Clinical trial NCT04947514
Conditions: Hematoma Postoperative Venous Thromboembolism
Keywords: breast reduction mammoplasty hematoma tranexamic acid
Sponsor: Montefiore Medical Center
Start date: 2021-10-29; Completion date: 2022-07-13
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Breast reduction mammoplasty (BRM) is among the most commonly performed procedures in plastic surgery. However, postoperative hematoma is one of the most common complications following BRM. Hematoma-related complications include unplanned surgery, need for blood transfusion, wound healing issues, and unfavorable surgical outcomes.

Tranexamic acid has emerged in the literature as a promising agent that reduces perioperative blood loss and need for transfusion. However, despite its consistently reported efficacy, low cost, and favorable safety profile, tranexamic acid remains underutilized in plastic surgery.

The investigators propose a prospective, double-blinded randomized controlled study of the efficacy of tranexamic acid in reducing hematoma development in patients undergoing reduction mammoplasty. The investigators hope to contribute to the growing body of literature supporting tranexamic acid to reduce unwanted surgical bleeding.

Detailed description:
Prevention of perioperative blood loss is a chief consideration in plastic surgery. Breast reduction mammoplasty (BRM) is one of the most commonly performed procedures in plastic surgery, with over 100,000 performed in the United States in 2019 alone. Postoperative hematomas are among the most frequent complications following BRM, with a reported incidence between 0.3-7% in the literature. Many of these hematomas require blood transfusions and/or urgent surgical evacuation to avoid the consequent wound healing issues arising from increased tension on the closure.

Tranexamic acid (TXA) has emerged in the literature as a promising agent that reduces perioperative blood loss and need for transfusion. TXA is an antifibrinolytic agent that acts by stabilizing clot formation, and may be administered intravenously, orally, or topically. Topical administration of TXA has been shown to be as efficacious as intravenous dosing, though with substantially less systemic absorption. Multiple randomized controlled trials have demonstrated that TXA significantly reduces intraoperative bleeding and need for subsequent blood transfusion, without an increased risk of thromboembolic events. Moreover, TXA has been shown to be cost-effective in the surgical setting, not only by reducing direct hospital costs (drug and blood products), but also by decreasing subsequent costs by shortening length of stay and lowering the incidence of complications. However, the use of TXA in plastic surgery has not been well described.

The investigators propose a prospective, double-blinded randomized controlled study of the efficacy of TXA in patients undergoing BRM. The primary outcome variable will be the rate of hematoma development. The secondary outcome variables will be the incidence of blood transfusion and the incidence of thromboembolic events. The investigators will also collect a broad range of preoperative variables, surgical details, and other characteristics that may impact the perioperative bleeding risk. All patients eligible for reduction mammoplasty between July 1, 2021 and June 30, 2022 will be included in this study. The investigators hypothesize that use of TXA will decrease total perioperative blood loss, hematoma formation, and transfusion rates following reduction mammoplasty without increasing the incidence of thromboembolic events. Better understanding of the effect of TXA in reduction mammoplasty may be of great utility to the field of plastic surgery.

Arms: arm 1: Each patient undergoing routine bilateral breast reduction will be randomized to receive the study drug (topical tranexamic acid) either to the right or left breast at the conclusion of the operation, prior to closure of the incisions. The other breast will receive topical saline. arm 2: Each patient undergoing routine bilateral breast reduction will be randomized to receive the study drug (topical tranexamic acid) either to the right or left breast at the conclusion of the operation, prior to closure of the incisions. The other breast will receive topical saline.
Interventions: intervention 1: Tranexamic acid intervention 2: Placebo (topical saline)
Intervention descriptions: intervention 1: Topical tranexamic acid (1000mg) will be administered to the raw surface of the breast prior to closure of the incisions. intervention 2: The untreated breast will receive topical saline.

