Conditions: Blood Loss Hip Arthritis Knee Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 246
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the relative effectiveness of two drug agents, Tranexamic acid (TXA) and aminocaproic acid (Amicar), that act through a similar mechanism of action. These agents are used to decrease blood loss that is a result of major surgery, like total joint arthroplasty. A secondary goal will be investigate the cost-analysis of total hospitalization. Both TXA and Amicar are both currently used in the care of patients undergoing total joint arthroplasty.

Subjects will be randomly assigned to the TXA or Amicar arm. All data needed for this study including blood loss, need for transfusion, preoperative and lowest postoperative hematocrit and hemoglobin, and complications will be collected during the hospitalization stay.

Our Hypothesis is that TXA and Amicar will have similar effectiveness in preventing intraoperative blood loss and the need for transfusion post-op than Amicar.

A detailed cost analysis will show that the overall cost of performing the operative procedure, including transfusions, OR time, and total costs associated with admission cost will be more decreased with Amicar as compared to TXA.

Detailed description:

Arms:
arm 1: TXA will be administered as a 1 gm dose IV prior to the procedure then as a repeat dose of 1 gram at the time of wound closure. These doses are currently used at Duke for Total Knee Arthroplasties (TKAs) and Total Hip Arthroplasties (THAs) per standard of care by the orthopaedic team.

All data needed for this study including blood loss, need for transfusion, preoperative and lowest postoperative hematocrit and hemoglobin, and complications will be collected during the hospitalization. arm 2: Administered 5g in 250mL of IV normal saline over 15 minutes prior to the procedure and then an infusion of 5g at the time of wound closure. These doses are currently used at Duke for Total Knee Arthroplasties (TKAs) and Total Hip Arthroplasties (THAs) per standard of care by the orthopaedic team.

All data needed for this study including blood loss, need for transfusion, preoperative and lowest postoperative hematocrit and hemoglobin, and complications will be collected during the hospitalization.

Interventions: intervention 1: Amicar intervention 2: TXA
Intervention descriptions: intervention 1: Subjects randomized to receive Amicar will receive this during surgical intervention intervention 2: Subjects randomized to receive TXA will receive this during surgical intervention

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
TXA (Tranexamic Acid) vs. Amicar (Aminocaproic Acid) in Total Knee and Hip Arthroplasty- Effectiveness, 
Safety, and Cost Analysis 
 
NCT02030821 
 
Document date: 2015-01-15 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
1  
     Department of Orthopaedic Surgery 
 
 
 
 
 
TXA (Tranexamic Acid) vs. Amicar (Aminocaproic Acid) in Total Knee and Hip 
Arthroplasty- Effectiveness, Safety, and Cost Analysis  
 
