Study Comparing Topical Versus Intravenous Tranexamic Acid in Anterior Total Hip Arthroplasty

Detailed Description Prospective Randomized Study Comparing Topical versus Intravenous
Tranexamic Acid in Anterior Total Hip Arthroplasty A. Study Background and Purpose Hip and
knee arthroplasty is one of the most successful procedures for relieving pain and correction
of deformity in patients with degenerative arthritis of the hip and knee with approximately 1
million procedures performed every year in the United States. However, these joint
replacements are associated with substantial amounts of blood loss varying between 500 and
1,500 milliliters often necessitating allogeneic blood transfusions in the post-operative
period. This potentially leads to delays in discharge, physical recovery, and increased
complications. In addition, it can escalate the cost of total joint arthroplasties in
healthcare organizations. Several strategies have been employed in the past with varying
efficacies to reduce transfusion requirements including preoperative autologous donation,
erythropoietin use, intra-operative hypotensive anesthesia, fibrin spray, cell salvage, and
post-operative auto-transfusions drains. Over the past decade the anti-fibrinolytic agent
tranexamic acid, a synthetic analog of the amino acid lysine, has been used extensively in
lower extremity arthroplasties to minimize intra-operative blood losses. Tranexamic acid
prevents the conversion of plasminogen to plasmin on the surface of fibrin, thereby
inhibiting fibrinolysis and reducing blood loss. Despite its almost universal use and
documented safety, there is significant controversy regarding the optimal route of
administration with several studies documenting equivalent efficacy of intravenous and
topical administration, with both routes of administration currently considered standard of
care in both hip and knee arthroplasties. Anecdotally, the senior author has found that
topical use of tranexamic acid has led to greater post-operative drainage and reduction in
hematocrit compared to intravenous use. This may be secondary to the absence of tamponade
effect with anterior total hip arthroplasty. However, few studies have compared the efficacy
of topical versus intravenous use of this medication in direct anterior total hip
arthroplasty. Therefore, in this prospective randomized study, the investigators will attempt
to evaluate if there exists any significant difference in the post-operative outcomes of
topical versus intravenous tranexamic acid following anterior total hip arthroplasty.

B. Study Design This will be a prospective randomized study in which subjects who have
exhausted non-operative treatment for hip osteoarthritis and are opting for total hip
arthroplasty will be randomized into 3 groups in a 1:1:1 ratio based on a computer generated
algorithm following inclusion and exclusion criteria as described below. The patients will be
recruited into the study by the principal investigator from his practice cohort. They will be
consented to enroll in to the study by any one of the co-investigators. They will either be
recruited in the office at Bone and Joint Center, 1367 Washington Avenue, Albany New York or
at Albany Medical Center, 43 New Scotland Avenue on the day of surgery. Patients will be
further stratified according to BMI (body mass index) as this may be a confounding variable
affecting blood loss. The patients will be distributed in to 3 groups as follows: Group A:
Intravenous Tranexamic acid at a dose of 1 gram administered 30 min prior to skin incision
and 1 gram 3 hours after the procedure. (Total dose administered is 2 grams); Group B:
Topical Tranexamic acid at a dose of 1 gram injected in to the peri-articular tissues prior
to closure and 1 gram injected into the joint through the drain following wound closure.
(Total dose administered is 2 grams); Group C: Combined Intravenous 1 gram given intravenous
30 min prior to skin incision and topical tranexamic acid (1 gram) injected in to the
peri-articular tissues prior to closure. (Total dose administered is 2 grams). Women who are
premenopausal will have a pregnancy test prior to total hip arthroplasty as per institutional
protocol. This will be covered by the patient's health insurance. Subjects will be assigned a
unique identification number. The principal investigators will maintain a list identifying
all subjects by their subject identification number and initials. Subjects will be screened
at the time of scheduling surgery in the outpatient clinic. Study procedures and information
regarding the nature of the study will be reviewed with potential subjects, and written
informed consent will be obtained prior to any study-related procedures. Alternatively,
patients may be contacted by phone regarding the study. In this case, the study information
will be reviewed with the subject over the phone and subjects will be asked to electronically
sign a consent form sent via e-mail. Patients will be given a flyer when they are booked for
surgery which will briefly outline our study and inform them that they may be contact about
the study via telephone. The phone consent will be performed by one of the primary or
co-investigators listed on this study. Adobe E-sign software will be used to send subjects a
consent form via e-mail after the phone conversation. The patient will be given an
opportunity to review the consent document and then the investigator will place a second call
to the subject to review any questions or concerns. The subject and the investigator will the
electronically sign the consent in succession. The Adobe E-signature software provides a date
and time stamp. After the consent is signed by both parties the subject will be provided a
copy of the signed consent by email. A copy of the consent will be maintained in a secure
network drive provided by Albany Medical Center which will be accessible by the investigators
listed on the study. A printed copy of the signed consent will be placed into the patients
chart on the date of surgery. A second printed copy will be placed in a locked file cabinet
in the preoperative unit at Albany Medical Center. All patients will have the right to
voluntarily withdraw from the study. Any intra-operative or post-operative adverse events
prior to discharge from the hospital will be recorded.