Protocol documents:
Prot_SAP_000.pdf: 
IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
1 
Use of tranexamic acid in reduction mammoplasty: a randomized controlled trial  
Study Protocol 
 
Prepared by: Amy Yao, MD (Plastic Surgery resident) 
 
Version Date: August 25, 2021 
 
1) Background 
Breast reduction mammoplasty (BRM) is among the most commonly performed 
procedures in plastic surgery, with reliable surgical techniques and consistent results.1 
However, postoperative hematoma is one of the most common complications following 
BRM.2-4 Despite meticulous hemostasis, up to 7,000 breast reduction patients develop a 
hematoma per year, leading to significant acute and long-term consequences. Hematoma-
related complications include unplanned surgery, need for blood transfusion, wound 
healing issues, and unfavorable surgical outcomes. Though blood transfusions may be 
indicated, transfusion-related complications include hemolytic reactions, immunologic 
complications, and mortality.5 The primary prevention of perioperative blood loss is 
therefore of critical importance.  
 
Tranexamic acid has emerged in the literature as a promising agent that reduces 
perioperative blood loss and need for transfusion. Tranexamic acid is an antifibrinolytic 
agent that acts by stabilizing clot formation.6 Tranexamic acid is currently FDA approved 
to reduce bleeding after tooth extraction in hemophiliacs, as well as to reduce heavy 
menstrual bleeding. Multiple randomized controlled trials in cardiac, orthopedic, and 
orthognathic surgery have demonstrated that tranexamic acid significantly reduces 
intraoperative bleeding and need for subsequent blood transfusion, without an increased 
risk of thromboembolic events including myocardial infarction, deep vein thrombosis, or 
pulmonary embolism.7-11 Moreover, tranexamic acid has been shown to be cost-effective 
in the surgical setting, not only by reducing direct hospital costs (drug and blood 
products), but also by decreasing subsequent costs such as shortening length of stay and 
lowering the incidence of complications.12 However, despite its consistently reported 
efficacy, low cost, and favorable safety profile, tranexamic acid remains underutilized in 
plastic surgery. This underutilization may be due to a relative lack of plastic surgery-
specific research, coupled with unfamiliarity and concern regarding its safety profile. 
There is a need for high-level research investigating the use of tranexamic acid in plastic 
surgery.  
  
We propose a prospective, double-blinded randomized controlled study of the efficacy of 
tranexamic acid in patients undergoing reduction mammoplasty. Our primary outcome 
variable will be rate of hematoma development. Our secondary outcome variables will be 
rate of blood transfusion, incidence of deep venous thrombosis, and rate of 
thromboembolic events. We will also collect a broad range of preoperative variables, 
surgical details, and other characteristics that may impact the perioperative bleeding risk. 
We hope to contribute to the growing body of literature supporting tranexamic acid to 
reduce unwanted surgical bleeding. Given the paradigm shifts evidenced by the recent 
surge in interest regarding tranexamic acid across multiple surgical subspecialties, better 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
2 
understanding of the efficacy of tranexamic acid in plastic surgery may have powerful 
implications for surgical outcomes in our field.  
 
2) Significance  
The current proposal builds logically upon the prior research at our institution, which has 
been conducted by the PI and the Co-Investigator (Dr. Amy Yao). We have sought to 
identify risk factors for hematoma development following reduction mammoplasty in our 
patient population, which has higher rates of obesity, hypertension, and diabetes 
compared to the national average. We have identified a hematoma rate of 7% in our 
patient population per a retrospective chart review, which is consistent with the prior 
literature. The PI’s research focuses on optimizing surgical outcomes in breast-related 
procedures, providing a strong and pertinent research background for the proposal.  
 