 
Principal Investigators: Michael Bolognesi, MD 
 
Sub-Investigator: Samuel S. Wellman, MD; David Attarian, MD; Stuart Grant, MD 
 
 
Research Summary 
 
 
2. 
Purpose 
 
Minimization of perioperative discomfort and complications, such as increased 
blood loss and length of hospital stay is a mutual goal amongst both patients and 
surgeons alike. To our knowledge, there have been no studies in the US and only one 
small study in Europe comparing the efficacy of tranexamic acid (TXA) and Ƹ-
aminocaproic acid (EACA or ACA, Amicar®) in TKA and total hip arthroplasty 
(THA). A double blind, randomized and placebo controlled trial in Spain involving 
127 patients sorted into three different arms found that there was significant 
reduction of blood transfusions in the TKA and Amicar arms, and also less of a 
reduction in hemoglobin levels by post-op day 5.1  There were no statistical 
significance in the 35 patients administered TXA compared to the 32 patients 
administered EACA, and authors noted that the limited number of patients may have 
prevented any findings.1 Given the potency of TXA, it may in fact be more efficacious 
than Amicar, leading to improved patient outcomes. Despite the clinical advantages 
to using TXA vs. placebo, it is frequently felt to be financially prohibitive. TXA 
currently costs between $100-200 per each IV dose. A unit of RBC costs between 
$500-1000 dollars.  A recent study comparing the cost of TKAs using TXA vs. those 
that did not found that although the pharmacy cost increased by $140, the total 
hospital cost was decreased by about $900 (looking at OR, blood, and total costs 
associated with admission).2 Amicar is significantly less expensive than TXA, and 
given its theoretically similar mechanism of action, is used as the agent of choice in 
many hospitals in the United States.  Currently TXA is being used at Duke University 
for total joint arthroplasty. There are limited data comparing the clinical efficacy 
and cost effectiveness of the two anti-fibrinolytics. Given the increased potency of 
TXA, it may be more efficacious and ultimately more cost effective than Amicar. The 
primary objective of this study is to determine the effectiveness of TXA vs. Amicar 
by determining the percentage of patients requiring transfusions and blood loss in 
total joint arthroplasty. A secondary objective is to determine the overall cost of 
hospitalization when the two different products are used. We hypothesize that that 
TXA will decrease the transfusion rate in patients as compared to Amicar. We also 
hypothesize that the overall cost of hospitalization will be less in patients with TXA, 
despite the increased pharmacy cost. 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
2  
     Department of Orthopaedic Surgery 
 
 
 
 
3. 
Background Information 
 
Hemostasis is an essential part of any surgical procedure, and especially in the case 
of total joint surgical procedures. Hemostasis is achieved through the steps of 
vasospasm, platelet adhesion, contact phase, and then fibrinolysis. Increased 
fibrinolysis can lead to increased intra-operative blood loss.3 Tourniquets during 
surgical procedures, such as the ones used during Total Knee Arthroplasty (TKA), 
have been shown to increase fibrinolysis during deflation, despite there being no 
change in circulating clotting factors.4 Medications that either retard or stop 
fibrinolysis potentially would decrease the breakdown of a clot leading to decreased 
operative blood loss while not impacting the risk of systemic thrombosis.5 
 
Currently there are three FDA-approved antifibrinolytic agents. Aprotinin is 
currently not being used in the US market as a study in 2007 suggested that there 
might be an increased mortality associated with its use during cardiac surgery.5 
While that conclusion was based largely on observational studies, A Cochrane 
review published in 2011 and a meta-analysis in 2012 concluded, regardless of the 
questionable increased risk caused by aprotinin, ε-aminocaproic acid  and 
tranexamic acid are safer in terms of risk of death and myocardial infarction than 
aprotinin.6-8 These lysine analogues have also been used to control non-surgical 
bleeding control such as the use of Amicar in thrombocytopenia and TXA in the 
treatment of uterine bleeding.9,10 Amicar and TXA are currently approved for non-
surgical settings of excessive bleeding where fibrinolysis is a contributing factor, 
like ocular bleeding, menorrhagia, cirrhosis, and placental abruption. Both of these 
agents are reversible competitive inhibitors of plasminogen/plasmin and are widely 
used in the fields of orthopaedics, cardiothoracic surgery, and transplantation to 
reduce blood loss. Amicar was the first agent to be used in hopes of reducing blood 
loss during major surgery, however shift began due to a worldwide shortage of 
Amicar. Although this shortage has since been corrected, TXA began being used as a 
result and is showing early promising results. TXA is 6-10 times more potent but has 
a similar toxicity profile.5  Amicar continues to still be widely used in cardiac 
surgery.  
 
TXA can be administered in both a topical or intravenous manner. Topical 
administration of TXA vs. placebo in a randomized controlled trial after cementing 
the implants resulted in higher postoperative hemoglobin and lower total blood 
loss.11 Studies using administration of intravenous TXA vs. placebo also initially 
demonstrated decreased blood loss and fewer transfusions of blood products. 
However, there has been concern that these studies were not able to detect if there 
was an increase in thromboembolic risk.12  A meta-analysis of 15 clinical 
randomized trials on TXA use demonstrated an average perioperative blood loss of 
504 ml less than the placebo group. Patients also used 1.4 times more units of blood 
compared with placebo, and were about six times less likely to need the transfusion.  
There was no difference in the rate of thromboembolic events.13 
 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
3  
     Department of Orthopaedic Surgery 
 
