Clinical trial NCT03690037: Investigating the Effect of Intravenous and Oral Tranexamic Acid on Blood Loss After Primary Hip and Knee Arthroplasty
Official title: Single Centre Randomised Controlled Trial to Assess the Effect of the Addition of Twenty-four Hours of Oral Tranexamic Acid Post-operatively to a Single Intra-operative Intravenous Dose of Tranexamic Acid on Calculated Blood Loss Following Primary Hip and Knee Arthroplasty.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Primary Total Knee Arthroplasty
Primary Total Hip Arthroplasty
Keywords: Tranexamic Acid
Lead sponsor: Belfast Health and Social Care Trust
Sponsor class: OTHER
First posted: 2018-10-01
Enrollment: 1089
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A Phase IV, single centred, open label, parallel group, randomised controlled trial
Primary purpose: TREATMENT

Brief summary: Patients having a hip or knee replacement can lose almost a third of their blood during and after the operation. Many patients, especially those who are older will need a blood transfusion, suffer from anaemia, or have a slow recovery after the operation. Tranexamic acid is a medication used to treat or prevent excessive blood loss, but in joint replacements, is only used in patients who are likely to bleed a lot. This trial aims to find out how well tranexamic acid works to reduce blood loss after the operation in a large group of patients having a hip or knee replacement, including those at risk of blood clots. This study also aims to find out how safe tranexamic acid treatment is to use in different patients and the best way to give tranexamic acid (in tablet form or through a drip), as well as how much to give and how long it should be given after an operation. All adults awaiting non-emergency hip or knee replacement surgery will be considered.

Patients who are suitable and agree to take part are randomly placed in one of two treatment groups: receiving tranexamic acid during the hip or knee operation through a drip, or receiving treatment during the hip or knee operation through a drip plus taking a tablet every 8 hours up to 24 hours after the operation. Initially, a no treatment group was included, however, one year after the trial started, the Data Monitoring and Ethics Committee who check safety, advised to stop allocation of patients to the no treatment group.

For all patients, blood loss is recorded up to 48 hours after surgery. Blood samples are also taken in order to measure how well the heart and blood clotting systems are working. If the routine kidney function tests taken before the operation show less than normal function, a lower dose of tranexamic acid is used.

It is expected that patients who receive the tranexamic acid will lose much less blood during and after their operation, and so be less likely to need a blood transfusion, have reduced stress on the heart and have an easier recovery. It is thought that patients with a history of clots are more likely to have another clot when taking tranexamic acid. Therefore, this trial will include these patients to try and find out if this is true as these patients will benefit the most from reduced blood loss.

Detailed description: Although numerous studies have demonstrated efficacy in using tranexamic acid (TXA) in primary hip and knee arthroplasty, it has not yet become a recognised standard of care in the United Kingdom (UK). In part, this is because trials to date have excluded many of the patients who could most benefit from a reduced peri-operative blood loss. This trial aims to maximize the potential of TXA by continuing administration post-operatively, at the time of greatest loss. In doing so, the aim is to establish a standardised protocol that can be adopted by other units. Also, despite any published evidence and the excellent safety profile of TXA, there have been concerns about a potential increased risk of venous thrombo-embolism (VTE) which in itself has been a contentious issue in the UK. The exclusion criteria have been adapted in this trial to address these safety concerns.This trial will contribute to establishing the effect of TXA on perioperative blood loss.

Reducing blood loss after hip and knee arthroplasty helps patients avoid anaemia and allogenic blood transfusion with their incumbent risks. TXA is effective intravenously and topically at reducing perioperative bleeding in various surgeries, the evidence in joint arthroplasty is compelling with calculated blood losses reduced by 30% and the need for a transfusion by 50%. However, it remains unclear as to whether extending a dosing regime of TXA beyond the immediate perioperative period would lead to further reductions in blood loss. Oral TXA would be a cheaper and less labour intensive mode of delivery post-operatively than either intravenous bolus or intravenous infusion regimes.

Patients undergoing joint arthroplasty are often elderly with co-morbidities; this frailty makes them particularly vulnerable to the adverse effects of major blood loss. Reducing bleeding in this group is likely to be particularly beneficial to patient outcomes.The majority of blood loss occurs in the first 24 hours post-operatively. A dosing regimen of intravenous TXA eight hourly for twenty-four hours has been suggested. Replacing this with an oral dose would be cheaper, less labour intensive for nursing staff and less disruptive for patients. One gram of oral TXA given 8 hourly for four doses following arthroplasty is consistent with prescribing guidance in the Summary of Product Characteristics (SPC) for local fibrinolysis.There is no evidence in the context of joint replacements to favour either 8 hourly or 6 hourly dosing. Both are licensed regimens as per SPC and therefore an 8 hourly regime is considered less intrusive to the patient.

