Osteoarthritis, Knee
Conditions
Keywords
Tranexamic Acid, Total Knee Arthroplasty, Total Knee Replacement
Brief summary
Tranexamic acid (TXA) is a drug that is being used more frequently at the Hospital for Special Surgery to lessen the amount of blood loss after total knee replacement (TKR). It is an anti-fibrinolytic agent, which means that it promotes the formation of blood clots. TXA can be given either intravenously or topically (placed directly on the open wound) before wound closure. Patients with certain medical conditions have been found to have a high risk of thrombosis after being given intravenous TXA, which may lead to serious complications. However, to date, no high-risk patients have been identified for use of topical TXA. This study will look at thrombogenic markers (proteins found in blood that promote clot formation) after TXA is given either intravenously or topically. If the effect on these markers is similar between intravenous and topical use of TXA, then the safety of topical TXA should be questioned. Of note, these markers have never been measured after TXA has been given topically. As a result, this information would be important for the medical community.
Interventions
Sponsors
Hospital for Special Surgery, New York
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients undergoing primary unilateral total knee replacement with a participating surgeon * Patients aged 18-80
Exclusion criteria
* All patients on steroid therapy regardless of dose, duration, or treatment or those requiring stress-dose steroids preoperatively * Patients who will require postoperative use of Coumadin, Xarelto, or Plavix * Use of non-steroidal anti-inflammatory drugs (NSAIDs) within 1 week of surgery * Hypersensitivity to tranexamic acid * Renal dysfunction (Creatinine clearance \< 40 ml/min) * Hepatic dysfunction (AST or ALT 2x upper limit of normal) * Cardiac exclusions: coronary stent, history of myocardial infarction, positive stress test, atrial fibrillation, advanced coronary artery disease * Advanced chronic obstructive pulmonary disease or advanced interstitial lung disease * History of venous thromboembolism * Hypercoagulability (e.g. antiphospholipid syndrome, genetic hypercoagulability with or without prior venous thromboembolism) * History of stroke or transient ischemic attack
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | 4 hours after tourniquet release | Levels of PAP will be measured in peripheral blood and wound drainage at 4 hours after tourniquet release. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Levels of Tranexamic Acid | Intraoperative (before cementing), 1 hour after tourniquet release (TQR), 4 hours after tourniquet release(TQR) | — |
| Calculated Postoperative Blood Loss | Duration of inpatient hospital stay (average of 3 days) | — |
| Levels of Hemoglobin | 1 hour after tourniquet release, POD 1, POD 2 | — |
| Levels of Hematocrit | 1 hour after tourniquet release, POD 1, POD 2 | — |
| Constavac Blood Drainage | 4 hours after tourniquet release | A wound drain is connected to a Constavac system, which postoperatively collects, filters, and allows for reinfusion of the patient's own blood. Shed blood passes through an internal prefilter and is collected in a reservoir. |
| Incidence of Thrombosis (DVT/PE) | Postoperative day 14 (2 weeks after surgery) | — |
| Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | before cementing, 1 hour after tourniquet release, 4 hours after tourniquet release | Systemic PAP blood level measured at the following time points - Intraoperative - Before cementing, 1 hour after tourniquet release, 4 hours after tourniquet release |
| Time to Physical Therapy Discharge | During Hospital Stay | — |
| Length of Hospital Stay | Length of Hospital Stay | — |
| Levels of IL-6 in Blood | Intraoperative, 1 hour post Tourniquet Release (TQR), 4 hour post Tourniquet Release (TQR) | — |
| Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Intraoperative, 1 hour post Tourniquet Release (TQR) | Levels of PAP will be measured in peripheral blood and wound drainage |
| Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood | Intraoperative, 4 hour post Tourniquet Release (TQR) | The values for the wound blood levels are given as the count of patients who had a level above the threshold of \>3600 pmol/L. |
| Patients Who Had 1 Unit of Blood Transfusion Administered | Duration of inpatient hospital stay (average of 3 days) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Tranexamic Acid Patients will receive 1g tranexamic acid in 100mL solution intravenously in the operating room before inflation of the tourniquet. They will again receive the same IV solution in the post-anesthesia care unit, approximately 3 hours after the first solution was given. They will also receive a 75cc topical saline solution approximately 5 minutes before the tourniquet is released.
