Osteoarthritis
Conditions
Keywords
tranexamic acid, enhanced recovery, arthroplasty, perioperative care
Brief summary
Total knee joint replacement surgery can lead to significant blood loss, which can affect recovery after surgery. Tranexamic acid (TXA) is a medication which stops the breakdown of blood clots and therefore prevents blood loss. The optimal use of TXA remains a point of debate. Growing interest in the topical application of TXA (directly into the surgical wound) has been suggested as an alternative way of administering TXA, and may demonstrate similar effectiveness as when it is given intravenously. Therefore, this multicentred, randomized controlled trial, aims to investigate the safety and effectiveness of both topical and intravenous administrations of TXA in total knee joint surgery. The investigators predict that both routes of administration will demonstrate similar results when compared to placebo.
Detailed description
Postoperative anaemia following elective arthroplasty can lead to prolonged hospital stay, delays in rehabilitation and is often poorly tolerated in patients with cardiovascular disease.(1) Tranexamic acid (TXA) in arthroplasty is used by many orthopaedic surgeons to reduce perioperative blood loss and subsequent transfusion of blood products in elective total hip and knee arthroplasty (THA and TKA). In several reviews, systemic TXA (sTXA) significantly reduces blood loss and transfusion rates when compared to placebo, without an increased risk for venous thromboembolism (VTE).(2-4) The CRASH-2 study, with over 20,000 randomised trauma patients, has also confirmed the efficacy and safety of TXA in this setting, particularly when given early.(5) The evidence for its use to date is overwhelming and when not contraindicated, should be employed by all arthroplasty units as part of their standard practice. However, despite the vast evidence for its use in arthroplasty some surgeons remain cautious over its safety profile when given systemically. TXA is a synthetic derivative of lysine which is responsible for binding reversibly to plasminogen effectively inhibiting clot degradation.(6) Although, this is not clot promoting, inhibiting clot breakdown theoretically may increase the likelihood of clot formation. This is of real concern for surgeons in patients who have had previous VTE. For this reason, some surgeons have utilised TXA as a topical application directly into the surgical field to reduce systemic absorption and avoid VTE.(7, 8) TXA administered topically in TKA has also been reported to reduce swelling which may have the advantage of earlier mobility and less pain.(9) In cardiac surgery, TXA has been touted as not only having blood conserving properties via the coagulation pathway but also reduces inflammation via attenuation of the pro-inflammatory cascade.(10, 11) Based on this rationale, this appears to be a sensible and reasonable route of administration for TXA in this population. However, surgeons should ensure they avoid placing undue risk on patients by altering their use of TXA given the strong evidence for sTXA. Therefore, the purpose of this study is to assess whether topical TXA is effective in reducing blood loss in knee joint replacement surgery, and is as safe and as effective as systemic TXA.
Interventions
DRUGTranexamic Acid
Given intravenously or topically
DRUGNormal saline (0.9% NaCl)
Administered in all 3 groups
Sponsors
Andrew G Hill, MBChB, MD (Thesis), EdD, FACS, FRACS
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 No maximum
Healthy volunteers
Yes
Inclusion criteria
* All patients at the participating sites on the waiting list for a unilateral total knee joint replacement
Exclusion criteria
* Patients with a history or risk of thrombosis * Active thromboembolic disease such as deep vein thrombosis, pulmonary embolism and cerebral thrombosis * Subarachnoid haemorrhage * Hypersensitivity to tranexamic acid or any of its ingredients. * Refusal of blood products * Colour blindness * Complex hematologic disorders requiring manipulation * Coagulopathy * Pregnant and Lactating Women * Anti-coagulant therapy pre-operatively within 5 days of surgery (warfarin, dabigatran, heparin) * Severe renal failure (eGFR \<29)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Loss | Post operative day 3 | The loss of haemoglobin (Hb) was then estimated according to the formula: Hb(loss) = Blood volume (BV) x (Hbi-Hbe) x 0.001+Hbt where Hb (loss) (g) is the amount of Hb lost, Hbi (g/L) the Hb concentration before surgery, Hbe (g/L) is the Hbe concentration on the third day after surgery, and Hbt (g) is the total amount of allogeneic Hb transfused. A unit of banked blood is considered to contain a minimum of 40g Hb (Blood component data sheet, New Zealand Blood Services \[NZBS\]). All units of blood are processed and stored in a nationally standardised manner. The blood loss (ml) was related to the patient's preoperative Hb value (g/L): Blood loss =1000 x Hb(loss) /Hbi |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Receiving Allogenic Blood Transfusion | Participants will be followed for the duration of their hospital stay expected to be an average of 3-5 days | Those patients receiving blood products. Standardised protocol is as follows: The criterion for transfusion of blood products will be a haemoglobin \< 80g/L or a haemoglobin \<100g/L in a patient with ischaemic heart disease or with significant symptomatology |
| Length of Stay (LOS) | Average length of stay is expected to be 3 to 5 days | Day of surgery is counted as Day 0. |
| Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | Postoperatively within 30 days after surgery | Rates of deep vein thrombosis (DVT) and pulmonary embolus (PE) in each group recorded as a percentage |
| Range of Active Flexion | Days 1-3 | Range of motion measured in degrees on postoperative days 1-3 |
| Perioperative Fluid Administration | Day 1 | Intravenous fluid (excluding blood transfusion) given during and first 24 hours after surgery |
| Range of Passive Flexion | Days 1-3 | Range of motion measured in degrees for postoperative days 1 to 3 |
Countries
New Zealand
Participant flow
Recruitment details
The hospital databases will be searched for eligible patients on the waiting list for unilateral total knee joint replacement. Patients will be approached in the preadmission clinics and then consented on the day of surgery. Recruitment period is to be over 2 years or sooner once we have recruited the final patient (n=150)
Pre-assignment details
Patients were excluded after consenting to participate, if they failed to receive spinal anaesthesia.