 
 
4.  
Study Design 
 
  This is a randomized prospective trial.  Eligible patients will include those who do  
      not screen positive for any of the exclusion criteria (history of stents, myocardial  
      infarction, cerebrovascular accident or stroke, deep venous thrombus, pulmonary  
      embolus late onset color blindness, and hypercoagulable state). Subjects will be  
      identified during clinic visits with their provider before their procedure.  After the  
     patient’s agreement to be enrolled in the study and formal consent process during  
     preoperative screening, they will be randomized to either the TXA or the Amicar   
arm.  
 
Primary total hip or knee surgery will be performed as per the standard of care as 
determined by the subject and the attending surgeon, with the exception of the 
administration of the type of antifibrinolytic product. There is no consensus as to 
the dosing of either Amicar or TXA in the literature. Previous studies have ranged in 
dosing of TXA from 10-150 mg/kg administered over different time periods and 
dosed Amicar at 10 mg/kg.1,5 This is consistent with the fact that TXA has been 
shown to be 6-10 times more potent in binding to plasminogen and plasmin.5 
Dosing guidelines for TXA and Amicar will be based on the dosing regimens 
approved at Duke.  These doses are currently used at Duke for TKAs and THAs per 
standard of care by the orthopaedic team.  If patients are not willing to participate in 
this study they will still receive the same dosage of either drug as prescribed by the 
ordering physician if they are screened and indicated for these medications.     
 
All data needed for this study including blood loss, need for transfusion, preoperative 
and lowest postoperative hematocrit and hemoglobin, and complications will be 
collected during the hospitalization.  Subject’s study participation will end at hospital 
discharge.  Costs of each component of the hospital stay will also be obtained and 
recorded. Adverse events will be recorded on case report form and submitted to the 
Duke IRB per Adverse Event policy. 
 
The recruitment goal of this study is to enroll 75% of eligible subjects electing to 
undergo either primary hip or knee arthroplasty performed by three attending 
surgeons at this institution over a year time period.  
 
5.     
Selection of Subjects 
 
Adult patients aged 18 and over electing to undergo primary total hip or knee       
arthroplasty will be considered for inclusion in the proposed study and identified 
preoperatively. 
 
 
6.      
Subject Identification, recruitment, and compensation 
 
Adult patients aged 18 and over electing to undergo primary total hip or knee 
arthroplasty will be considered for inclusion in the proposed study and identified 
preoperatively. Exclusion criteria will include history of stents, MI, CVA, DVT, PE, 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
4  
     Department of Orthopaedic Surgery 
 
 
 
color blindness, and hypercoagulable state. Females of childbearing age will also 
have a serum pregnancy test drawn before inclusion in this study. A positive 
pregnancy will result in exclusion from the study. We aim to recruit 400 subjects, 
200 total hip and 200 total knees. Subjects may withdraw at anytime. Post 
operatively, surgery data will be collected via the electronic medical record. Consent 
will be signed and witnessed before surgery takes place in clinic.  
 
7.      
Consent Process 
 
The investigator or his/her authorized designee will inform the subject of all aspects 
pertaining to the subject’s participation in the study during the consent process.  
The process of obtaining informed consent will be in accordance with all applicable 
regulatory requirements (Federal Register Vol. 48, No. 17, 1982, pp 8951-2).   
 
8.       Subject’s Capacity to Give Legally Effective Consent 
 
Each patient aged 18 years or older will consent for him or herself. If the patient is 
less than 18 years of age they will not be considered for the study. 
 
9.       Study Interventions 
 
Subjects will be randomly assigned in a 1:1 ratio to either an Amicar  or TXA arm 
which are both standard of care at Duke.  Subject’s study participation will end at 
hospital discharge.   
 
