Clinical trial NCT03328832
Conditions: Osteoarthritis, Knee
Keywords: Thrombin-gelatin matrix Floseal Tranexamic Acid Total Knee Arthroplasty
Sponsor: Chang Gung Memorial Hospital
Start date: 2017-09-12; Completion date: 2018-12-30
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Our purpose of this study therefore is to conduct a prospective randomized controlled trial to investigate the blood-conservation effect of combined topical application of these two hemostatic agents in different time during surgery and the safety compared with single topical application of TKA in a primary TKA procedure

Detailed description:
Total knee arthroplasty (TKA) is associated with considerable blood loss and increasing needs for allogenic blood transfusion. Tranexamic acid (TXA), an inhibitor of fibrinolysis, was reportedly effective reducing blood loss after standard TKA. Our previous experiences in minimally invasive (MIS) TKA showed that intraoperative infusion of TXA reduced 45% of postoperative blood loss and needs for transfusion from 20% to 4%. There were some reports demonstrating the cost-effectiveness of topical application of TXA in TKA patients.

Besides, thrombin-based hemostatic agents, Floseal®(Baxter, Deerfield, Illinois), have been widely used in surgical procedure. Some recent studies demonstrated that topical use of Floseal® in primary TKA can reduce hemoglobin decline and calculated total blood loss after TKA. But other studies showed Floseal® does not reduce blood loss in TKA procedures.

We believe the topical use of hemostatic agent in patients with high risk of thromboembolism can avoid its systematic effect and decrease its potential perioperative risk of thromboembolic complications (arterial thrombosis, myocardial infarction and pulmonary embolism). Recently, there were some reports demonstrating the cost-effectiveness of topical application of TXA in TKA patients. The blood saving effect of topical application of TXA in primary TKA was similar with systemic administration. The mean total blood loss of topical route of TXA inTKA patients was 940-1295 ml in different reports which was still high for patients with high thromboembolic risks. However, the efficacy and safety of topical use of TXA in TKA patients with history of thromboembolic disease is still unclear. A more effective regimen for bleeding prophylaxis afer primary TKA is necessary.

We believe that combined topical applications of two hemostatic agents of different mechanisms can bring a synergistic effect in blood saving and does not increase the risk of thromboembolic disease after TKA.

Our purpose of this study therefore is to conduct a prospective randomized controlled trial to investigate the blood-conservation effect of combined topical application of these two hemostatic agents in different time during surgery and the safety compared with single topical application of TKA in a primary TKA procedure.

Arms: arm 1: Floseal® was applied on potential bleeding sites before prosthesis implantation, and intraarticular application of topical tranexamic acid after capsule closure Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14. arm 2: Intraarticular application of topical tranexamic acid after capsule closure Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14.
Interventions: intervention 1: Topical tranexamic acid intervention 2: Floseal® intervention 3: rivaroxaban (10mg)
Intervention descriptions: intervention 1: Intraarticular application of tranexamic acid 3g in 60 ml normal saline into knee joint after closure of the joint capsule intervention 2: Floseal® (Hemostatic matrix, 10ml, Baxter) was applied on potential bleeding sites: the femoral insertion of the posterior cruciate ligament, the lateral genicular artery after resection of the meniscus, the posterior capsule of the knee joint, the bony surfaces not covered by the implant as well as the pinholes (femur and tibia). The entire content of a 10 mL vial containing the active product (Floseal®) was used. The HM remained in place for 3 minutes and was then gently rinsed from the knee as recommended by the manufacturer (Baxter) intervention 3: Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14.

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol  
Title: Comparison of combined topical tranexamic 
acid with Floseal®  with intravenous tranexamic 
acid on blood loss in total knee arthroplasty 
 
Principal Investigator:  Wang Jun-Wen   
Official Title: Professor 
Affiliation: Kaohsiung Chang Gung Memorial Hospital  
 
 
Date: 2016, Nov, 29 
 
 
 
 
 


 
Study Design and Protocol 
We plan to compare acute blood loss (every two hours for 8 hours), total blood loss 
and risk of blood transfusion, after primary total knee arthroplasty (TKA) within three 
groups.  
 
Group I (N=35): Primary total knee replacement with application of 
Floseal®  on potential bleeding sites before prosthesis implantation and 
intraarticular application of tranexamic acid 3g in 40 ml normal saline into 
knee joint after closure of the joint capsule.  
 
