Clinical trial NCT02615366: Tranexamic Acid for Bleeding in Breast Surgery
Official title: Minimization of Bleeding Complications Through Utilization of Perioperative Tranexamic Acid in Breast Surgery: A Randomized Double-blinded Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hematoma
Seroma
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
First posted: 2015-11-26
Enrollment: 800
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Bleeding is an important consideration in breast surgeries that involve large resections of soft tissues in the breast. Inappropriate bleeding during or after surgery, can lead to uncomfortable fluid buildup in the breasts known as a hematoma or seroma, which may require additional procedures or reoperation. Patients may experience a great deal of discomfort and additional costs as a result; additional hospital time and procedures also burdens health care spending. Tranexamic acid (TXA) is commonly used drug in many medical settings to reduce excessive bleeding; however, no such drug is standard practice in breast surgery. The aim of this study is to determine if TXA is superior to placebo in reducing the bleeding complications in breast surgeries, including reduction mammaplasty, mastectomy with and without immediate tissue expander and implant-based reconstruction, and oncoplastic breast surgery. This study is a randomized, double-blind, placebo-controlled trial. Patients undergoing these procedures will be randomly allocated to receive either TXA or placebo. Patients will be placed on a drug/placebo regimen of 3 doses/day for 6 days starting on the day of their surgery. The primary outcome is the incidence of hematoma and/or seroma formation following breast surgery. Cost analysis of the intervention will also be performed.

Detailed description: Background:

Aberrant bleeding is an important consideration in breast surgery, which can involve large resections of soft tissues in the breasts. Hematomas and/or seromas are common complications with these procedures, and can lead to further complications, such as flap necrosis. Seromas, perhaps the commonest complication, are documented to occur at rates as high as 85% in certain breast procedures. Hematoma rates are typically lower than that of seroma, ranging from 1% to 2% in mastectomy procedures and 5% to 8% in reduction mammaplasty. These bleeding complications pose an obvious risk to patient safety, and their management can result in significant costs to patients and healthcare alike.

Tranexamic acid (TXA), also known by the brand name Cyklokapron® from Pfizer™, is a lysine analogue used to prevent and/or treat bleeding by competitively blocking the activation of plasminogen to plasmin, thereby preventing plasmin from binding to blood clots. Tranexamic acid is used safely in several medical and surgical settings, such as cone biopsies, epistaxis and hyphaema control, and dental surgery. This antifibrinolytic medication is commonly used in many surgical procedures, namely cardiac and orthopedic surgery, for the purposes of preventing blood loss. TXA has been demonstrated to effectively reduce perioperative blood loss and transfusion rates in many different surgical procedures, such as cardiac, urology, gynecology, and orthopedic surgeries, without any significant safety concerns.

Despite these findings, there is a clear paucity of studies on TXA in breast surgery. There are currently no studies exploring perioperative TXA use in breast reduction, and only one study in breast surgery overall. This study by Oertli et al. looked at the use of TXA in mastectomy or lumpectomy with axial dissection, in a randomized placebo-controlled trial (RCT). Seroma rate was shown to be reduced by 10% with a reduction in TXA versus placebo. However, due to a low power of the study, Oertli et al. were unable to determine statistical significance.

Purpose:

The purpose of this study is to determine if perioperative administration of tranexamic acid (TXA) is superior to placebo in minimizing bleeding complications (as determined by: hematoma/seroma incidence in the breast, re-operation and/or additional procedures, blood transfusion volume, drainage volume (Jackson-Pratt drain or percutaneous drainage), number of days spent in hospital) in breast surgery (Reduction mammaplasty, mastectomy with and without immediate tissue expander and implant-based reconstruction, oncoplastic breast surgery). Conterminous with this objective, the investigators also intend to study the safety of tranexamic acid use perioperatively in these procedures by recording any adverse effects that occur at the time of surgery and throughout the follow-up period. The study will randomize and prospectively observe two patient populations undergoing any one of these procedures: one group receiving preoperative and subsequent post-operative 1g doses of tranexamic acid, and the other receiving placebo (normal saline). These two groups will be observed based on specific properties and complications from surgery. Finally, to determine if perioperative TXA use is more cost-effective than placebo in the setting of breast surgery. Information on health care utilization will be collected prospectively in both groups to provide a cost analysis of tranexamic acid.

The following hypotheses will be tested:

1. Perioperative TXA use is superior to placebo in reducing bleeding complications (ie. hematoma, seroma, and excessive blood loss) in the surgical or donor site.
2. Perioperative TXA is safe for use in this patient population.