There is a large body of evidence supporting the use of tranexamic acid to reduce 
perioperative blood loss and need for transfusion in trauma, orthopedic, and cardiac 
surgery.7-11 Within the field of plastic surgery, previous research has focused on 
craniomaxillofacial surgery, though there have been preliminary studies of tranexamic 
acid’s utility in burn surgery and aesthetic surgery.6,13 Though virtually all authors 
endorse the integration of tranexamic acid into clinical practice based on their findings, 
there have been few adequately powered randomized studies in plastic surgery.14,15 
Furthermore, the majority of prior studies utilized primary outcome variables of unclear 
clinical significance. In a 2015 randomized controlled trial of 30 patients undergoing 
reduction mammoplasty, Ausen et al described an average 10 cc decrease in 24-hour 
drain output from topical TXA-treated breasts compared to contralateral controls, which 
was found to be statistically significant, but otherwise with uncertain clinical 
implications.16 In their discussion, Ausen et al write that their study was inadequately 
powered to determine whether or not tranexamic acid could prevent postoperative 
hematoma.  
 
This study would be the first randomized controlled trial to evaluate the use of 
tranexamic acid in reducing the rate of hematoma development in patients undergoing 
reduction mammoplasty. We plan to expand on the findings of Ausen et al by selecting 
hematoma development as the primary outcome variable. Selecting reduction 
mammoplasty patients as the study population allows us to evaluate each patient as their 
own internal control, thereby eliminating potential confounders associated with an 
increased risk of hematoma, such as hypertension.14 Moreover, breast procedures have 
been identified as an independent risk factor for hematoma development compared to 
trunk, extremity, or facial plastic surgery procedures.3 With the large volume of body 
contouring surgery at our institution, as well as the higher rates of medical comorbidities 
associated with hematoma formation present in our patient population, we are uniquely 
equipped to conduct this study. This innovative study will provide high-level evidence 
regarding the use of tranexamic acid in plastic surgery in an elegant model.  
 
3) Study Design 
a) Study Objectives 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
3 
The primary goal of this proposal is to determine the efficacy of tranexamic acid in 
reducing the rate of hematoma formation after breast reduction surgery. This will be a 
double-blinded, randomized controlled study. The research will be achieved by 
randomizing one breast in a bilateral breast reduction to receive topical tranexamic 
acid, while the other breast will not receive the study drug. Both the surgical team and 
the patient will be blinded to which side has received the study drug. The patient will 
then be followed for the standard postoperative period and the rate of hematoma 
development will be recorded. Patient demographics, comorbidities, treatment 
history, and surgical details will be collected from these charts and analyzed for their 
impact on perioperative blood loss. We hypothesize that use of topical tranexamic 
acid will decrease the rate of hematoma formation and the rate of blood 
transfusion without increasing the incidence of deep vein thrombosis or 
thromboembolic events.  
 
b) Target Population and Recruitment Methods 
Consecutive patients presenting for breast reduction mammoplasty performed by 
plastic surgeons affiliated with Montefiore Medical Center will be offered enrollment 
in the study. Potential study participants will be recruited at their preoperative 
consultation appointments that take place at the Hutchinson Metro Center campus. 
Written informed consent (detailed below) will be obtained from all participants 
before inclusion. As this proposal involves greater than minimal risk to patients, we 
will have a Data and Safety Monitoring Plan in place prior to beginning the study. 
 
c) Inclusion and Exclusion Criteria 
Inclusion criteria include: being over the age of 18 and being scheduled for reduction 
mammoplasty at the Hutchinson Metro Center campus of Montefiore Medical Center.  
 
Exclusion criteria include: oncologic breast reductions, unilateral breast reductions, 
history of thromboembolic disease, history of bleeding diatheses, history of stroke, 
current pregnancy, severe comorbidity (defined as American Society of 
Anesthesiologists (ASA) fitness grade IV or above).  
 
d) Primary and Secondary Outcomes 
Primary outcome: development of hematoma within 30 days of surgery 
Rationale: Topical tranexamic acid has been shown to reduce perioperative blood loss 
and need for transfusion. A recent randomized controlled trial showed that topical 
tranexamic acid significantly decreased 24-hour drain output following reduction 
mammoplasty, though the clinical significance of this was unclear.  
- 
We hypothesize that breasts treated with topical tranexamic acid will have a 
lower rate of hematoma development compared to the contralateral control.  
 