10.     Risk/Benefit Assessment 
 
Potential Benefits: Despite being off-label, TXA and Amicar are already both being 
used across various fields, including orthopaedics, for their benefit in reducing 
blood loss, the need for transfusion, and a drop in hemoglobin during major surgery 
and have shown to be safe to use.1,14,15 Patients given TXA or Amicar will likely 
experience decreased blood loss and decreased risk of transfusion and as a result 
may experience shorter hospital stay, fewer complications and decreased cost.  Both 
are currently used as standard of care in total hip and knee replacements. 
 
Potential risks: Although initially there was a fear that TXA or EACA would increase 
the risk of death and thromboembolic events, current evidence suggests that this 
increase is not statistically significant.8 TXA is currently used as the standard of care 
at Duke University Hospital.  
 
However, subjects in the TXA arm may experience the following adverse effects 
including GI disturbances (nausea, vomiting, diarrhea), allergic dermatitis, 
giddiness, and hypotension. The FDA also lists the risk of serious rare side effects 
including thromboembolic events (such as deep vein thrombosis, pulmonary 
embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal 
artery and vein obstruction), convulsion, chromatopsia, and visual impairment.  


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
5  
     Department of Orthopaedic Surgery 
 
 
 
Adverse effects associated with Amicar include edema, headache, malaise, 
hypersensitivity (anaphylaxis), cardiovascular effects (bradycardia, hypotension, 
peripheral ischemia, thrombosis), GI disturbances (abdominal pain, diarrhea, 
nausea, vomiting), hematologic effects (agranulocytosis, coagulation disorder, 
leukopenia, thrombocytopenia), musculoskeletal effects (CPK increase, muscle 
weakness, myalgia, myopathy, myositis, rhabdomylolysis), neurologic complications 
(confusion, 
convulsions, 
delirium, 
dizziness, 
hallucinations, 
intracranial 
hypertension, stroke, and syncope),  respiratory effects (dyspnea, nasal congestion, 
pulmonary embolism), rash, pruritis, tinnitus, decreased vision, watery eyes, and 
urogenital effects (increased BUN and renal failure).  Amicar is less potent than TXA 
so it may lead to increased blood loss and therefore increased risk of transfusion 
according to one study.1 
 
Many of the above side effects for both TXA and Amicar have been reported in 
patients with hemophilia.  
 
 
11.    Costs to the Subject:  
  
Subject or their insurance provider will be responsible for all costs related to your medical 
care, including the drugs used in this study.    
 
No direct monetary compensation will be offered for inclusion in the proposed 
study.  
 
12.     Data Analysis & Statistical Considerations  
 
Subject characteristics and study results including those outlined above (considered 
complications or adverse events) will be recorded. 1 The primary endpoint for this 
study is the percentage of patients requiring transfusions. The secondary endpoint 
include total blood loss (recorded as estimated blood loss intraoperatively as 
determined by anesthesia staff, and postoperatively recorded by nurses from the 
output in drains), change in hemoglobin (preoperative vs. postoperative 
hemoglobin that is routinely measured before discharge), and the total cost of 
hospitalization as billed by Duke University (including pharmacy cost, price each 
night in hospitalization, all other charges incurred during admission). Binary 
variable results will be compared using chi-square and Fisher’s exact tests (where 
appropriate). We plan a comparison of continuous variable results using Wilcoxon 
rank sum and t-tests (where appropriate).  We will consider multivariable logistic 
regression in determination of TXA and Amicar and their correlation with the above 
listed complications and adverse events.  Anesthetic techniques will be recorded for 
analysis and covariate analysis will be performed at the end of the study. In order to 
perform a cost analysis, total cost of hospitalization including pharmacy cost, 
potential transfusion costs, and cost of stay.  Based on the one small European study, 
sample size for finding the difference between two proportions was calculated using 
a proportion of 0.125 patients given Amicar were transfused (n=32 vs. 0.028 (n=35) 
given TXA. Using an alpha value of .05 and power of .90 it was determined that there 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
6  
     Department of Orthopaedic Surgery 
 