Intravenous tranexamic acid
Topical saline | 31 |
| Topical Tranexamic Acid Patients will receive 3g tranexamic acid in 75mL solution topically in the operating room, approximately 5 minutes before the tourniquet is released. It will sit for 5 minutes before the solution is suctioned off by the surgeon. They will also receive 2 intravenous saline solutions: one in the operating room before inflation of the tourniquet, and one in the post-anesthesia care unit 3 hours after the first solution was given.
Topical tranexamic acid
Intravenous saline | 32 |
| Total | 63 |
Baseline characteristics
| Characteristic | Intravenous Tranexamic Acid | Topical Tranexamic Acid | Total |
|---|---|---|---|
| Age, Continuous | 65.6 years STANDARD_DEVIATION 8.4 | 65.0 years STANDARD_DEVIATION 6.9 | 65.3 years STANDARD_DEVIATION 7.6 |
| ASA Grade (II/III) ASA II | 28 Participants | 32 Participants | 60 Participants |
| ASA Grade (II/III) ASA III | 3 Participants | 0 Participants | 3 Participants |
| BMI | 31.6 kg/m^2 STANDARD_DEVIATION 7.1 | 31.1 kg/m^2 STANDARD_DEVIATION 5.2 | 31.4 kg/m^2 STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 28 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Preoperative Hematocrit | 40.8 % STANDARD_DEVIATION 3.2 | 41.0 % STANDARD_DEVIATION 2.8 | 40.9 % STANDARD_DEVIATION 3 |
| Preoperative Hemoglobin | 135 g/dL STANDARD_DEVIATION 11 | 138 g/dL STANDARD_DEVIATION 11 | 136.4 g/dL STANDARD_DEVIATION 11.3 |
| Preoperative Platelet count | 241 platelets/uL STANDARD_DEVIATION 50 | 241 platelets/uL STANDARD_DEVIATION 60 | 241.0 platelets/uL STANDARD_DEVIATION 55.1 |
| Region of Enrollment United States | 31 participants | 32 participants | 63 participants |
| Sex: Female, Male Female | 20 Participants | 12 Participants | 32 Participants |
| Sex: Female, Male Male | 11 Participants | 20 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 32 |
| other Total, other adverse events | 0 / 31 | 0 / 32 |
| serious Total, serious adverse events | 0 / 31 | 0 / 32 |
Outcome results
Primary
Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis
Levels of PAP will be measured in peripheral blood and wound drainage at 4 hours after tourniquet release.
Time frame: 4 hours after tourniquet release
Population: A wound drain was not inserted in all patients - hence why wound blood was not able to be collected 4 hours post tourniquet release.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic PAP blood level 4 HR post TQR | 117.8 ug/L | Standard Deviation 478.9 |
| Intravenous Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Wound PAP Blood Level 4 HR post TQR | 1032 ug/L | Standard Deviation 354.4 |
| Topical Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic PAP blood level 4 HR post TQR | 1280.7 ug/L | Standard Deviation 646.5 |
| Topical Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Wound PAP Blood Level 4 HR post TQR | 1041.2 ug/L | Standard Deviation 365.8 |
Secondary
Calculated Postoperative Blood Loss
Time frame: Duration of inpatient hospital stay (average of 3 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Tranexamic Acid | Calculated Postoperative Blood Loss | 1237 mL |
| Topical Tranexamic Acid | Calculated Postoperative Blood Loss | 1405 mL |
Secondary
Constavac Blood Drainage
A wound drain is connected to a Constavac system, which postoperatively collects, filters, and allows for reinfusion of the patient's own blood. Shed blood passes through an internal prefilter and is collected in a reservoir.
