Clinical trial NCT04089865
Conditions: Blood Loss Blood Transfusion
Sponsor: Hospital for Special Surgery, New York
Start date: 2019-09-17; Completion date: 2021-11-10
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this randomized clinical control trial is to determine whether oral TXA dosing in THA/TKA result in more blood loss and more transfusions compared to IV TXA dosing in patients undergoing THA/TKA under neuraxial anesthesia. The main questions it aims to answer are:

Does oral TXA dosing in THA/TKA result in more blood loss compared to IV TXA dosing?

Does oral TXA dosing in THA/TKA result in more transfusions compared to IV TXA dosing?

Participants will be randomly assigned to either get the Oral TXA (1950mg) or the IV TXA (1g) on their day of surgery. Researchers will compare these groups to see if any differences emerged. 200 THA patients (100 Oral, 100 IV), 200 TKA patients (100 oral, 100 IV).

Detailed description:
Tranexamic acid (TXA) is an antifibrinolytic medication used to reduce bleeding in a variety of medical settings. The use of TXA in total hip arthroplasty (THA) and total knee arthroplasty (TKA) has resulted in dramatic decreases in operative blood loss and transfusion rates, revolutionizing the field of arthroplasty. The use of TXA, now common, has made autologous blood donation programs largely obsolete. Additionally, it has made perioperative blood transfusion uncommon.

While AAOS guidelines suggest that all three available preparations of TXA (oral, IV, topical) are effective, preferred route of dosing varies by provider and institution. These preferences are based on habit, understanding of pharmacodynamics, and logistical issues regarding effective dosing. Oral TXA is the cheapest option, but some surgeons prefer IV dosing due to concerns regarding efficacy and controlled dosing.

In this study, we seek to compare the efficacy of a single pre-op oral dose of TXA to a single pre-op IV dose of TXA.

Arms: arm 1: 100 Total Hip Arthroplasty (THA) and 100 Total Knee Arthroplasty (TKA) patients will be randomized to receive 1950 mg of oral TXA in the pre-operative area. arm 2: 100 Total Hip Arthroplasty (THA) and 100 Total Knee Arthroplasty (TKA) patients will be randomized to receive 1 g of intravenous (IV) TXA upon transfer to the operating room.
Interventions: intervention 1: Tranexamic Acid
Intervention descriptions: intervention 1: Tranexamic acid (TXA) is an antifibrinolytic medication used to reduce bleeding in a variety of medical settings. Patients will be randomized to receive either oral or intravenous tranexamic acid.

Protocol documents:
Prot_SAP_000.pdf: 
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Blood Loss in Arthroplasty with Oral Versus IV 
Tranexamic Acid 
 
FUNDER: 
Department of Anesthesiology 
PROTOCOL NO.: 
2019-0882 
VERSION & DATE: 
3/8/2022 
 