 
 
would need to be 154 patients in each sample size to find a significant difference in 
independent samples. Our goal of enrolling 400 patients total (200 in each arm) will 
therefore be appropriate for this study 
 
13.   
Data & Safety Monitoring 
 
The primary investigator will collect data from the subject’s electronic medical 
record and will extract necessary study data and then transfer this data into a 
limited access electronic Excel spreadsheet housed on the Duke Orthopaedic share 
drive. We will have an independent safety reviewer in lieu of a formal DSMB 
committee to ensure the safety of subjects. Dr. Steve Olson, head of the orthopaedic 
clinical research unit will be asked to serve in this role. He will review available 
safety data, including thrombotic complications after 100, 200, and 300 patients are 
enrolled.  
During collection, data will be indexed by the subject’s medical record number. After 
data collection, a case number will be assigned to the data, and the medical record 
number, name and any dates associated with clinical care (the only identifying data 
collected) will be stripped from the database. The code linking medical record 
number to case number will be kept in an Excel spreadsheet with access limited to 
the primary investigator and his research team. Electronic research records will be 
stored on a DHTS server in the following limited access folder O:\CLINICAL 
RESEARCH DATA\JOINT\50108 - Bolo TXA vs. Amicar.  Paper research documents 
will be stored in the PI’s locked research office in a locked cabinet with keys in 
possession of the CRC.  Paper documents will be housed in the PI’s locked research 
office in a locked cabinet with access limited to his research team and keys in 
possession of the CRC.  When the study is complete, the code linking medical record 
numbers to case numbers will be destroyed. During data collection and review, 
protected health information will be available only to the primary investigator and 
will not be reused or disclosed to any other person or entity, except as required by 
law, for authorized oversight of the research study.   
 
14.   
Privacy, Data Storage & Confidentiality 
 
All data collection will be performed on a secure PIN station protected by DHT 
firewalls. Only researchers participating in the study will have access to the data.  
With the exception of medical records numbers, data collection will not contain 
patient identifiers as specified in the HIPPA regulations (45CFR164.514(b)(2)(i)). 
All data will be stored as outlined in the research data security plan (RDSP) included 
with this submission. Subject identity will be made anonymous after completion of 
the data accrual and prior to statistical analysis to assure confidentiality. Original 
signed consent forms and collected data will be kept in subject folders in a locked 
secure location. 
 
 
References 
 


TXA vs. Amicar in TKA- Effectiveness, safety and cost analysis 
PI: Michael Bolognesi, MD 
 
Version Date 1.15.2015 
7  
     Department of Orthopaedic Surgery 
 
 
 
1. 
Camarasa M, Ollé G, Serra-Prat M, et al. Efficacy of aminocaproic, tranexamic acids in 
the control of bleeding during total knee replacement: a randomized clinical trial. British 
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2. 
Gilette B, DeSimone L, Kremers H, et al. Economic Impact of Tranexamic Acid in 
Healthy Patients Undergoing Primary Hip and Knee Arthroplasty.  AAHKS annual meeting; 
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Hardy J-F, Desroches J. Natural and synthetic antifibrinolytics in cardiac surgery. 
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Klenerman L, Chakrabarti R, Mackie I, Brozovic M, Stirling Y. Changes in haemostatic 
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Eubanks JD. Antifibrinolytics in major orthopaedic surgery. Journal of the American 
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Hutton B, Joseph L, Fergusson D, Mazer CD, Shapiro S, Tinmouth A. Risks of harms 
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Henry D, Carless P, Fergusson D, Laupacis A. The safety of aprotinin and lysine-
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Henry D, Carless P, Moxey A, et al. Anti-fibrinolytic use for minimising perioperative 
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Bartholomew JR, Salgia R, Bell WR. Control of bleeding in patients with immune and 
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Aguilera X, Videia S, Almenara M, Fernandez JA, Gich I, Celaya F. Effectiveness of 
Tranexamic Acid in revision total knee arthroplasty. Acta Orthopædica Belgica 2012;78:68. 
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Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason J. Tranexamic acid in 
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