Other screening procedures are as follows:

i. Review inclusion and exclusion criteria. ii. Collect demographic information including
age, sex, weight, height, BMI, American Society of Anesthesiology status, co-morbidities, and
medication use.

iii. Record medical history. iv. Collect baseline data with regards to pre-operative
hematocrit, creatinine levels, and coagulation profile.

All patients will have combined spinal with 0.75% bupivacaine heavy with lumbar and sacral
plexus blocks. The total hip arthroplasties will be performed through a direct anterior
approach. A closed suction drain will be placed intra-operatively and daily outputs measured
will be recorded. The drain will be clamped in all patients for 1 hour in the immediate
post-operative period after wound closure. For group B, the drain will be clamped after 1
gram tranexamic acid is injected through the drain following completion of wound closure.
Blood transfusion postoperatively will be dictated by the institutional policy of
post-operative hemoglobin concentration of <7 g/dl or hematocrit of <21 or when patients
developed any anemia-related organ dysfunction such as alteration of mental status,
respiratory distress, or palpitations. The total blood loss will be calculated using a
modification of the Gross formula where, if a reinfusion or an allogeneic transfusion was
performed, the total blood loss will be equal to the loss calculated from the change in the
hematocrit plus the volume transfused 20-22.

Prophylaxis against venous thromboembolism will be administered according to standard
practice at our center which includes anti-embolic stockings, intermittent pneumatic
compression, and early physical therapy on the day after surgery, aspirin 325 milligrams
twice daily started on first post-operative day and continued at discharge. Analgesic
irrigation with 7.5 ml of 1% Ropivacaine, 0.25 ml of Epinephrine 1mg/1ml, 1 ml of Morphine
10mg/ml, 1 ml of Ketorolac 30mg/ml, 1 ml of methylprednisolone acetate 40mg/ml, and 60 ml of
normal saline will be administered for wound infiltration in the peri-capsular tissues prior
to closure unless the patient possesses allergies to any of the aforementioned medications.
Post-operatively, all patients (Groups, A, B, and C) will receive standard post-operative
analgesic medications. All patients will be discharged with pregabalin 75 mg twice daily
(BID), celecoxib 200 mg BID, Oxycodone/acetaminophen 5/325 mg to take 1-2 tabs every four
hours as needed for pain control, and aspirin 325 mg BID for thromboprophylaxis unless they
possess allergies to the aforementioned medications.

Duration of the study The proposed data collection period of this study is two years.
Patients will not be brought back for follow-up beyond their normal post-operative visit
schedule. They will be seen earlier if any complications arise. During their visits metrics
that will be specifically assessed include wound infections rates and incidences of deep vein
thrombosis/ pulmonary thromboembolism (DVT/PE). Emergency department visits and readmissions,
if any, will be recorded.

Withdrawal

Any of the subjects may withdraw from the study at any time without prejudice. However, every
attempt should be made to encourage subjects to complete the study. If a subject discontinues
from the study, the reason given must be fully evaluated and recorded appropriately in source
documentation and the electronic health record. If the subject is withdrawn because of an
adverse event (AE), that AE must be indicated as the reason for withdrawal. The investigator
can discontinue a subject at any time if medically necessary. The primary investigator may
replace subjects that are withdrawn. In addition, subjects meeting the following criteria
must be withdrawn from the study:

- Occurrence of any adverse event (AE), post-operative bleeding complications requiring
return to operating room or a vascular intervention radiology procedure, or laboratory
abnormality which, in the opinion of the primary investigator, warrants the subject's
permanent withdrawal from the study;

- Subject noncompliance, defined as refusal or inability to adhere to the study schedule;

- At the request of the subject, primary investigator, or regulatory authority

- Subject is lost to follow-up.

C. Subject Population The subjects will be male and female patients of the principal
orthopedic surgeon's practice who are eligible for unilateral anterior total hip
arthroplasty. They must meet the above stated inclusion criteria and be willing to
participate in the study and receive any of the three routes of tranexamic acid. They will be
preoperatively evaluated for medical clearance by either their primary care physician and/or
cardiologist as they otherwise would regardless of study inclusion.