Secondary outcome: incidence of blood transfusion within 30 days of surgery, 
incidence of deep vein thrombosis, and incidence of pulmonary embolism 
Rationale: Tranexamic acid is an antifibrinolytic, and therefore acts by inhibiting 
fibrinolysis and stabilizing clot formation. There has historically been concern that 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
4 
use of tranexamic acid will increase the incidence of thromboembolic events such as 
deep venous thrombosis and pulmonary embolism.  
- 
We hypothesize that patients treated with topical tranexamic acid will not have an 
increased rate of thromboembolic events compared to nationally published rates 
and those of our own historical controls.  
 
e) Study Timelines 
We anticipate that data collection from the treatment arm will take 8 months and 
analysis and manuscript preparation will take another 4 months. 
 
4) Study Population 
 
a) Study Population 
The study population will comprise all patients over the age of 18 scheduled to 
undergo breast reduction surgery at the Hutchinson Medical Center campus of 
Montefiore Medical Center, who meet the inclusion and exclusion criteria outlined 
above. No patients from before the beginning of electronic medical record use at 
Montefiore Medical Center will be used, as it will not be possible to explore these 
patients’ medical records. As this proposal involves greater than minimal risk to 
patients, we will have a Data and Safety Monitoring Plan in place prior to beginning 
the study. 
 
b) Vulnerable Populations  
Include 
Exclude 
Vulnerable Population Type 
 
X 
Adults unable to consent 
 
X 
Individuals who are not yet adults (e.g., infants, children, 
teenagers) 
 
X 
Wards of the State (e.g., foster children) 
 
X 
Pregnant women 
 
X 
Prisoners 
 
c) Informed Consent Process 
It will be documented at an 8th grade reading level that they are being asked to enroll 
in a study involving research. The purpose of the research is to investigate the off-
label use of an antifibrinolytic on perioperative blood loss and hematoma formation. 
It will be explained that the procedure will include the topical administration of 
tranexamic acid at the conclusion of their operation, which is above and beyond the 
standard of care for body contouring procedures.  
- 
Potential benefits include the reduction in perioperative blood loss, a lower risk of 
hematoma formation, and a decrease in possible transfusion requirement  
- 
Potential risks include a slight increase in the following risks: seizure, pulmonary 
embolism, deep venous thrombosis (DVT), and allergic reaction.  Though the 
proposed research involves greater than minimal risk to the subjects, several prior 
randomized controlled trials have demonstrated the overall safety of the study 
drug:  
o For example, the Clinical Randomisation of an Antifibrinolytic in 
Significant Haemorrhage-2 (CRASH-2) trial, a major multicountry, 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
5 
prospective, placebo-controlled trial of 20,211 adult trauma patients 
showed that tranexamic acid provided a mortality benefit without an 
increased risk for thromboembolic events17 
o The Aspirin and Tranexamic Acid for Coronary Artery Surgery trial of 
4,631 patients showed that the use of tranexamic acid does not increase 
the risk of thromboembolic events; however, it did show that the incidence 
of seizures increased from 0.1% to 0.7% (p=0.002), though this largely 
occurred in patients undergoing open chamber procedures, a known 
independent risk factor for seizure  
- 
An additional risk to subjects in this study is a breach of confidentiality. This will 
be protected against with the use of well-trained research staff, encrypted and 
password protected data, and a locked linking file. 
 