Group II (N=35): Primary total knee replacement with intraarticular 
application of tranexamic acid 3g in 40 ml normal saline into knee joint 
after closure of the joint capsule.  
 
A : How to enroll the patient 
 Patients who plan to undergo primary total knee replacement were 
recruited to this study first. Second, we exclude the patients according to 
our exclusion criteria. Then we will explain the study design, purpose and 
risk to the patient and the family. At last, we will enroll the patient into this 
study after patient and family agree and sign the informed consent. 
Inclusion criteria :  
1. 
Patients who have advanced knee osteoarthritis are scheduled to 
undergo primary, unilateral elective total knee replacement surgery 
2. 
Age > 50 years and < 90 years 
3. 
Failure of medical treatment or rehabilitation. 
4. 
Hemoglobin > 11g/dl,  
5. 
No use of non-steroid anti-inflammatory agent one week before 
operation 
 
Exclusion criteria 
1. Preoperative Hemoglobin ≦11 g/dl 
2. History of infection or intraarticular fracture of the affective knee 
3. Renal function deficiency (GFR <30 ml/min/1.73m2)which is relative 
contraindicated for chemical venous thromboembolism 
4. Elevated liver enzyme, history of liver cirrhosis, impaired liver 
function and coagulopathy (including long-term use anticoagulant) 
5. History of deep vein thrombosis, ischemic heart disease or stroke 


6. Contraindications of tranexamic acid, floseal, or rivaroxaban 
7. Allergy to tranexamic acid, floseal, rivaroxaban, or the excipients 
8. History of heparin-induced thrombocytopenia (HIT) 
9. Coagulopathy or bleeding tendency caused by organ dysfunction, 
such as cirrhosis, bone marrow suppression etc. 
10. Patient who have active bleeding disorder, such as intracranial 
hemorrhage, upper GI bleeding, hematuria. 
11. Patients with known allergies to materials of bovine origin. 
 
Withdrawal criteria 
Patients can refuse to participate this study and withdraw from this 
study at any time of this study, even if the TKA has been done. The data 
will not be collected for statistics. 
Regulations of self-medications of participants 
1. Every participant should follow the physician’s instructions to use 
anti-coagulants. Any drug which influences the hemostatic status 
[including aspirin, clopidogrel, warfarin, etc] should not be used in this 
study. 
2. Drugs which do not influence the hemostasis can be used during the 
period of this study 
 
Study grading : 
   Prospective, randomized control trial, single-blinded 
 
Ongoing procedure : 
1. All patients receive primary total knee replacement with cemented 
prosthesis  
2. Skin incision using midline longitudinal incision with midvastus 
approach 
3. All operative procedure is performed through minimally invasive 
technique (8-12 cm) 
4. Use of intramedullary guide system for femoral bone cutting, 
extramedullary guide for tibia cutting. 
5. Use of bone plugs in the femoral canal 
6. No hemostasis or release of tourniquet before wound closure 
7. The hemostasis strategy is different depending on which group the 
patient is assigned in: 
i. 
Patients in the first group will receive Floseal®  5ml on potential 


bleeding sites before insert implantation, then receive injection 
tranexamic acid 3g in 40 ml normal saline into knee joint after 
closure of the joint capsule and before deflating the tourniquet. 
ii. 
Patients in the second group will receive injection tranexamic acid 
3g in 40 ml normal saline into knee joint after closure of the joint 
capsule and before deflating the tourniquet 
8. A hemovac drain is in place before wound closure 
9. Deflate the tourniquet after wound closure, and the hemovac drain will 
be clamped for 1 hour after topical TXA injection. 
 
Postoperative management   
 Estimating blood loss 
Amount of hemovac drainage 
postop 0-2 hours 
2-4 hours 
4-6 hours 
6-8 hours 
8-16 hours 
16-24 hours 
24-32 hours  
          32-40 hours 
 Deep vein thrombosis (DVT) prophylaxis with oral rivaroxabam 
10mg Qd Day 1 to 14. 
 
Start ambulation immediately after operation 
 Check Hb/Hct preoperatively and postop. Day 1, 2, 3 and 14. 
 Indication for allogenic blood transfusion 
 
Hb < 8.0g/dl with clinical manifestation of anemia (dizziness, 
palpitation, palor etc) or Hb < 9.0g/dl in elderly paitents with 
risk of cardio pulmonary complications 
 Bulking dressing x 2 days 
 Ice packing q6h 
 Ward exercise training starting from 1st post op day 
 Check D-Dimer preoperatively and postop. Day 1. 
 
