Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02553122 |
| Other study ID # |
13-12-178 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 3
|
| First received |
September 15, 2015 |
| Last updated |
March 23, 2018 |
| Start date |
October 2015 |
| Est. completion date |
December 2016 |
Study information
| Verified date |
March 2018 |
| Source |
Montefiore Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Total knee arthroplasty is a surgical procedure that involves a significant amount of blood
loss and it has always been the surgeons' goal to try to minimize blood loss. In the current
study, we will investigate the effect of blood loss after total knee arthroplasty with the
combination of Evicel, a fibrin sealant and Tranexamic Acid.
Description:
Introduction and Background: Total knee arthroplasty is characterized by a large amount of
postoperative blood loss and frequent need for blood transfusions.1 Also of concern is the
risk of hematomas which can potentially lead to infection or wound complications and delay
the overall rehabilitation process.2 By reducing postoperative bleeding, the outcomes of
total knee arthroplasty would be improved by better range of motion, less frequency of blood
transfusion and decreased incidence of arthrofibrosis.3 Several studies have looked at
different blood conservation strategies including reinfusion of drains, tourniquets,
autologous blood transfusions, topical and intravenous antifibrinolytic alone, topical fibrin
sealant alone, and monopolar and bipolar electrocautery. The combined use of a topical fibrin
sealant (Evicel®) with an antifibrinolytic (Tranexamic acid) represents another approach to
reducing blood loss in patients undergoing total knee arthroplasty. Evicel® is a fibrin
sealant consisting of human-derived thrombin and fibrinogen that work in combination to form
a stable blood clot at the bleeding site. Evicel® is regularly used in orthopaedic and other
sub-specialty surgeries. One investigation has reported on the use of a topical hemostatic
agent in total knee arthroplasty.4 It compared the use of a fibrin sealant for hemostasis
with standard hemostasis protocols and found that the topical hemostatic agent decreased post
operative blood loss, increased post operative hemoglobin levels, and resulted in a decrease
in the need for post operative blood transfusion. Tranexamic Acid is given topically or
intravenously to occlude the fibrin cleavage sites on plasminogen and inhibit the breakdown
of fibrin clots. Tranexamic acid is also regularly used in orthopaedic and other
sub-specialty surgeries. Studies have found that intravenous dosing of tranexamic acid prior
to incision, and again after tourniquet release reduces the need for the blood transfusion
versus standard hemostasis.5, 6
Research Questions/Objectives: Does the combination use of a fibrin sealant and an
antifibrinolytic in our institutional total knee arthroplasty protocol decrease postoperative
drain output/hematocrit drop/hemoglobin drop or the need for post operative blood
transfusions compared to standard hemostasis technique? Secondary objectives will be
measuring differences in postoperative pain, postoperative range of motion, and rates of
postoperative complications including pulmonary embolism, deep vein thrombosis, and wound
complications requiring a return to the operating room between treatment and control groups.
Study Design: The null hypothesis states that the combined use of a topical fibrin sealant
and an antifibrinolytic in total knee arthroplasty will show no difference in the amount of
postoperative blood loss compared to the standard means of hemostasis (tourniquet and
electrocauterization). The study will be a prospective randomized trial with patients that
are undergoing elective primary, unilateral, cemented total knee arthroplasty. Patients will
be randomly divided into two groups. A control group, in which the standard means of
hemostasis will be applied and a treatment group, in which the standard means of hemostasis
will be applied with the additional use of Evicel® (a fibrin sealant) and Tranexamic acid (an
antifibrinolytic). All operations will be standardized between four surgeons.
Subjects: The target population is patients seen in the outpatient office who are indicated
for primary total knee arthroplasty. Patients will be asked if they would like to participate
in the study; only patients capable of consenting to surgery will be enrolled. Patients
undergoing total knee arthroplasty revisions and patients with blood disorders, on chronic
anti-thrombotic medication such as Coumadin and any patients with a history of deep vein
thrombosis and/or pulmonary embolism will be excluded. Despite that Evicel® contains
human-derived blood products, Jehovah's Witnesses will not be excluded and these patients
will be given an opportunity whether they would like to participate or not. As tranexamic
acid is renally cleared, renally impaired individuals will be excluded.