d) Protection of Human Subjects 
The alternative to participating in this study includes proceeding with the standard of 
care in reduction mammoplasty, without the administration of topical tranexamic 
acid. Confidentiality of records identifying the participant will be maintained. In the 
event of a research-related injury, the participant will be instructed to contact the PI. 
In the event of potential complications that may ensue, including those that are known 
potential complications following reduction mammoplasty such as hematoma 
development and wound healing issues, the participant will be treated with the 
appropriate medical treatment per standard of care. There will be no compensation for 
participating in this study, nor will compensation be available in the event of a 
postoperative complication. Contact information for the research team will be 
provided in the event the participant wishes to ask pertinent research questions. 
Participation is voluntary, refusal to participate will involve no penalty or loss of 
benefits to which the participant is otherwise entitled, and the participant may 
discontinue participation at any time without penalty or loss of benefits to which the 
participant is otherwise entitled. Significant new findings developed during the course 
of the research which may affect the participant’s willingness to continue 
participation will be provided to the participant.  
 
e) Sources of Research Material  
This project relies on the scheduling system used by the Epic electronic medical 
record system. Patients presenting for breast reduction surgery who are deemed 
eligible and scheduled for surgery from the plastic surgery clinic will be offered 
enrollment in the study.  
 
5) Participant Recruitment 
a) Plan for Participant Recruitment 
All patients over 18 presenting for breast reduction surgery who are deemed eligible 
and scheduled for surgery from the plastic surgery clinic will be offered enrollment in 
the study, unless they meet exclusion criteria as outlined above.  
 
b) Data Management and Confidentiality 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
6 
Although creation of the data-set will require use of patient names and medical record 
numbers, these will be stripped as soon as data-collection is complete and a linking 
file will be kept under lock and key by the primary investigator. The data set will be 
stored on Montefiore’s encrypted server. Only the study team will have access to the 
stored data, and only the study team will have access to the linking file. Data will be 
stored until the data is analyzed and scholarly output is generated. All members of the 
research team have undergone appropriate Human Subjects Protection training. 
 
c) Provisions to Monitor the Data to Ensure the Safety of Subjects/Data Safety and 
Monitoring Plan 
There will be regularly scheduled monitoring reviews by a Data Safety Monitoring 
Board (DSMB) at 6-month time intervals to review rates of adverse events, which 
will determine if the study poses sufficiently low risk to proceed. The DSMB will be 
comprised of two members of the Department of Surgery who are not affiliated with 
the study (Dr. Sheldon Feldman, MD and Dr. Prashanth Sreeramoju, MD), as well as 
a biostatistician from the Albert Einstein College of Medicine/Montefiore Medical 
Center (Dr. Shankar Viswanathan, DrPH). The incidence of venous 
thromboembolism (VTE) in reduction mammoplasty ranges from 0.22% to 2.9%. A 
recent National Surgical Quality Improvement Program study describes a 0.17% rate 
of pulmonary embolism and a 0.07% rate of deep vein thrombosis in BRM patients.18 
Furthermore, the incidence of seizure in the general population is estimated at 3%.19 
With an anticipated sample size of 100 patients, if more than 2 patients (1.5%) 
develop either a deep vein thrombosis, pulmonary embolism, or seizure 
postoperatively, the study will be paused while further investigation regarding safety 
takes place. In the case of increased incidence of adverse events that warrant further 
investigation, the study will be paused and the PSF grant office will be kept apprised. 
We do not anticipate increased risk for thromboembolic events or seizure, given the 
well-described safety profile of tranexamic acid even in hypercoagulable populations 
such as bedbound or cancer patients, and given that we are using a low, topical 
dosage with fractional systemic absorption.  
 
d) Provisions to Protect the Privacy Interests of Subjects 
 We will be requesting a waiver of consent and HIPAA authorization for recruitment 
purposes (so as to find eligible participants for the study), but we are not seeking a 
waiver for the study as a whole as we are obtaining informed consent from the study 
participants. 
 
e) Economic Impact on Subjects 
None 
 
7. Protocol Methodology 
We have based our research strategy on that of the previously published randomized 
controlled trial performed by Ausen et al.16 The randomization will be performed 
electronically by the Albert Einstein College of Medicine Clinical Research Center. 
Patients will be randomized to receive topical tranexamic acid to one breast and 
placebo (topical saline) to the other, after obtaining hemostasis but prior to closure 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
7 
during reduction mammoplasty. The study drug will be prepared and randomized 
with the assistance of the Einstein Investigational Drug Service as detailed below. 
 