結果測量 
1. 
Primary outcome measure: 
Total Blood Loss  
         The total blood loss was calculated according to Nadler et 
al., which uses maximum postoperative decrease of the Hb level 
adjusted for weight and height of the patient.  Total blood loss 


consists of amount of blood loss calculated from the maximum Hb loss 
and amount of blood transfused 
   Total blood volume =(K1 x height3[ml]) + (K2 x weight [kg]) + K3 
Where K1 =0.3669 , K2=0.03219, and K3=0.6041 for men and  
K1=0.3561, K2=0.03308, and K3=0.1833 for women 
Total blood loss ={total blood volume * (preop. Hb level – 3th day 
postop. Hb level)+ hemoglobin count of transfused 
blood}/preoperative hemoglobin x 1000 
 
Secondary outcome measure 
1. 
Blood transfusion rate 
We will record the event of blood transfusion, and calculate the 
incidence of transfusion, 
2. 
Thrombosis risk evaluation:  
We will record all thrombotic events in our study, and calculate 
the incidence of them. The diagnosis of them as followings: 
 
Deep vein thrombosis (DVT): Bilateral ascending 
venography of the legs if symptomatic DVT is suspected 
according to Well’s criteria, ie, limb edema with thigh or leg 
circumference > 3cm compared at contralateral limb 
 
Pulmonary embolism (PE) evaluation : Chest CT scan if PE 
is highly suspicious 
 
Coronary 
artery 
disease 
evaluation: 
12
‑
lead 
electrocardiogram (ECG), cardiac enzyme level was checked 
if chest pain, exertional dyspnea, or heart attack was highly 
suspicious 
 
Cerebrovascular accident evaluation: Brain CT or MRI if the 
patient has change of consciousness or focal neurologic sign. 
 
Discharge Criteria 
1. Clear operative wound without discharge 
2. Knee range of motion : 90 degree or more 
3. Able to ambulate with walker support. 
 
Out patient department Follow up  
 2 weeks after operation : Check Hb/Hct, Remove stitches, clinical 
evaluation of the knee, Record range of motion of the knee and continue 
rehabilitation program, watch signs of DVT. 
 6 weeks after operation : Record range of motion of the knee and clinical 
evaluation of the knee, record knee score and functional score, watch for 


signs of DVT. 
 3 months after operation : Knee radiography follow up, record knee score 
and functional score, watch for signs of DVT 
4. The Duration of the Trial: one year 
 
Statistical Analysis Plan 
 
. Sample size calculation  
The sample size estimation is based on the difference in the primary 
outcome (postoperative blood loss) in the three study groups. No clinicial 
research was found to investigate the blood saving effect of combination of 
topical TXA and Floseal® in TKA. We refer to our primitive data of eight 
patients who received combination of topic TXA and Floseal® resulting in 
518ml (SD=225ml) blood loss. The Efficacy of Combined Use of 
Intraarticular and Intravenous Tranexamic Acid on Reducing Blood Loss 
and Transfusion Rate in Total Knee Arthroplasty” by SY Lin which topical 
application of TXA group resulted in 705.1± 213.9 mL.  
We set the null hypothesis (H0) is that the values of total blood loss of both 
group is equal. Alterna-tive hypothesis (H1) is that the total blood loss of 
two groups are different. We used G-power soft-ware to calculate the 
sample size. To refuse the H0, under the level of alpha =0.05, and the power 
=0.95, the smallest sample size is 31 patients in each group (total case 
number is 62 patients. We plan to recruit 35 patients in each group (total 
case number is 70 patients to compensate for ex-pected dropouts and 
incomplete data. 
 
Statistical Analysis 
The independent t- test was used to determine the differences between two 
groups in the distribution of demographics, preoperative clinical data, total 
blood loss, postoperarive drainage amount, postoperative hemoglobin level, 
length of hospital stay, and wound length. 
Descriptive data, including gender, ASA level, the incidence of 
thromboembolic events, the blood transfusion rate between the three groups 
were compared using chi-square test or Fisher’s exact test. All statistical 
comparisons were made using the Statistical Package for Social Sciences 
(SPSS) (version 18; SPSS Inc., Chicago, Illinois).