D. Study Location The study will be conducted at Albany Medical Center, 43 New Scotland
Avenue, Albany New York, Zip 12208, (Phone: 518-262-4000) and Bone and Joint Center, 1367
Washington Avenue, Albany New York, 12206 (Phone 518-489-2666).

E. Data analysis All data metrics including demographic variables and primary and secondary
endpoints will be tabulated in to an excel spreadsheet (Microsoft Inc., Redmond, WA). Data
analysis will be performed using software GraphPad Prism (GraphPad Software Inc., CA).
Quantitative data will be analyzed using non-directional analysis of variance (ANOVA) with
Tukey's test for multiple comparisons. Non-normality or heteroscedasticity of data will
either be corrected by transformation or a non-parametric (Kruskal Wallis) test will be used.
Data will be presented as mean and standard deviation if normal or median and interquartile
range if not. Categorical data will be analyzed using chi-square tests (or Fisher's exact
test if any cells expected value is 5 or less). A p-value <0.05 will be considered
statistically significant. Risks of total hip arthroplasty, equally applicable to all
participants in the study, include intra-operative fracture, post-operative infection,
deep-vein thrombosis, pulmonary embolism, post-operative hip pain, and need for future
surgery. Complications associated with the use of tranexamic acid include unforeseen allergic
complications.

G. Benefits The primary advantage, which study subjects may derive from being a part of this
study include considerable improvements in blood loss in the immediate peri-operative period.
The benefit expected for study subjects enrolled in this study may include a reduction in
length of stay, fewer blood transfusions, and earlier achievement of rehabilitative outcomes.

H. Confidentiality All primary data, or copies thereof (e.g., laboratory records, data
sheets, correspondence, photographs, and computer records), which are a result of the
original observations and activities of the study and are necessary for the reconstruction
and evaluation of any study report, will be retained by the Principal Investigator. Data
sources will be Albany Medical Center Sorian electronic health record and from Electronic
health records (EHR) at Bone and Joint Center. The results from screening and data collected
during the study will be recorded in the electronic health records and/or source documents,
as appropriate, for each subject. To maintain confidentiality, the subjects will be
identified by numbers and/or initials on the electronic health records. Beginning on the day
of surgery, all patients included in the study will be given a number associated with a
randomly assigned opaque envelope. The only association between patients and their assigned
numbers will be stored in the principal investigator's locked file cabinet in the locked
office. However, as an inpatient, all data will be stored under the patient's name in the
medical record in standard fashion. After discharge, data will be copied onto a file by one
of the co-investigators and stored under the patient's confidential number. From this point
on, all data identifying information will be de-identified from the patient.

I. Options Since intraoperative tranexamic acid use has been shown to be standard of care,
option of not using tranexamic acid increases the risks of bleeding and post-operative blood
transfusions.

Inclusion Criteria

To be eligible to participate in the study, subjects must meet the following criteria:

1. Males or females age > 18 years and <80 years

2. Informed consent

3. Diagnosis of primary osteoarthritis or osteonecrosis

4. Previous history of contralateral hip or knee arthroplasty will not be excluded from
the study Exclusion criteria

Subjects who meet any of the following criteria will NOT be eligible to participate in the
study:

1. Unable to comply with study requirements i.e unable to complete first follow-up visit
at 4 weeks or if they are unable to follow-up.

2. Has an active joint infection\

3. Immuno-suppression, e.g., human immunodeficiency virus (HIV) infection, s/p organ
transplantation, receipt of steroids for > 10 days at > 10 mg of prednisone equivalent
daily within the 90 days prior to enrollment

4. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

5. Body mass index > 45

6. Life expectancy < 6 months

7. Renal insufficiency (serum creatinine >2.5 mg/dl)

8. Pre-operative Hemoglobin <8 gm/dl

9. Congenital and acquired coagulopathy

10. Patients on pre-operative therapeutic anticoagulation

11. Patients who need post-operative therapeutic anticoagulation

12. Pregnancy and nursing mothers or women who are expected to nurse their babies within
one month of surgery

13. History of thromboembolism, stroke, transient ischemic attack, traumatic brain injury,
subdural, or subarachnoid hemorrhage

14. History of reported allergy to tranexamic acid

15. Uncontrolled Hypertension

16. Non-steroidal antiinflammatory use within 3 weeks of surgery other than Celebrex.

17. Patients who continue the use of aspirin and have not stopped for more than 7 days
prior to surgery.

18. Patients who need to be on any anticoagulation other than aspirin 325 mg BID will be
excluded from the study.

19. Prisoners will be excluded from the study.

20. Patients with history of acquired defective color vision

21. Plan for staged bilateral total hip procedures within 14 days

22. Family history of thromboembolism

23. Patient unable to receive spinal anesthesia