A custom order for the study drug will be created in Epic. Each week, the list of 
patients scheduled to undergo reduction mammoplasty the following week will be 
provided to the pharmacy. The Investigational Drug Service at Einstein will prepare 
randomization kits comprised of two identical 20cc syringes labeled “LEFT” or 
“RIGHT” based on the existing randomization table. Our pharmacy carries a standard 
vial of tranexamic acid at a concentration of 100mg/mL, with 10mL per vial (total 1g 
of TXA). We will dilute the tranexamic acid to a volume capable of moistening the 
typical wound surface of reduction mammoplasty; 20 mL has been shown to 
sufficiently moisten at least 1500cm2.16 The side pre-randomized to treatment will 
contain 10cc of 100mg/mL of tranexamic acid diluted in 10cc of normal saline (0.9% 
sodium chloride). The other vial will contain 20cc of of normal saline. Tranexamic 
acid is colorless, therefore the two syringes will appear identical.  
 
The randomization kits will be brought to the operating facility the day prior to 
surgery and will be kept under lock and key. The randomization kits will be labeled 
with a unique identification number, separate from patient medical record numbers, 
and will expire twenty-four hours after pickup. At the end of each week, unused 
randomization kits will be returned. The pharmacy will prepare a dispensing log and 
transfer log, to be stored at the Investigational Drug Service headquarters. The 
dispensing and transfer log will be signed at each visit and the database (including the 
number of the randomization kit corresponding to each patient) will be closely 
maintained by the PI.  
 
All personnel involved in the operation and postoperative follow-up, including the 
attending physician, resident and physician assistant team, and clinic staff are to be 
blinded to the randomization. The randomization code will not be broken until 30 
days after the last patient has undergone surgery.  
 
There is not yet a consensus on the recommended dosing of tranexamic acid. Prior 
comparative trials and meta-analyses indicate that topical tranexamic acid has 
comparable or superior efficacy to that of intravenous dosing,20-23 with the added 
benefit of minimizing systemic exposure. The plasma concentration of topical 
tranexamic acid is less than one-tenth the amount after intravenous 
administration.24,25 Prior research suggests that a dose of 1 gram is sufficient to 
achieve an antifibrinolytic effect.13 Higher doses have generally fallen out of favor 
due to meta-analyses showing that they do not yield any greater benefit, and that 
higher dosage (>80 mg/kg total dose) led to an increased risk of seizures.26 We will 
therefore administer 1 gram of topical TXA to the treated breast.  
 
The reduction mammoplasty will be performed per our standard protocol. After 
achieving adequate surgical hemostasis, the contents of the vials will be applied to the 
raw wound surface of each breast. Drains will be placed bilaterally, per our protocol, 
and the incisions will be closed in the standard fashion. The patients will have 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
8 
surgical brassieres fitted postoperatively and will have routine follow-up scheduled in 
clinic. It is standard in our practice to have patients present for follow-up at one week 
postoperatively. Patients are instructed to record their daily drain output, and drains 
are typically removed once 24-hour output falls below 30cc.  
 
Subject treatment assignments will remain blinded until the final subject has 
completed follow up and all data has been recorded and validated.  Urgent, immediate 
unblinding due to medical emergency may be authorized by the Investigator.  When 
possible, the treatment assignment will be provided to the treating physician in order 
to maintain the blind for the Investigator and study staff.  
 
