an average change of 0.3g/dl in hemoglobin level 
per unit change in TXA dose. Assuming the standard deviation of the dose values to be 
5, and a small correlation between hemoglobin and dose levels of 0.3, we will need a total of 82 
subjects to detect such a change with 80% power at the 5% level of significance (PASS 13). Thus, 
28 subjects will be required in each group. 
 
For secondary outcomes, the statistical analysis will be dependent on the type of variable being 
analyzed. For the changes in hemoglobin between baseline and POD#0, and between baseline 
and POD#2, linear regression analysis will also be used in a similar fashion to the analysis of the 

 
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primary outcome. The expectation for this outcome is similar to that of the primary outcome: 
increasing doses of TXA will cause progressively smaller changes in hemoglobin. 
 
For the outcome measuring the number of units of blood given from the intra-operative period 
into the end of POD#2, linear regression analysis will be used. The expectation is that with 
increasing doses of TXA, fewer units of blood will be transfused. 
For the outcomes measuring the total estimated intra-operative blood loss and the volume of 
blood in the surgical suction canister at the end of surgery, linear regression analysis will be 
used. The expectation is that with increasing TXA doses, the total blood loss and the volume of 
blood in the suction canister will decrease. 
 
For the outcome measuring the ability to sit, stand, and walk (yes/no) during participation in 
physical therapy on POD#1 and POD#2, logistic regression analysis will be used. The expectation 
is that patients in the groups that have received higher doses of TXA will be more likely to 
participate in these outcomes than the patients who have received lower doses of TXA. 
 
For the outcome measuring VAS scores, linear regression analysis will be used. The expectation 
is that patients who receive increasingly higher doses of TXA will have less pain and report 
lower scores on the VAS. 
 
For the outcome measuring patients’ self-reported scores on a scale of overall feeling of well-
being on POD#1 and POD#2, linear regression analysis will be used. The expectation is that 
patients who receive increasingly higher doses of TXA will report increasingly higher scores on 
the wellbeing scale. 
 
For the outcome measuring incidence of seizure, transient ischemic attack, stroke, myocardial 
infarction, deep venous thrombosis, or pulmonary embolus in the first 48 hours post-
operatively, logistic regression will be used. It is possible that higher doses may be associated 
with more of these events, but this is not expected by the study investigators. 
 
3. Study Procedures:  
 
Patients will initially be identified by their orthopedic surgeon if they meet the inclusion criteria 
listed (see #6 below). They will be informed about the study and provided with the consent 
form, which they will be able to review further prior to the date of surgery. On the day of 
surgery, the patients assigned anesthesiologist of record will again discuss the study with the 
patient to assess continued interest in participation. If the patient wishes to participate, formal 
written consent will be completed by one of the study investigators or a member of the 
regional anesthesia team. Final consent will be obtained on the day of surgery, as this is the 
time when patients meet their 
anesthesiologist (the patient's anesthesiologist is not assigned until the afternoon or evening on 
the day prior to surgery). The appropriate timing of the discussion between patient and 
assigned anesthesiologist and subsequent consent is at therefore at the standard pre-operative 

 
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interview and assessment on the day of surgery. Patients will be randomized to one of three 
groups. Randomization will be performed via pre-assigning doses and placing them into 
envelopes labeled with the subject number. The dose will be looked at 
by the individual who draws up the medication; this will be an anesthesiologist not otherwise 
involved in the subject patient’s care. This individual will draw up the appropriate amount of 
TXA or saline, as mandated by the dose assignment, and label two syringes as “Study 
medication #1” and “Study medication #2." 
 
For all consented study patients, the anesthesia team responsible for the subject patient's care 
will receive two twenty milliliter syringes of medication. Instructions will be to administer the 
syringe labeled “Study medication #1” intravenously over 20 minutes beginning at the start of 
surgical skin preparation, and then to administer the syringe labeled “Study medication #2” 
over 20 minutes beginning at the start of surgical wound closure. The syringes for group 1 (low-
dose TXA) will each contain 5mg/kg TXA, diluted to 20 milliliters with saline. The syringes for 
group 2 (moderate-dose TXA) will each contain 10mg/kg TXA, diluted to 20 milliliters with 
saline. The syringes for group 3 (high-dose TXA) will each contain 15mg/kg TXA, diluted to 20 
milliliters with saline. 
 