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 
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 Number: 2019-0882  
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................ 2 
PROTOCOL SYNOPSIS ........................................... 3 
1.0 
INTRODUCTION ............................................. 5 
2.0 
OBJECTIVE(S) OF CLINICAL STUDY .......... 6 
3.0 
STUDY HYPOTHESES .................................. 6 
4.0 
STUDY DESIGN ............................................. 6 
4.1 
Endpoints ....................................................................................................................... 6 
4.1.1 
Primary Endpoint ...................................................................................................... 6 
4.1.2 
Secondary Endpoints ................................................................................................ 6 
4.2 
Study Sites ..................................................................................................................... 6 
5.0 
STUDY POPULATION ................................... 7 
5.1 
Number of Subjects ........................................................................................................ 7 
5.2 
Inclusion Criteria............................................................................................................. 7 
5.3 
Exclusion Criteria ........................................................................................................... 7 
6.0 
PROCEDURES ............................................... 7 
6.1 
Intraoperative Protocol ................................................................................................... 7 
6.2 
Postoperative Protocol ................................................................................................... 8 
6.3 
Data Collection ............................................................................................................... 8 
7.0 
STATISTICAL ANALYSIS .............................. 9 
8.0 
ADVERSE EVENT ASSESSMENT .............. 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol Number: 2019-0882  
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PROTOCOL SYNOPSIS 
Protocol Title: 
Blood Loss in Arthroplasty with Oral Versus IV Tranexamic Acid 
Protocol Number: 
2019_0882 
Protocol Date: 
3/8/2022 
Sponsor: 
Department of Anesthesiology 
Principal Investigator: 
Stavros Memtsoudis, MD PhD 
Objective: 
Tranexamic acid (TXA) is an antifibrinolytic medication used to 
reduce bleeding in a variety of medical settings. The use of TXA 
in total hip arthroplasty (THA) and total knee arthroplasty (TKA) 
has resulted in dramatic decreases in operative blood loss and 
transfusion rates, revolutionizing the field of arthroplasty. The 
use of TXA, now common, has made autologous blood donation 
programs largely obsolete. Additionally, it has made 
perioperative blood transfusion uncommon. While AAOS 
guidelines suggest that all three available preparations of TXA 
(oral, IV, topical) are effective, preferred route of dosing varies 
by provider and institution. These preferences are based on 
habit, understanding of pharmacodynamics, and logistical issues 
regarding effective dosing. Oral TXA is the cheapest option, but 
some surgeons prefer IV dosing due to concerns regarding 
efficacy and controlled dosing. In this study, we seek to compare 
the efficacy of a single pre-operative oral dose of TXA to a 
single pre-operative IV dose of TXA. 
Study Design: 
Randomized controlled clinical trial  
Enrollment: 
400 
Subject Criteria: 
 
1. Patients undergoing total hip arthroplasty (THA) through a 
posterior approach 
2. Patients undergoing total knee arthroplasty (TKA) 
3. Patients between the ages of 18-80 
Data Collection: 
Sources: EPIC, Patient and Medical Records. 
Variables: Name, MRN, DOB, Race/ethnicity, sex, Co-
morbidities, diabetes, heart disease, prior use of blood thinners, 
patient weight/height/BMI, Date of surgery, Time PO txa given in 
holding, surgeon, time of IV txa infusion (start, end), surgery 
start/end time, incision time, Procedure (TKA or THA), 
Tourniquet use (onset, release, duration, inflation pressure), 
Anesthesiologist, ASA physical status, Anesthesia start/end 
times, Constavac drainage, Transfusion volume, incidence of 


 
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DVT/PE, LOS, transfer to higher level of care, CBC (at PSS, 
upon PACU entry, at AM labs POD1), Post-Transfusion (if 
transfusion required). 
Statistical Analysis: 
• 
Proposed analysis (e.g., student’s t-test, ANOVA, chi-
square, regression, etc.): Non-inferiority tests for two 
primary outcomes: a t-test or Mann Whitney U test will 
be used for calculated blood loss and chi-square or 
Fisher’s exact test will be used for proportion of blood 
transfusions 
• 
Interim analysis planned? Yes 
• 
Alpha level: 0.025 
• 
Beta or power level: 0.80 
• 
Primary outcome variable estimate (mean +/- s.d. for 
continuous outcome, frequency/percentage for 
categorical variable): Two primary outcomes for joint 
hypothesis: 1—Calculated blood loss: 1173±479mL for 
IV TXA (Jules IV vs Topical TXA); 20% (235 mL) 
increase in blood loss clinically meaningful difference 
(based on clinical experience) 2—Blood transfusion: 3% 
average proportion of cases requiring transfusions; 20% 
difference clinically meaningful (both based on clinical 
experience) 
• 
Number of groups being compared (use 1 for paired 
analysis within the same subjects): 2 
• 
Resulting number per group: 200 THAs, 200 TKAs 
• 
Total sample size required: 400 
 
 
 


 
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1.0 INTRODUCTION 
 
 
The interventions to be studied are oral and IV tranexamic acid. The conditions to be 
studied are blood loss and transfusion rate. 
 