8. Data Analysis  
We hypothesize that use of topical tranexamic acid will decrease total perioperative blood 
loss, hematoma formation, and transfusion rates without increasing the incidence of deep 
vein thrombosis or thromboembolic events.  
 
a) Chart review data: 
Patient charts will be abstracted for baseline demographic data and medical 
comorbidities that may independently increase the risk of developing a postoperative 
hematoma. Data to be abstracted from the medical record includes: demographic data 
(including patient gender, age, ethnicity), medical data (including body mass index, 
comorbidities (e.g. hypertension, diabetes, hyperlipidemia, coronary artery disease), 
smoking history, history of neoadjuvant radiation therapy or chemotherapy, history of 
thromboembolic disease, bleeding diatheses, or use of anticoagulant medications), 
surgical data (including type of operation performed, surgical team involved, weights 
of tissue removed, estimated blood loss, drain outputs in the immediate postoperative 
period, date that drain(s) were removed) and complications within 30 days of the 
index operation including hematoma requiring operative washout or bedside 
evacuation, seroma, cellulitis, nipple-areolar complex necrosis, fat necrosis, delayed 
wound healing, deep vein thrombosis and pulmonary embolism. Patients with 
insufficient records or those who are lost to follow-up will be excluded from the final 
analysis.  
 
b) Statistical Analysis 
We have partnered with our institution’s Department of Surgery faculty 
biostatisticians on the statistical methods for this proposal. Based on a Bayesian 
approach, a sample size of 100 patients will be sufficient to adequately power this 
study.  
 
The primary objective of this pilot study is to explore whether, and to what extent, 
treatment using TXA decreases the risk of hematoma in patients undergoing breast 
reduction mammoplasty (BRM) compared to a saline placebo. A double-blind within-
subjects design will be used with each patient receiving both treatments and thus 
serving as their own control.  A simple randomization scheme will determine which 
treatment will be used for each side (left or right) for each patient. A Bayesian 
approach will be employed to estimate the posterior probability distribution of the 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
9 
relative risk reduction in post-surgical hematoma between treatment rate between 
treatment with TXA and control. This posterior probability distribution provides the 
information necessary to answer the salient questions informative about the presence 
and strength of an efficacy signal for TXA; specifically, what is the probability that 
treatment with TXA reduces the risk of hematoma, compared to control by an amount 
d for any 0< d <1. Note that the probability that the relative risk < 1 corresponds to 
the probability that treatment with TXA is superior to the control. A description of 
this approach follows. 
 
Prior to data collection and consistent with a null hypothesis of no difference between 
treatments we assume that the effect of treatment with TXA is equal to the effect of 
treatment with control. This assumption is formalized by assuming that the 
probability of developing a hematoma is the same for each treatment. The Bayesian 
approach considers this prior probability of developing a hematoma to be a random 
variable, which we specify to be a beta distribution with parameters 0.35 and 4.65, 
translating into a mean of 0.07 (the assumed hematoma rate for both treatments under 
the “null” hypothesis) and a standard deviation of about 0.10. Since patients will be 
treated with both treatments, the prior probabilities of developing a hematoma are not 
assumed to be independent. In our approach, we assume a conservative correlation of 
0.30. 
 
This prior probability is combined with the observed data, the number of observed 
hematomas under each treatment (a binomial random variable) to yield an estimated 
posterior probability distribution for each hematoma rate. These estimated rates will 
be used to estimate the posterior distribution for the relative risk, and its natural 
logarithm which has the advantage of being approximately normally distributed and 
less skewed given the low expected hematoma rates. 
An illustration of the estimated 
probability distribution for the natural 
logarithm of the relative risk is shown 
(left) under the “alternative” 
hypothesis that treatment with TXA 
reduces the rate of hematoma by a 
relative 50% compared to control 
based on a sample of 100 patients, the 
proposed sample size. The 
distribution is obtained by simulation 
using 100,000 replications.  The 
sample size of 100 was chosen to 
ensure a high probability of detecting 
an efficacy signal (a relative risk of 
0.5 or less) should it exist. 
Specifically, with a sample size of 100, the probability of estimating a relative risk < 
1, or natural logarithm of the relative risk < 0 (i.e., estimating that treatment with 
TXA is superior to treatment with control) is approximately 80%, corresponding to an 
odds of 4:1.  This 80% probability corresponds to the frequentist notion of power.  