Study Procedures: All participating surgeons will adhere to the same protocol. Upon enrolling
in the study, patient demographics including age, gender, height, weight will be recorded and
stored in an encrypted, protected database. Eligible / consenting patients will be randomized
in a 1:1 ratio to receive either treatment or non-treatment. The randomization will be
stratified by surgeon to ensure balanced assignment of treatment / non-treatment in each of
participating surgeons. Randomization schemes will be generated and maintained by Dr. David
Leibelt, the study statistician. Dr. Leibelt will provide Mr. Bharat Tiwari with a set of
randomization envelopes to be stored and used in the study clinic. Mr. Tiwari will assign
these envelopes in sequential order, by envelope number and surgeon, to eligible /consenting
patients. . During the process, Dr. Jason Wong and Mr. Andrew Schwartz will be blinded and
will have no access to the randomization assignment. Preoperative blood work including
hematocrit and hemoglobin will be performed, a standard for patients undergoing joint
arthroplasty. On the day of surgery, the patients will be seen in the preoperative holding
area, and again be asked if they consent to take part in the study. Total knee arthroplasty
will then be performed with a standard medial parapatellar approach using a 350 mm Hg
pneumatic tourniquet on the operative leg. All surgeons will use Zimmer implants. After
patient is put to sleep, attending surgeon will inform the operating team that whether the
patient is randomized into the treatment or control group. If the patient is part of the
treatment group, they will receive a 10 mg/kg dose of tranexamic acid prior to tourniquet
inflation. After removal of trial implants and irrigation/thorough drying, 2 mL of Evicel®
will be sprayed (under 15-25 psi of CO2) into the posterior joint capsule (via the gap
between femur and tibia). Once the implants are in place and the methylmethacrylate cement is
cured, the joints will be irrigated copiously and dried thoroughly for the final time. 2 mL
of Evicel® will be dripped into pinholes, another 2 mL of Evicel® will be dripped along the
exposed edges of bony tissue, and an additional 2 mL of Evicel® will be sprayed on all
remaining soft tissue. After 2 minutes, the tourniquet will be released and a second dose of
10 mg/kg tranexamic acid will be given as electrocautery is being performed. After joint
capsule closure, a final 2 mL of Evicel® will be sprayed along the arthrotomy incision and on
subcutaneous soft tissue. On top of the treatment protocol mentioned above, patient will also
receive the standard tourniquet protocol and electrocautery. If the patient is in the control
group, the standard tourniquet protocol and electrocautery alone will be used for hemostasis.
In both groups, an auto transfusion drain will then be placed within the deep layer of the
knee. The joint will then be closed and dressed in standard fashion. The patient will then be
taken to the postoperative anesthesia care unit. Immediate postoperative hemoglobin and
hematocrit levels will be recorded, a standard practice at our institution. The drain output
will be recorded over a 24-hour period. As is standard, hemoglobin and hematocrit levels will
be recorded for the three days postoperatively. Any transfusions and/or complications
(pulmonary embolism, deep vein thrombosis, and wound complications requiring a return to the
operating room) and length of stay will be monitored (according to standard protocol) and
recorded. Pain scores utilizing the WOMAC, SF-36, and VAS scales will be recorded during
postoperative follow up in the clinic. Range of motion will be compared to preoperative
values at two and six weeks postoperatively.
Safety outcomes to be monitored
Potential complications associated with the study such as pulmonary embolism, deep vein
thrombosis, and wound complications that require a return to the operating room will be
monitored by the surgical team.
Risks and Benefits
Potential benefits include decreased perioperative blood loss, which would sequentially
decrease the chance of blood transfusion (lower costs, fewer infections and errors, and less
frequent seroconversion) and decreased pain secondary to joint hematoma. This study also aims
to eliminate the need for post-operative drain usage (lower cost, fewer infections, fewer
drain complications and less time in the operating room).