Time frame: 4 hours after tourniquet release
Population: Some patients did not get a contavac drain put in hence the discrepancy in analysis population description.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Tranexamic Acid | Constavac Blood Drainage | 100 mL |
| Topical Tranexamic Acid | Constavac Blood Drainage | 170 mL |
Secondary
Incidence of Thrombosis (DVT/PE)
Time frame: Postoperative day 14 (2 weeks after surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Tranexamic Acid | Incidence of Thrombosis (DVT/PE) | 0 Participants |
| Topical Tranexamic Acid | Incidence of Thrombosis (DVT/PE) | 0 Participants |
Secondary
Length of Hospital Stay
Time frame: Length of Hospital Stay
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Tranexamic Acid | Length of Hospital Stay | 2.3 days |
| Topical Tranexamic Acid | Length of Hospital Stay | 3.0 days |
Secondary
Levels of Hematocrit
Time frame: 1 hour after tourniquet release, POD 1, POD 2
Population: The number in one or more rows differs from overall number analyzed because patients were either discharged early or there was a missing blood draw.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Hematocrit | 1 hour after tourniquet release | 33.6 % of red blood cells in blood | Standard Deviation 3.6 |
| Intravenous Tranexamic Acid | Levels of Hematocrit | POD1 | 35.6 % of red blood cells in blood | Standard Deviation 12 |
| Intravenous Tranexamic Acid | Levels of Hematocrit | POD2 | 31 % of red blood cells in blood | Standard Deviation 3.5 |
| Topical Tranexamic Acid | Levels of Hematocrit | 1 hour after tourniquet release | 33.8 % of red blood cells in blood | Standard Deviation 2.6 |
| Topical Tranexamic Acid | Levels of Hematocrit | POD1 | 31.5 % of red blood cells in blood | Standard Deviation 4 |
| Topical Tranexamic Acid | Levels of Hematocrit | POD2 | 29.8 % of red blood cells in blood | Standard Deviation 2.7 |
Secondary
Levels of Hemoglobin
Time frame: 1 hour after tourniquet release, POD 1, POD 2
Population: The number in one or more rows differs from overall number analyzed because patients were either discharged early or there was a missing blood draw.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Hemoglobin | POD2 | 10.28 g/dL | Standard Deviation 1.19 |
| Intravenous Tranexamic Acid | Levels of Hemoglobin | 1 hour after tourniquet release | 11.29 g/dL | Standard Deviation 1.21 |
| Intravenous Tranexamic Acid | Levels of Hemoglobin | POD1 | 11.12 g/dL | Standard Deviation 1.04 |
| Topical Tranexamic Acid | Levels of Hemoglobin | POD2 | 9.94 g/dL | Standard Deviation 1.03 |
| Topical Tranexamic Acid | Levels of Hemoglobin | 1 hour after tourniquet release | 11.41 g/dL | Standard Deviation 1.02 |
| Topical Tranexamic Acid | Levels of Hemoglobin | POD1 | 10.53 g/dL | Standard Deviation 0.13 |
Secondary
Levels of IL-6 in Blood
Time frame: Intraoperative, 1 hour post Tourniquet Release (TQR), 4 hour post Tourniquet Release (TQR)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of IL-6 in Blood | Systemic Level - 1 Hour Post TQR | 1.8 pg/mL | Standard Deviation 1.2 |
| Intravenous Tranexamic Acid | Levels of IL-6 in Blood | Wound Blood - Intraoperative (before cemeting) | 5.2 pg/mL | Standard Deviation 7.6 |
| Intravenous Tranexamic Acid | Levels of IL-6 in Blood | Systemic Level - 4 Hour Post TQR | 17.2 pg/mL | Standard Deviation 14.9 |
| Intravenous Tranexamic Acid | Levels of IL-6 in Blood | Wound Level - 4 Hour Post TQR | 5774.8 pg/mL | Standard Deviation 4360.7 |
| Intravenous Tranexamic Acid | Levels of IL-6 in Blood | Intraoperative (before cemeting) | 1.1 pg/mL | Standard Deviation 0.9 |
| Topical Tranexamic Acid | Levels of IL-6 in Blood | Wound Level - 4 Hour Post TQR | 4497.6 pg/mL | Standard Deviation 3325.5 |
| Topical Tranexamic Acid | Levels of IL-6 in Blood | Intraoperative (before cemeting) | 3.9 pg/mL | Standard Deviation 11.5 |
| Topical Tranexamic Acid | Levels of IL-6 in Blood | Systemic Level - 1 Hour Post TQR | 5 pg/mL | Standard Deviation 12.7 |
| Topical Tranexamic Acid | Levels of IL-6 in Blood | Systemic Level - 4 Hour Post TQR | 25.6 pg/mL | Standard Deviation 33.9 |
| Topical Tranexamic Acid | Levels of IL-6 in Blood | Wound Blood - Intraoperative (before cemeting) | 6.7 pg/mL | Standard Deviation 12.1 |
Secondary
Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis
Levels of PAP will be measured in peripheral blood and wound drainage
Time frame: Intraoperative, 1 hour post Tourniquet Release (TQR)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic Blood - Intraoperative (before cemeting) | 31.0 mg/L | Standard Deviation 15.2 |
| Intravenous Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic Level - 1 Hour Post TQR | 19.9 mg/L | Standard Deviation 8.3 |
