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Over 1.7 million hip and knee replacements are performed every year worldwide. These surgeries are associated with high blood loss and transfusion rates. In older patients, the high blood loss can result in postoperative anemia. Anemia is a condition where there is a lack of healthy red blood cells to carry oxygen around the body. This means, the patient may need a blood transfusion. This can result in different immune responses such as lung injury, fluid overload, and sepsis.
The purpose of this study is to find an optimal dose of tranexamic acid (TXA) to be given during a hip or knee replacement surgery. TXA is one of the drugs given during surgery because it lowers the amount of bleeding and the risk of a blood transfusion.
Individuals who are chosen to participate in the study will be split into two separate groups. After anesthesia is administered, study participant will be given the hospitals standard dose of TXA which is 20mg/kg. However, in patients with kidney problems and lower kidney functions, the dose will be lowered because TXA is filtered out of the body through the kidneys. Throughout the surgery and after it, patients will have about 30-50mL (3-5 tablespoons) of blood samples drawn at specific time points. This will be done through IV line which will stay in place during the surgery and post operation to minimize the amount of needle puncturing's.
This study will help to development a new dosing guideline for TXA in patients who are undergoing joint replacement surgery.
Our study follows a prospective cohort study design without randomization or blinding. 20 patients undergoing unilateral hip or knee replacement will be recruited and stratified into 2 groups (each with 10 patients) with either glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (and dialysis) or GFR ≥ 60 mL/min/1.73m2. This GFR cut-off was chosen based on previous data showing low variability at GFR below and above 60, and plasma TXA levels differed due to reduction in TXA clearance rates between patients in each group.
After spinal/regional or general anesthesia, a single intravenous bolus of 20 mg/kg TXA will be administered (as per our standard of care) over 15 minutes. Serial 4-5 ml blood samples will be drawn at: baseline/pre-TXA administration, 5 min, 15 min, 30 min, 1h, 1.5h, 2h, 6h+/-2h and 12h+/-4h post-bolus. These time points capture 2-3 TXA half-lives, including peak and end of surgery (average 2 h) concentrations.
Each blood sample will be collected into standard citrate collection tubes. Tubes will be inverted a minimum of 5 times to ensure proper mixing with anti-coagulant (sodium citrate). Each sample will be labeled with an anonymized patient study number (to de-identify patient information) and sample time. The tubes will be stored on ice bath following sample collection and then centrifuged within 2 hours at 2000g for about 15 min at 4˚C. The subsequent supernatant will be frozen and stored at -70˚C until analyzed. Measurement of TXA and other drug concentrations, renal biomarkers and metabolomics will be performed using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) using previously described methodology. Patients will otherwise receive routine perioperative care. Patient follow up will be to hospital discharge.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group I | Experimental | Participants with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (and dialysis) |
|
| Group II | Experimental | Participants with GFR ≥ 60 mL/min/1.73m2 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tranexamic acid | Drug | Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Plasma TXA Concentration - Total Body Clearance | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
| Blood Plasma TXA Concentration - Area Under the Concentration-time Curve | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
| Blood Plasma TXA Concentration - Elimination Rate Constant | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
| Blood Plasma TXA Concentration - Volume of Central Compartment | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
| Blood Plasma TXA Concentration - Steady State Volume of Distribution |
| Measure | Description | Time Frame |
|---|---|---|
| Intraoperative Blood Loss and Transfusion | intraoperative measurement of blood loss | Assessed intraoperatively on the day of surgery |
| % Change in Pre- and Postoperative Hemoglobin | perioperative value of hemoglobin. The % change is calculated as the postoperative hemoglobin minus preoperative hemoglobin, and reported as a percentage of pre-operative hemoglobin. Negative values indicate a reduction in hemoglobin. |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Angela Jerath | Sunnybrook Health Sciences Centre | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sunnybrook Health Sciences Centre | Toronto | Ontario | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39878614 | Derived | Yang Q, He J, Peng HB, Wen B, Idestrup C, Ravi B, Murnaghan J, McCarron A, Hadley H, Shin H, Kaustov L, Wong J, Lin Y, Choi S, Orser BA, Van Der Vyver M, Safa B, Pang KS, Jerath A. Tranexamic Dosing for Major Joint Arthroplasty in Adult Patients with Chronic Kidney Disease: A Pharmacokinetic Study and New Dosing Regimen. Anesthesiology. 2025 May 1;142(5):863-873. doi: 10.1097/ALN.0000000000005397. Epub 2025 Jan 29. |
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All de-identified participants data collected during this trial that underlie the results reported in the publication(s) will be available upon request after publication of the primary results.