 
Tranexamic acid (TXA) is an antifibrinolytic medication used to reduce bleeding in a 
variety of medical settings. The use of TXA in total hip arthroplasty (THA) and total knee 
arthroplasty (TKA) has resulted in dramatic decreases in operative blood loss and 
transfusion rates, revolutionizing the field of arthroplasty. The use of TXA, now common, 
has made autologous blood donation programs largely obsolete. Additionally, it has made 
perioperative blood transfusion uncommon. While AAOS guidelines suggest that all three 
available preparations of TXA (oral, IV, topical) are effective, preferred route of dosing varies 
by provider and institution. These preferences are based on habit, understanding of 
pharmacodynamics, and logistical issues regarding effective dosing. Oral TXA is the 
cheapest option, but some surgeons prefer IV dosing due to concerns regarding efficacy 
and controlled dosing. In this study, we seek to compare the efficacy of a single pre-
operative oral dose of TXA to a single pre-operative IV dose of TXA. 
 
 
The standard oral TXA dose is 2g and costs about $2 per dose. The standard IV 
TXA dose is 1g and costs about $4 per dose (plus the cost of extra equipment such as 
syringes). Some surgeons prefer IV over oral TXA because it has rapid onset and the 
dosing can be easily timed with regard to incision. Oral TXA, on the other hand, would have 
to be taken at some time prior to surgery since its peak plasma concentration is achieved 3 
hours after administration (Pilbrant, PMID 7308275). With oral dosing, operating room 
delays could potentially mean that the peak effect of oral TXA would not coincide with 
surgery. The benefits of giving oral rather than IV TXA include a significant cost savings and 
not having to administer an IV medication. A recent meta-analysis (Wang, PMID 30200167) 
showed similar blood loss and transfusion rate in patients given oral TXA vs IV TXA. 
 
 
Data and guidelines suggest no functional difference between oral and IV TXA use 
(Della Valle PMID 29805106). Prior work has investigated oral and IV TXA head-tohead 
(Kayupov PMID 28244907, Fillingham, PMID 27113948), finding equivalent reductions in 
blood loss but with great cost savings for oral TXA. This study will attempt to corroborate 
these findings. However, it will also function as a feasibility study in investigating whether 
oral TXA can effectively be administered consistently in a pre-operative setting. 
 
 
 
 
 
 


 
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2.0 OBJECTIVE(S) OF CLINICAL STUDY 
 
 
 
Primary questions  
1. Does oral TXA dosing in THA/TKA result in more blood loss compared to IV TXA dosing? 
2. Does oral TXA dosing in THA/TKA result in more transfusions compared to IV TXA 
dosing?  
Secondary question  
3. Does oral TXA dosing in THA/TKA result in longer length-of-stay (LOS) after THA/TKA 
compared to IV TXA dosing? 
If we further establish that oral TXA can effectively be administered prior to surgery with 
comparable results to IV TXA, it could potentially shift use away from IV toward oral dosing. 
This would create an enormous cost savings for our hospital (estimated between $100,000 
and $200,000) and might make perioperative workflows function more smoothly, as well. 
3.0 STUDY HYPOTHESES 
1. Oral TXA administration results in no greater blood loss compared to IV TXA 
administration. 
2. Oral TXA administration results in no increased transfusion rate compared to IV TXA 
administration. 
3. Oral TXA administration results in no increased LOS compared to IV TXA 
administration. 
4.0 STUDY DESIGN 
4.1 
Endpoints 
4.1.1 
Primary Endpoint 
• 
Calculated blood loss (CBL) in cc, to be calculated according to Gao (PMID 
26521781). 
• 
Transfusion during hospital stay (both binary yes/no and discrete volume 
transfused) 
 
4.1.2 
Secondary Endpoints 
o Time to discharge from PT 
o Length of stay  
 
4.2 
Study Sites 
This study will take place at the main campus of the Hospital for Special Surgery (HSS). 


 
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5.0 STUDY POPULATION 
5.1 
Number of Subjects 
400 
 