| Intravenous Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Wound Blood - Intraoperative | 21.1 mg/L | Standard Deviation 11.2 |
| Topical Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic Blood - Intraoperative (before cemeting) | 3.9 mg/L | Standard Deviation 13.1 |
| Topical Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Systemic Level - 1 Hour Post TQR | 7.2 mg/L | Standard Deviation 7.4 |
| Topical Tranexamic Acid | Levels of Plasmin Anti-plasmin (PAP) - Marker of Fibrinolysis | Wound Blood - Intraoperative | 2.2 mg/L | Standard Deviation 9.2 |
Secondary
Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation
Systemic PAP blood level measured at the following time points - Intraoperative - Before cementing, 1 hour after tourniquet release, 4 hours after tourniquet release
Time frame: before cementing, 1 hour after tourniquet release, 4 hours after tourniquet release
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | Intraoperative (before cemeting) | 400.2 pmol/L | Standard Deviation 235.6 |
| Intravenous Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | 1 hour after tourniquet release | 661 pmol/L | Standard Deviation 243.5 |
| Intravenous Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | 4 hour after tourniquet release | 812.9 pmol/L | Standard Deviation 349.9 |
| Topical Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | Intraoperative (before cemeting) | 377.3 pmol/L | Standard Deviation 218.4 |
| Topical Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | 1 hour after tourniquet release | 636.2 pmol/L | Standard Deviation 241.6 |
| Topical Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation | 4 hour after tourniquet release | 868.8 pmol/L | Standard Deviation 336.2 |
Secondary
Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood
The values for the wound blood levels are given as the count of patients who had a level above the threshold of \>3600 pmol/L.
Time frame: Intraoperative, 4 hour post Tourniquet Release (TQR)
Population: Blood samples could not be collected at the 4-hour post tourniquet release for some patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood | Intraoperative (before cemeting) | 16 Participants |
| Intravenous Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood | 4 hour after tourniquet release | 13 Participants |
| Topical Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood | Intraoperative (before cemeting) | 14 Participants |
| Topical Tranexamic Acid | Levels of Prothrombin Fragment 1.2 (PF1.2) - Marker of Thrombin Generation in Wound Blood | 4 hour after tourniquet release | 11 Participants |
Secondary
Levels of Tranexamic Acid
Time frame: Intraoperative (before cementing), 1 hour after tourniquet release (TQR), 4 hours after tourniquet release(TQR)
Population: Blood was collected from the A-Line or CostaVac Drain. If no drain was placed, the wound 4 hour post TQR blood could not be collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - 1 Hour Post TQR | 19.9 mg/L | Standard Deviation 8.3 |
| Intravenous Tranexamic Acid | Levels of Tranexamic Acid | Wound Level - Intraoperative (before cemeting) | 21.1 mg/L | Standard Deviation 11.2 |
| Intravenous Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - 4 Hour Post TQR | 27.4 mg/L | Standard Deviation 13.7 |
| Intravenous Tranexamic Acid | Levels of Tranexamic Acid | Wound Level - 4 Hour Post TQR | 37.9 mg/L | Standard Deviation 16.1 |
| Intravenous Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - Intraoperative (before cemeting) | 31.0 mg/L | Standard Deviation 15.2 |
| Topical Tranexamic Acid | Levels of Tranexamic Acid | Wound Level - 4 Hour Post TQR | 31.4 mg/L | Standard Deviation 47 |
| Topical Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - Intraoperative (before cemeting) | 3.9 mg/L | Standard Deviation 13.1 |
| Topical Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - 1 Hour Post TQR | 7.2 mg/L | Standard Deviation 7.4 |
| Topical Tranexamic Acid | Levels of Tranexamic Acid | Systemic Level - 4 Hour Post TQR | 5.2 mg/L | Standard Deviation 8.8 |
| Topical Tranexamic Acid | Levels of Tranexamic Acid | Wound Level - Intraoperative (before cemeting) | 2.2 mg/L | Standard Deviation 9.2 |
Secondary
Patients Who Had 1 Unit of Blood Transfusion Administered
Time frame: Duration of inpatient hospital stay (average of 3 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Tranexamic Acid | Patients Who Had 1 Unit of Blood Transfusion Administered | 1 Participants |
| Topical Tranexamic Acid | Patients Who Had 1 Unit of Blood Transfusion Administered | 1 Participants |
Secondary
Time to Physical Therapy Discharge
Time frame: During Hospital Stay
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Tranexamic Acid | Time to Physical Therapy Discharge | 1.9 days |
| Topical Tranexamic Acid | Time to Physical Therapy Discharge | 2.9 days |