The syringes will be given to the patient’s anesthesiology team before the patient is taken to 
the operating room. The intra-operative anesthesia team will be instructed to administer the 
study medications as described above. In addition, the anesthesia team will also document the 
total intra-operative estimated blood loss as well as the amount of blood in the suction canister 
at the end of the surgery (as calculated by volume in the suction bucket minus volume of 
irrigation 
used). The intraoperative course will be standardized for all patients included in the study. For 
total knee arthroplasty patients, the anesthesia will consist of a long-acting femoral or adductor 
canal peripheral nerve block, followed by a standardized spinal anesthetic using 15mg of plain 
isobaric bupivacaine. These modalities are the standard anesthetic 
management for total knee and total hip arthroplasty at this institution. In those patients for 
whom spinal anesthesia is contraindicated or refused, general anesthesia will be performed and 
these patients will be excluded from the study. For total hip arthroplasty patients, the 
anesthesia will consist of a standardized spinal anesthetic using 15mg of plain isobaric 
bupivacaine. In those patients for whom spinal anesthesia is contraindicated or refused, general 
anesthesia will 
be performed and these patients will be excluded from the study. All patients initially enrolled, 
but excluded secondary to administration of a general anesthetic will be analyzed via an 
intention-to-treat method. Administration of intravenous crystalloid solutions will be per the 
discretion of the anesthesia team participating in the intra-operative portion of each patient’s 
care, and will be documented for purposes of this study by the anesthesia team. 
 
On PODs #0, #1 and #2, all patients will undergo standard post-operative blood work which 
includes a complete blood count. When working with physical therapy on POD#1 and POD#2, 
assessment of ability to sit, stand, and walk (yes/ no) will be recorded. Assessment of pain 

 
6 
scores via a VAS (0-10 scale, with 0 being no pain and 10 being the worst pain) will be recorded 
on POD#1 and POD#2. Assessment of subjective sense of overall wellbeing (a 0-10 scale, with 
0 being the worst patients have ever felt, and 10 representing pre-operative baseline) will be 
recorded on POD #1 and #2. Patients will also be monitored via clinical exam for incidence of 
seizure, transient ischemic attack, stroke, myocardial infarction, deep venous thrombosis, and 
pulmonary embolus in the first 48 post-operatively. 
 
Post-operative anti-coagulation for deep venous thrombosis prophylaxis for all patients will 
consist of 10mg oral rivaroxaban, given every 24 hours starting on POD#1. This is the standard 
anti-coagulation regimen used by the surgeons who will perform the total joint arthroplasties 
involved in the study. If patients are on warfarin preoperatively, in the post-operative period 
they will be bridged to warfarin via enoxaparin and rivaroxaban in a standardized fashion by the 
primary team, and this will be noted for purposes of subgroup analysis. 
 
 
4. Study drugs or devices:  
 
Tranexamic acid 100 mg/mL vial will be used. Medication will be administered as 5 mg/kg, 
10 mg/kg, or 15 mg/kg according to a weight-based dose, up to a maximum patient weight of 
100 kg (maximum potential dose will be 1500 mg). The medication will then be diluted to a 
total volume of 20 mL with preservative-free saline. All medications will be administered via 
peripheral or central intravenous line over 20 minutes, with the first dose given at the start of 
surgical skin preparation (approximately 20 minutes prior to incision) and the second dose 
given at the start of surgical wound closure. 
 
5. Study instruments:  
 
A hemoglobin level will be reported with the complete blood count that is routinely obtained 
pre-operatively, and on POD#0, #1 and #2 for total hip and total knee arthroplasty patients. The 
number of units of blood transfused will be observed by the primary team, as well as anesthesia 
providers involved in the study. The transfusion threshold will be a hemoglobin value of less 
than or equal to 8; this is mandated by the study. If the decision is made to transfuse at a 
hemoglobin value that deviates from this protocol, those patients will be excluded, but 
analyzed via intention to treat. The anesthesia provider partaking in the intraoperative care of 
each study patient will estimate the total blood loss for each case, as well as the volume of 
blood in the suction canister. 
 
Ability to sit, stand, and walk with physical therapy on POD#1 and #2 will be documented by the 
research team. Patients’ self reported scores on the VAS and self reported scores of well-being 
will also be reported to the research team on POD#1 and #2. The incidence of seizure, transient 
ischemic attack, stroke, myocardial infarction, deep venous thrombosis, and pulmonary 
embolus in the first 48 hours post-operatively will be recorded by the primary team and 
reported to the research team. 
 