Study Design

The present study will be a randomized, double-blind, placebo-controlled trial. This RCT will follow the CONSORT statement. Conterminous to this RCT, data on treatment costs (hospital and patient cost) will be recorded. The study will last approximately two years. Case Report Forms will be filled out at each follow-up period. Follow-up will occur at 2 weeks, 6 weeks, and 12 weeks postoperatively. Cost-analysis of the intervention will also be performed.

Sample Size:

Based on published data, the incidence of the combined hematoma/seroma endpoint is expected to range between 6 and 10% in the reductions patients and 16-87% in the mastectomy patients. Since the investigators expect to have equal numbers of each type of patient, the investigators anticipate the overall event rate in the placebo arm to range between 11-47%. Taking the midpoint, the investigators anticipate a placebo arm event rate of 29%. The investigators would consider a 30% relative reduction (i.e., an absolute difference of 9%) to be the minimal clinically important difference that would, if demonstrated, change practice. To detect this difference with 80% power, the investigators require 385 patients per arm using a two-sided test at the 5% level of significance To account for attrition of 15 patients per arm (\<5%), the investigators will aim to 400 patients per group.

Data Analysis:

The unit of analysis will be each individual patient for all outcomes. Baseline characteristics will be compared between study arms using descriptive statistics (frequencies and proportions for categorical variables, mean and standard deviation for continuous variables with a normal distribution and median and inter-quartile range for variables with a skewed distribution). The investigators' primary outcome, the incidence of hematoma and/or seroma, will be analyzed using a chi-square test with continuity correction. The difference between the arms will be described using a relative risk with 95% confidence interval. The overall rate in each group will also be reported. Secondary outcomes will be analyzed using chi-square tests (dichotomous outcomes) or Wilcoxon tests (drainage volume, transfusion volume, and days in hospital). Drainage and transfusion volume, as well as the number of days in hospital, will be summarized as median and interquartile range. All data analysis will be carried out by a statistician from the Ottawa Hospital Research Institute.

Eligibility criteria: Inclusion Criteria:

* Patient requires and is a candidate for any of the following surgical procedures: Reduction mammaplasty, mastectomy with and without immediate tissue expander and implant-based reconstruction, oncoplastic breast surgery.
* Patient has OHIP approval for surgery.
* Patient is willing and able (ie. English/French-speaking and cognitively intact) to read and complete patient diaries, demographic forms, and consent forms and be followed-up for a 2 weeks, 6 weeks, 12 weeks postoperatively.
* Patient is 18 years of age or older

Exclusion Criteria:

* Patient is allergic to tranexamic acid
* Patient has a history or present laboratory signs of bleeding disorders (abnormal platelet counts, prothrombin time, partial thromboplastin time, etc.), coagulopathy or thromboembolic events
* Patient is being treated for a stroke
* Patient has a history of bleeding in the brain
* Patient has an acquired disturbance of colour vision
* Patient has a history of myocardial infarction within the last year
* Patient is presenting with unstable angina or severe coronary disease
* Patient has reduced renal function with plasma creatinine levels above 250 umol/L ix.
* Patient has haematuria
* Patient is currently using a form of birth control that contains estrogen and a progestin
* Patient has irregular menstrual bleeding of unknown cause
* Patient is unable to complete required forms due to language and cognitive problems
* Patient is not capable of communicating in, and understanding, English or French
* Patient is currently pregnant and is expected to be pregnant during any point of the study

Primary outcomes:
measure: Incidence of hematoma or seroma formation in breast surgical site as assessed by clinical examination.
timeFrame: 12 weeks following the operation
Secondary outcomes:
measure: Tranexamic Acid Adverse Events:
timeFrame: 12 weeks following the operation
measure: Drainage volume as measured from Jackson-Pratt drain or percutaneous drainage
timeFrame: 12 weeks following the operation
measure: Blood transfusion volume
timeFrame: During surgical operating time, during post-operative hospital admission time (1-7 days on average).
measure: Incidence of secondary breast operation
timeFrame: 12 weeks following the operation
measure: Incidence of additional procedures following initial breast operation to address hematoma or seroma
timeFrame: 12 weeks following the operation
measure: Number of days spent in hospital
timeFrame: 12 weeks following the operation
measure: Cost associated with bleeding complications
timeFrame: 12 weeks following the operation
Other outcomes:
Locations:
Study officials:
References:
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