Data will be available upon request immediately after publication of the primary results. No end date.
Direct request to PI. Anyone who wishes to access the data.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group I | Participants with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (and dialysis) Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
| FG001 | Group II | Participants with GFR ≥ 60 mL/min/1.73m2 Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Group I | Participants with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (and dialysis) Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Blood Plasma TXA Concentration - Total Body Clearance | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Posted | Mean | Standard Deviation | mL/min | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
|
Baseline until hospital discharge (up to 7 days after surgery)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group I | Participants with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (and dialysis) Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Angela Jerath | Sunnybrook Health Sciences Centre | 416-480-4864 | angela.jerath@sunnybrook.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 28, 2021 | Feb 24, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014148 | Tranexamic Acid |
| ID | Term |
|---|---|
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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The main objective of this prospective observational study is to assess TXA blood concentrations in patients requiring major arthroplasty surgery with varied preoperative renal function. We will use this information to create new dosing guidelines for patients undergoing major arthroplasty surgery.
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Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. |
| Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
| Perioperative |
| Postoperative Creatinine | postoperative value of creatinine | Collected within 24 hours after surgery |
| Postoperative eGFR | postoperative value of the estimated glomerular filtration rate | Collected within 24 hours after surgery |
| In-hospital Mortality | death occurring during the hospital stay | Baseline until hospital discharge (up to 7 days after surgery) |
| Hospital Length of Stay | duration of hospitalization | Baseline until hospital discharge (up to 7 days after surgery) |
| Group II |
Participants with GFR ≥ 60 mL/min/1.73m2 Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Weight | Median | Inter-Quartile Range | Kilograms |
|
| eGFR | Median | Inter-Quartile Range | mL/min/1.73 m^2 |
|
| Surgery type | Count of Participants | Participants |
|
| Group II |
Participants with GFR ≥ 60 mL/min/1.73m2 Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. |
|
|
| Secondary | Intraoperative Blood Loss and Transfusion | intraoperative measurement of blood loss | Posted | Median | Inter-Quartile Range | mL | Assessed intraoperatively on the day of surgery |
|
|
|
| Secondary | % Change in Pre- and Postoperative Hemoglobin | perioperative value of hemoglobin. The % change is calculated as the postoperative hemoglobin minus preoperative hemoglobin, and reported as a percentage of pre-operative hemoglobin. Negative values indicate a reduction in hemoglobin. | Posted | Mean | Standard Deviation | % decrease | Perioperative |
|
|
|
| Secondary | Postoperative Creatinine | postoperative value of creatinine | Posted | Median | Inter-Quartile Range | umol/L | Collected within 24 hours after surgery |
|
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| Secondary | Postoperative eGFR | postoperative value of the estimated glomerular filtration rate | Posted | Median | Inter-Quartile Range | ml/min/1.72 m^2 | Collected within 24 hours after surgery |
|
|
|
| Secondary | In-hospital Mortality | death occurring during the hospital stay | Posted | Count of Participants | Participants | Baseline until hospital discharge (up to 7 days after surgery) |
|
|
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| Secondary | Hospital Length of Stay | duration of hospitalization | Posted | Median | Inter-Quartile Range | hours | Baseline until hospital discharge (up to 7 days after surgery) |
|
|
|
| Primary | Blood Plasma TXA Concentration - Area Under the Concentration-time Curve | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Posted | Mean | Standard Deviation | (mg/L)h | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
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| Primary | Blood Plasma TXA Concentration - Elimination Rate Constant | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Posted | Mean | Standard Deviation | /min | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
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| Primary | Blood Plasma TXA Concentration - Volume of Central Compartment | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Posted | Mean | Standard Deviation | L | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
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| Primary | Blood Plasma TXA Concentration - Steady State Volume of Distribution | Measurement of serial blood plasma TXA concentration to build a pharmacokinetic model and dosing regimens for patients within both groups. Curve-stripping of the plasma TXA concentration data according to the 2-compartment model was used to calculate a single value for the measure per participant, which was then averaged. | Posted | Mean | Standard Deviation | L | Collected at 5/15/30/60/90/180/360/540 minutes after bolus |
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| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Group II | Participants with GFR ≥ 60 mL/min/1.73m2 Tranexamic acid: Participants in both groups will be given single intravenous bolus of TXA 20 mg/kg over 15 min after induction of spinal (or other regional technique) or general anesthesia as per standard of care. | 0 | 11 | 0 | 11 | 0 | 11 |
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