 
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6. Study Subjects:  
 
All patients 18 years of age or older undergoing primary unilateral total knee arthroplasty or 
primary unilateral total hip arthroplasty at Columbia University Medical Center/ New York 
Presbyterian Hospital will be eligible to participate. Exclusion criteria will include non-English 
speaking patients, patient refusal to participate, weight exceeding 100kg, a baseline 
hemoglobin of less than 10, and repeat, revision, or bilateral surgery. Exclusion criteria will also 
include a known sensitivity or allergy to TXA, active intra-vascular clotting, a history of 
coagulopathy 
or congenital thrombophilia, a thromboembolic event in the last 12 months, a percutaneous 
coronary intervention requiring a drug eluting stent in the last 12 months, and a history of 
anticoagulant medication use unless stopped prior to surgery as recommended by and in 
accordance with the American Society of Regional Anesthesia Guidelines. 
Exclusion criteria after enrollment in the study will include use of a general anesthetic, and 
blood transfusion for a hemoglobin value which deviates from the study's transfusion protocol. 
 
 
 
7. Recruitment:  
 
All patients scheduled for primary total hip and knee arthroplasty who meet the inclusion 
criteria 
without meeting exclusion criteria (see #6) will be asked by an anesthesia provider to 
participate in a voluntary fashion. 
 
8. Informed Consent Process:  
 
All participants will be consented by one of the study investigators with use of a written 
consent form requiring a signature (attached). 
 
9. Confidentiality of subject data:  
 
Patients will be identified only by unique identifier subject numbers, which will be 
recorded on the envelope and the enclosed instruction sheet that also contains the randomized 
group information and dosing instructions. Patients will be anonymous for the purposes of data 
collection and analysis. 
 
10. Privacy Protections:  
 
Every effort will be made to maintain privacy and anonymity of the participants. No patient 
names will be used for the purposes of the study, aside from the use of name and telephone 
number for the sole purpose of follow-up for data collection. Each participant will instead be 
given a unique identifier number for use in the study. 
 

 
8 
11. Potential risks:  
 
Risks include those related to medication side effects, medication error, and a potentially 
lessened benefit for patients randomized to the low-dose TXA group. It has become standard at 
this institution and many others nation-wide to administer TXA during total hip and total knee 
arthroplasty. This drug would therefore most likely be given even if a patient is not part of this 
study; the current standard dosing regimen at this institution is 10mg/kg IV over 20 minutes 
before incision and again at the start of surgical wound closure. Therefore the study 
intervention will likely only change the dose received to either half of this standard dose, or 
50% more. According to the drug’s FDA package insert, side effects of TXA include diarrhea, 
nausea, vomiting, hypotension if administered too rapidly intravenously, and blurred vision. 
Thromboembolic events are another potential risk; in addition, some studies have 
also shown a higher risk of post-operative seizures in patients receiving high dose TXA. The 
latter two risks in particular deserve special attention. 
 
Risk of thrombosis: 
Thromboembolic events have been discussed as a potential risk of TXA administration.(5) While 
TXA is not a procoagulant, it does inhibit the fibrinolytic system which acts to break down 
already formed clot. However, multiple meta-analyses, including studies with dosing before 
tourniquet inflation, have shown that TXA is not associated with changes in prothrombin time 
or activated partial thromboplastin time, and is not associated with increased risk of deep 
vein thrombosis or pulmonary embolus.(4) This may result from TXA inhibiting fibrinolysis in the 
wound bed to a greater extent than in the systemic circulation, thus exhibiting minimal effect 
on vein walls.(4) Routine screening for thrombosis in study patients via bilateral lower 
extremity venography and lung perfusion imaging 7-14 days after surgery has found no 
differences between TXA and non-TXA patients.(8) Several studies have found no difference in 
occurrence of thromboembolic events in any study group who received TXA.(2,17) 
 