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
10 
Note that the prior odds (assuming equal rates of hematoma) of observing a relative 
risk less than one is 1:1. Also, the the probability of observing odds of 4:1 in favor of 
TXA under the assumption of equal hematoma rates using each treatment is 
approximately 20%. This 20% is a false positive rate corresponding to the frequentist 
Type I error rate.  
 
We will perform a corresponding frequentist analysis using conditional logistic 
regression to estimate the odds ratio and corresponding 95% confidence interval for 
developing a hematoma using TXA compared to control. Our use of a non-
informative prior ensures that these results will be consistent with those provided by 
the Bayesian approach, and thus enhance interpretation of the trial’s results.  
Descriptive statistics, using both numerical and graphical summaries, will be used to 
describe the sample with respect to demographics, baseline characteristics, and 
important outcomes. 
 
Secondary endpoints will be analyzed using classical frequentist methods, with 
generalized linear models used to assess treatment group difference in blood 
transfusion, incidence of deep vein thrombosis, and incidence of thromboembolic 
events.  
 
9. Data Safety Monitoring Plan 
There will be regularly scheduled monitoring reviews at 6-month time intervals to 
review rates of adverse events, which will determine if the study poses sufficiently 
low risk to proceed. The DSMB will be comprised of two members of the 
Department of Surgery who are not affiliated with the study (Dr. Sheldon Feldman, 
MD and Dr. Prashanth Sreeramoju, MD), as well as a biostatistician from the Albert 
Einstein College of Medicine/Montefiore Medical Center (Dr. Shankar Viswanathan, 
DrPH). The incidence of venous thromboembolism (VTE) in reduction mammoplasty 
ranges from 0.22% to 2.9%. A recent National Surgical Quality Improvement 
Program study describes a 0.17% rate of pulmonary embolism and a 0.07% rate of 
deep vein thrombosis in BRM patients.18 Furthermore, the incidence of seizure in the 
general population is estimated at 3%.19 With an anticipated sample size of 100 
patients, if more than 2 patients (1.5%) develop either a deep vein thrombosis, 
pulmonary embolism, or seizure postoperatively, the study will be paused while 
further investigation regarding safety takes place. In the case of increased incidence 
of adverse events that warrant further investigation, the study will be paused and the 
PSF grant office will be kept apprised. We do not anticipate increased risk for 
thromboembolic events or seizure, given the well-described safety profile of 
tranexamic acid even in hypercoagulable populations such as bedbound or cancer 
patients, and given that we are using a low, topical dosage with fractional systemic 
absorption.  
 
Although creation of the data-set will require use of patient names and medical record 
numbers, these will be stripped as soon as data-collection is complete and a linking 
file will be kept under lock and key by the primary investigator. The data set will be 
stored on Montefiore’s encrypted server. Only the study team will have access to the 


IRB # 2021-13090 
PI: Joseph A. Ricci, MD 
11 
stored data, and only the study team will have access to the linking file. Data will be 
stored until the data is analyzed and scholarly output is generated. All members of the 
research team have undergone appropriate Human Subjects Protection training. 
 
 
 


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PI: Joseph A. Ricci, MD 
12 
10. References  
 
1. 
Surgeons ASoP. ASPS National Clearinghouse of Plastic Surgery Procedural Statistics. 
2019; https://www.plasticsurgery.org/documents/News/Statistics/2019/plastic-surgery-
statistics-full-report-2019.pdf. Accessed November 3, 2020. 
2. 
Hussien M, Lee S, Malyon A, et al. The impact of intraoperative hypotension on the 
development of wound haematoma after breast reduction. British journal of plastic 
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