5.2 
Inclusion Criteria 
Subjects of either gender will be included if: 
1. Patients undergoing total hip arthroplasty (THA) through a posterior approach  
2. Patients undergoing total knee arthroplasty (TKA) 
3. Patients between the ages of 18-80  
 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if: 
• 
Patient declines enrollment  
• 
Patients greater than 80 years if age or less than 18 years of age 
• 
Patients with a BMI over 40  
• 
Patients undergoing general anesthesia  
• 
Patients with a history of major ipsilateral joint surgery 
• 
Patients on pre-operative anticoagulation or anti-platelet drugs (other than 
aspirin) 
• 
Patients with a history of bleeding disorders  
• 
Patients with platelet levels less than 100/nl 
• 
Patients with new-onset/active atrial fibrillation 
• 
Patients with a history of myocardial infarction in the past year 
• 
Patients with a history of a stroke in the past year  
6.0 PROCEDURES 
6.1 
Intraoperative Protocol 
 
Two blocked, 1:1 patient randomization schedules (one for THA and one for TKA 
patients) will be created using SASsoftware by a biostatistician not otherwise involved 
in the trial. Randomization cards will be sealed in opaque envelopes and given to the 
anesthesiologist once the patient consents. 
 
A total of 400 patients will be enrolled, 200 THA patients and 200 TKA patients. 
 
200 THA (posterior approach) patients will be randomized to receive either: 
Oral TXA (1950mg) in holding area (N=100) 
IV TXA 1g upon transfer to OR (N=100) 
 
200 TKA patients will be randomized to receive either: 


 
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Oral TXA (1950mg) in holding area (N=100) 
IV TXA 1g upon transfer to OR (N=100) 
 
 
6.2 
Postoperative Protocol 
CBC at AM labs done on POD1 
6.3 
Data Collection 
The following data will be collected: 
 
Pre-operative/Baseline 
• 
Time PO txa given in holding 
 
Post-Operative  
• 
Name 
• 
MRN 
• 
DOB 
• 
Race/Ethnicity  
• 
Sex 
• 
Co-morbidities, diabetes, heart disease, prior use of blood thinners 
• 
Patient weight/height/BMI 
• 
Date of surgery 
• 
Surgeon 
• 
Time of IV txa infusion (start,end) 
• 
Surgery start/end time 
• 
Incision time 
• 
Procedure (TKA or THA) 
• 
Tourniquet use 
• 
Anesthesiologist  
• 
ASA physical status  
• 
Anesthesia start/end time 
• 
Constavac drainage 
 
 
Post-Discharge  
• 
 Transfusion volume 
• 
Incidence of DVT/PE 
• 
LOS 
• 
Transfer to higher level of care 
• 
CBC at PSS, upon PACU entry, at AM labs POD1 
• 
Post-transfusion  
 
  


 
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7.0 STATISTICAL ANALYSIS 
• 
Proposed analysis: Non-inferiority tests for two primary outcomes: a t-test or 
Mann Whitney U test will be used for calculated blood loss and chi-square or 
Fisher’s exact test will be used for proportion of blood transfusions 
• 
Interim analysis planned: Yes 
• 
Alpha level: 0.025 
• 
Beta or power level: 0.80 
• 
Primary outcome variable estimate: Two primary outcomes for joint 
hypothesis: 1—Calculated blood loss: 1173±479mL for IV TXA (Jules IV vs 
Topical TXA); 20% (235 mL) increase in blood loss clinically meaningful 
difference (based on clinical experience) 2—Blood transfusion: 3% average 
proportion of cases requiring transfusions; 20% difference clinically 
meaningful (both based on clinical experience) 
• 
Number of groups being compared: 2 
• 
Effect size or change expected between groups: N/A  
• 
Resulting number per group: 200 THAs, 200 TKAs 
• 
Total sample size required: 400 


 
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Protocol Number: 2019-0882  
Version Date: 3/8/2022  
 
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Calculated blood loss (CBL) in cc, to be calculated according to Gao (PMID 26521781). We 
will calculate CBL according to all 4 methods described by Gao and plan to use the Hb-
balance equations, since it is thought to be most reliable. We will compare the 4 CBL 
calculations as well as EBL to assess the validity of our CBL calculations 
 
8.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report.