Evicel consists of human-derived thrombin and fibrinogen. Patients with known allergies to
human blood products should not participate in this study. Also, the human-derived blood
products carry a risk of transmitting infectious agents such as viruses and theoretically,
the Creutzfeldt-Jakob disease (CJD) agent. This risk is theoretically equal to the risk of a
blood transfusion; however, there have been NO known incidents of infectious agent being
transmitted from the use of Evicel. Evicel is FDA approved and routinely used in orthopaedic
surgery.
Tranexamic acid is a pro-coagulant molecule that should not be used in patients with a past
medical history of intravascular clotting. Dosing of tranexamic acid should be reduced in a
renally impaired patient. The compound also should be avoided in those with known allergies
to tranexamic acid. Tranexamic acid is FDA approved and routinely used in a variety of
surgeries, including orthopaedics
Data Safety Monitoring Plan
A data safety monitoring board consists of an independent physician, Dr. Tony Wanich, Mr.
Bharat Tiwari and Dr.Yungtai Lo. At the 50 and 100 patient mark, the board will decide based
on the following criteria and decide on whether or not the study should be continued:
1. whether or not the complications rates (includes deep vein thrombosis, cerebrovascular
accidents) between the treatment group and the control group is significantly different
2. whether or not the transfusion rates between the treatment group and control group is
significantly different
3. whether or not the drain output between the treatment group and the control group is
significant different If any of the above criteria is met, the board will inform the
principle investigator and decide on whether or not the study should be terminated
early.
Data Management and Analysis:
Measures: The primary outcome measured will be 24-hour drain output that will be measured
from the time it is introduced. Secondary measures will be the serum hemoglobin and
hematocrit levels measured approximately 2 weeks prior to surgery and each of the first three
days after surgery. Transfusions throughout the duration of stay and the length of hospital
stay will also be recorded. Scores obtained from 3 pain scales will be recorded: WOMAC
(Pre-op and Post-op at 6 months), SF-36 (Pre-op and Post-op at 6 months), and VAS (Pre-op,
Post-op day # 1, 2, 3, Post-op visit #1 and 2). Range of motion at two and six weeks
postoperatively will be compared to the preoperative range. All measurements will be recorded
in an encrypted and protected database.
Statistical Analysis: The primary (drain output) and secondary (hemoglobin/hematocrit)
outcomes are continuous variables. Values for the intervention (Evicel®/Tranexamic acid) and
the standard of care control groups will be compared with the Mann-Whitney test. Results for
individual day measures and the summary measures (total drainage and average
hemoglobin/hematocrit) will not be adjusted for multiple comparisons. However, if any
statistically significant results from different days of the same measure and the composite
measure are not consistent, the possibility of type I error will be emphasized. We will
assume the data will not be normally distributed and therefore a non-parametric test, Mann
Whitney test, will be performed. We expect our randomization to result in balanced study
groups in regards to characteristics like age, sex, race, and BMI. Therefore stratified
randomization is unnecessary. However, if the two study arms are not reasonably balanced,
additional analyses using linear regression adjusting for any unbalanced variables will be
performed. Intention to treat analyses will be performed. Statistical analyses will be
completed by Dr. Jason Wong and medical student, Andrew Schwartz. Both Dr. Wong and Mr.
Schwartz will be blinded about the randomization.
Sample Size: Based on previous studies looking at similar outcomes and using a conservative
estimate for true difference of means of drain output, we need 50 patients per group for 90%
power and 150 patients per group for 97% power to detect a difference in 24 hour drain
output.
Implementation Plan/Timetable: Patients will be seen in the office and, if indicated for
total knee arthroplasty, we will request consent for the study. The attending surgeons will
answer any question at that time. A physician assistant who is blinded will collect data
daily. An average of 15-20 total knee arthroplasties are done each week. The data collection
will likely take 3-6 months. The data collected will be kept on an encrypted and protected
database accessible only to the physicians caring for the patients enrolled in the study.