Participants by arm
| Arm | Count |
|---|---|
| Control Application of 20ml of normal saline (NaCl 0.9%) topically after implantation of prosthesis; application of 15ml of normal saline intravenously at the same time prior to release of tourniquet.
Normal saline (0.9% NaCl): Administered in all 3 groups | 23 |
| Intraarticular Application of 1.5g in 20ml tranexamic acid topically after implantation of prosthesis; application of 15ml of normal saline intravenously at the same time prior to release of tourniquet.
Tranexamic Acid: Given intraarticularly
Normal saline (0.9% NaCl): Administered in all 3 groups | 60 |
| Systemic Application of 20ml of normal saline topically after implantation of prosthesis; Application of tranexamic acid intravenously (1.5g/15ml) at the same time prior to release of tourniquet
Tranexamic Acid: Given intravenously
Normal saline (0.9% NaCl): Administered in all 3 groups | 51 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 7 | 0 | 9 |
Baseline characteristics
| Characteristic | Control | Intraarticular | Systemic | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 45 Participants | 40 Participants | 102 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 15 Participants | 11 Participants | 32 Participants |
| Age, Continuous | 69.67 years STANDARD_DEVIATION 7.75 | 69.72 years STANDARD_DEVIATION 8.85 | 70.79 years STANDARD_DEVIATION 8.61 | 70.12 years STANDARD_DEVIATION 8.53 |
| Body Mass Index | 32.3 kg/m^2 STANDARD_DEVIATION 6.6 | 31.2 kg/m^2 STANDARD_DEVIATION 5.5 | 31.2 kg/m^2 STANDARD_DEVIATION 5.5 | 31.3 kg/m^2 STANDARD_DEVIATION 5.7 |
| Preoperative Hb | 134 grams/L STANDARD_DEVIATION 11.8 | 138 grams/L STANDARD_DEVIATION 12.2 | 138 grams/L STANDARD_DEVIATION 10.6 | 137 grams/L STANDARD_DEVIATION 11.5 |
| Preop Hb (number of days prior to surgery date) | 28 days STANDARD_DEVIATION 34 | 39 days STANDARD_DEVIATION 40 | 28 days STANDARD_DEVIATION 34 | 31 days STANDARD_DEVIATION 33 |
| Region of Enrollment New Zealand | 23 participants | 60 participants | 51 participants | 134 participants |
| Sex: Female, Male Female | 19 Participants | 32 Participants | 24 Participants | 75 Participants |
| Sex: Female, Male Male | 4 Participants | 28 Participants | 27 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 23 | 4 / 60 | 5 / 51 |
| serious Total, serious adverse events | 0 / 23 | 2 / 60 | 1 / 51 |
Outcome results
Primary
Blood Loss
The loss of haemoglobin (Hb) was then estimated according to the formula: Hb(loss) = Blood volume (BV) x (Hbi-Hbe) x 0.001+Hbt where Hb (loss) (g) is the amount of Hb lost, Hbi (g/L) the Hb concentration before surgery, Hbe (g/L) is the Hbe concentration on the third day after surgery, and Hbt (g) is the total amount of allogeneic Hb transfused. A unit of banked blood is considered to contain a minimum of 40g Hb (Blood component data sheet, New Zealand Blood Services \[NZBS\]). All units of blood are processed and stored in a nationally standardised manner. The blood loss (ml) was related to the patient's preoperative Hb value (g/L): Blood loss =1000 x Hb(loss) /Hbi
Time frame: Post operative day 3
Population: The number provided here for each group are those patients analyzed after patients had been excluded due to breaches in the study protocol. As stated in the power calculation for this primary outcome, an attrition rate of 15% (ie breaches in study protocol, drop out etc) had been accounted for. Hence the discrepancy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Blood Loss | 1090 mls | Standard Deviation 589 |
| Intraarticular | Blood Loss | 716 mls | Standard Deviation 377 |
| Systemic | Blood Loss | 746 mls | Standard Deviation 321 |
Comparison: Assuming a common standard deviation of 412 mL, to detect a difference of 300 mL of blood loss between the two treatment arms (sTXA and tTXA) and the placebo group, a sample size of 125 participants is required for a statistical power of 0.85, and a type I error of 0.05. The sample size required was 125 participants in total. The was increased by 15% to allow for expected dropouts. Therefore, a minimum of 147 patients was required for the study.p-value: <0.05ANOVA
Secondary
Length of Stay (LOS)
Day of surgery is counted as Day 0.