Risk of seizure: 
Seizure has been reported as a complication of high dose TXA and has been isolated to the 
cardiac surgery literature where routine doses of TXA tend to be much higher than those used 
in orthopedic surgery.(18) In one study of 1188 patients undergoing cardiac surgery with 
administration of either TXA or aprotinin, the TXA group had a higher incidence of post-
operative seizure (7.9% vs 1.2%).(19) However, TXA was administered with a loading dose of 2 
gm intravenously, plus 2 gm added to the cardiopulmonary bypass (CPB) pump priming 
solution, followed by an intravenous infusion of 0.5 gm/hr until chest closure at the end of the 
surgery.(19) With an average reported patient weight of 77 kg and an average CPB time of 102 
minutes (therefore a modest estimate of TXA infusion duration being 3 hours), the total dose of 
TXA during these surgeries was approximately 5.5 gm, which correlates with an average 
total dose of approximately 70mg/kg. This is more than twice the absolute maximum dose 
proposed in our study, which is 30mg/kg (15mg/kg bolus given twice). An increased incidence 
of post-operative seizures associated with TXA was also reported in another study, which was a 
retrospective analysis of 669 cardiac surgery patients.(18) These patients underwent care at 
two institutions, and received a loading dose of TXA ranging from 20 to 100 mg/kg, followed by 

 
9 
an infusion of 10-25 mcg/kg/hr, with a total peri-operative dose of TXA ranging from 61 to 259 
mg/kg. (18) The incidence of post-operative seizure was 3.8% in the group receiving high dose 
TXA, compared to a previous benchmark of 1.3% prior to the use of TXA.(18) Again, it should be 
noted that the minimum dose of TXA used in the latter study was at least twice the maximum 
dose proposed in this study. 
 
Given that seizures have been reported with high dose TXA, it has been suggested that the risk 
of seizure increases concordantly with the dose of TXA administered.(20) One study reported 
that when the total average peri-operative dose of TXA was less than 2 gm, the incidence of 
seizure was 0-0.6%; this number increased to 0.8% when the dose of TXA increased to 3 gm, 
and increased further to 1.4% when the reported TXA dose was 5 gm.(20) Similarly, when the 
dose of TXA was reduced, the incidence of seizure also decreased.(20) It should be noted that 
the studies referenced above involved patients undergoing cardiac surgery, which may itself be 
an independent risk factor for postoperative seizures, regardless of TXA administration.(20) 
One case report series of seven patients reported that the baseline seizure rate of 0% increased 
to 0.66% with high dose TXA (60mg/kg bolus followed by a 5mg/kg/hr infusion or a 30mg/kg 
bolus followed by a 15/mg/hr infusion).(21) However all seven patients were elderly, and 
underwent open chamber cardiac surgery procedures.(21) The TXA doses used in these studies 
were all considerably higher than those routinely used during orthopedic surgery, or the doses 
proposed in this study. Furthermore, there have been no reports of increased risk of seizure in 
studies involving TXA in orthopedic surgery. However, due to the apparent dose dependent 
nature of seizure associated with TXA, it would be beneficial to define the most effective dose 
of TXA in orthopedic surgery patients, which will minimize intra-operative blood loss but avoid 
any increased risks of adverse sequelae. 
 
12. Data and safety monitoring:  
 
TXA will only be administered by an anesthesia provider during the intra-operative 
period per the study protocol. Thus, all patients included in the study will be monitored as they 
would be while undergoing standard anesthetic care. Data will be obtained via routine 
bloodwork as described in #2 & 3 above, and via the observation of anesthesia and primary 
team members. The data collected will be part of the usual postoperative care routine, and 
thus will create no additional burden to the patient, the orthopedic surgery or anesthesia care 
providers, or to the hospital. Monitoring of potential adverse events associated with TXA will be 
done by the primary team via clinical exam in the first 48 hours post-operatively; such events 
include seizure, transient ischemic attack, stroke, myocardial infarction, deep venous 
thrombosis, and pulmonary embolus. 
 
13. Potential benefits:  
 
There is no individual benefit for study participants, aside from the potential benefit of 
decreased blood loss. The overall benefit will be to advance the field of orthopedic surgery and 
orthopedic anesthesia by defining the most efficacious dose of TXA in limiting blood loss during 
total joint arthroplasty, while minimizing risks of adverse sequelae. 

 
10 
 
14. Alternatives:  
 
Patients may waive their participation in the study with no consequences. If they choose to 
waive 
participation, they will receive standard anesthetic care as discussed and mutually agreed upon 
by the patient and the anesthesiologist, which may or may not include the administration of 
TXA. Standard anesthetic care for total hip and total knee arthroplasty at this institution 
includes the administration of TXA at least 90% of the time. 
 
15. Research at external sites: No. 
 
16. Columbia as lead institution: N/A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
11 
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