Time frame: Average length of stay is expected to be 3 to 5 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Length of Stay (LOS) | 4 days |
| Intraarticular | Length of Stay (LOS) | 4 days |
| Systemic | Length of Stay (LOS) | 4 days |
Secondary
Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease
Rates of deep vein thrombosis (DVT) and pulmonary embolus (PE) in each group recorded as a percentage
Time frame: Postoperatively within 30 days after surgery
Population: Logistic regression for categorical/binary outcomes
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | DVT | 0 Participants |
| Control | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | PE | 0 Participants |
| Intraarticular | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | DVT | 0 Participants |
| Intraarticular | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | PE | 2 Participants |
| Systemic | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | DVT | 0 Participants |
| Systemic | Number of Participants Experiencing Symptomatic Venothromboembolic (VTE) Disease | PE | 1 Participants |
Secondary
Number of Participants Receiving Allogenic Blood Transfusion
Those patients receiving blood products. Standardised protocol is as follows: The criterion for transfusion of blood products will be a haemoglobin \< 80g/L or a haemoglobin \<100g/L in a patient with ischaemic heart disease or with significant symptomatology
Time frame: Participants will be followed for the duration of their hospital stay expected to be an average of 3-5 days
Population: Logistic regression for binary outcomes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants Receiving Allogenic Blood Transfusion | 2 Participants |
| Intraarticular | Number of Participants Receiving Allogenic Blood Transfusion | 1 Participants |
| Systemic | Number of Participants Receiving Allogenic Blood Transfusion | 0 Participants |
Secondary
Perioperative Fluid Administration
Intravenous fluid (excluding blood transfusion) given during and first 24 hours after surgery
Time frame: Day 1
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Perioperative Fluid Administration | 1765 mls |
| Intraarticular | Perioperative Fluid Administration | 1613 mls |
| Systemic | Perioperative Fluid Administration | 1807 mls |
Secondary
Range of Active Flexion
Range of motion measured in degrees on postoperative days 1-3
Time frame: Days 1-3
Population: Range of active flexion measured and the data presented here represent the average active flexion with SD.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Range of Active Flexion | Day 2 | 71 degrees | Standard Deviation 15 |
| Control | Range of Active Flexion | Day 1 | 57 degrees | Standard Deviation 23 |
| Control | Range of Active Flexion | Day 3 | 75 degrees | Standard Deviation 11 |
| Intraarticular | Range of Active Flexion | Day 2 | 75 degrees | Standard Deviation 14 |
| Intraarticular | Range of Active Flexion | Day 1 | 65 degrees | Standard Deviation 18 |
| Intraarticular | Range of Active Flexion | Day 3 | 82 degrees | Standard Deviation 12 |
| Systemic | Range of Active Flexion | Day 1 | 58 degrees | Standard Deviation 16 |
| Systemic | Range of Active Flexion | Day 3 | 78 degrees | Standard Deviation 16 |
| Systemic | Range of Active Flexion | Day 2 | 72 degrees | Standard Deviation 16 |
Secondary
Range of Passive Flexion
Range of motion measured in degrees for postoperative days 1 to 3
Time frame: Days 1-3
Population: Range of passive flexion measured and the data presented here are the averages with standard deviations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Range of Passive Flexion | Day 2 | 76 degrees | Standard Deviation 15 |
| Control | Range of Passive Flexion | Day 1 | 65 degrees | Standard Deviation 28 |
| Control | Range of Passive Flexion | Day 3 | 82 degrees | Standard Deviation 13 |
| Intraarticular | Range of Passive Flexion | Day 2 | 81 degrees | Standard Deviation 13 |
| Intraarticular | Range of Passive Flexion | Day 1 | 74 degrees | Standard Deviation 15 |
| Intraarticular | Range of Passive Flexion | Day 3 | 87 degrees | Standard Deviation 11 |
| Systemic | Range of Passive Flexion | Day 1 | 68 degrees | Standard Deviation 15 |
| Systemic | Range of Passive Flexion | Day 3 | 87 degrees | Standard Deviation 13 |
| Systemic | Range of Passive Flexion | Day 2 | 80 degrees | Standard Deviation 13 |