Intravenous (IV) TXA has an elimination half-life of 3 hours (almost completely excreted unchanged in urine). Five hours after a dose of 10mg/kg IV bolus, the serum level is 5µg/L and it is thought that a level of 10µg/L provides 80% inhibition of fibrinolysis and is considered clinically effective. Oral TXA has a peak level 2 hours following ingestion. By administering the dose in the recovery ward 2 hours following knife to skin (KTS), this will give its peak effect just over 4 hours after the IV dose is administered in both hip and knee arthroplasty.

The aim is to minimise sub therapeutic TXA levels at the time of the highest bleeding risk. Nilsson (1987) noted that after total hip arthroplasty (THA), blood loss from drains was lower following a single 10mg/kg bolus intra-operatively in the first 2 hours but that the drain outputs then equilibrated between the TXA group and the control group after that for the following 10 hours. This supports the current hypothesis that administering further doses of TXA early post-operatively could further reduce blood loss. Also it will be easier to ensure accurate time of the first dose administration in recovery rather than on the ward due to greater staff availability.

This study initially used two tranexamic acid intervention groups (Groups 1 \& 2) and one no treatment comparator group (Control Group 3). Although the benefits of using TXA in elective hip and knee arthroplasty to reduce blood loss has been shown, it has not become standard of care in the UK and hence the initial need for the Control Group 3. Following an interim analysis, it was recommended to stop randomisation to Control Group 3.

In addition, this study will incrementally contribute to the growing data relating to use of TXA in patients with a history of VTE. However, to definitively determine what impact TXA has on VTE in the peri-operative period would require a large appropriately powered multi-centre study.

Study Aim and Objectives

This is a Phase IV, single centred, open label, parallel group, randomised controlled trial involving primary hip and knee arthroplasty patients.

The overall aim of this study is to reduce blood loss in THA and Total Knee Arthroplasty (TKA) patients using TXA. While TXA has been shown to reduce blood loss in THA/TKA patients, the optimum method of delivery, optimum number of doses and optimum period of use is not clear. A previous audit of patients under the care of the Chief Investigator demonstrated that 5/6 of the blood loss occurs post wound closure. Therefore, hypothetically if TXA is given to a patient for over 24 hours following surgery it should further reduce blood loss as compared to TXA dosing in the immediate peri-operative period.

-Primary Objective: The primary objective is to determine if the use of oral TXA post-operatively for up to 24 hours will confer a reduction in the calculated blood loss at 48 hours beyond an intra-operative intravenous bolus alone for patients undergoing unilateral primary total hip or knee replacement.

-Secondary Objective: The secondary objective is to determine if the addition of oral TXA post-operatively to an intra-operative intravenous bolus of TXA produces any change in other measurable parameters as compared to those observed either with an intra-operative intravenous bolus alone or no TXA for patients undergoing unilateral primary THA/TKA.

While this study is not powered to answer questions such as whether the use of TXA can lower complications, it is important that complications are reported on. If it was found that using TXA increased the number of complications, this would be a clinically important outcome which should be reported.

Eligible participants were initially allocated to Intervention Group 1 (IV TXA peri-operatively plus 1g oral TXA every 8hrs for up to 24hrs), Intervention Group 2 (IV TXA peri-operatively) or Control Group 3 (standard care) with an allocation ratio of 2:2:1.

Patients with a renal impairment receive a reduced dose dependent on pre-operative serum creatinine.

Following the interim analysis it was recommended to stop randomisation to Control Group 3. Eligible participants are allocated to Intervention Group 1 or Intervention Group 2 with an allocation ratio of 1:1.

Anaesthetists, surgeons, other theatre, recovery and ward staff will not be blinded to the treatment, nor will the study investigators or the patient themselves.

However, the number of patients falling below the transfusion trigger will be blinded.The transfusion trigger will be set as per standardised protocol after consent and prior to randomisation. Therefore, the decision about whether or not to transfuse will not be blinded but the transfusion trigger will be blinded.

Staff in an off-site laboratory who are processing the blood samples will be blinded to the treatment Group allocation.

The TRAC-24 trial initially required a minimum of 1166 patients to be recruited. Recruitment was due to stop when 583 participants had been recruited for both the TKA and THA patients. However, following the interim analysis, randomisation of patients to Control Group 3 was stopped. Recruitment will now continue until a minimum of 932 patients, comprising of 466 TKA and 466 THA, is reached.

Eligibility criteria: Inclusion Criteria:

1. Awaiting primary elective hip or knee replacement
2. ≥ 18 years of age and ≤100 years

Exclusion Criteria:

1. Patients who do not pass a pre-operative assessment for elective total hip or knee arthroplasty (THA/TKA)
2. Fractured neck of femur
3. Haemophiliac or coagulation disorders that require TXA
4. Allergy to tranexamic acid or any of its excipients
5. Platelets less than 75,000/mm3 at pre-operative assessment\*
6. Patients on active treatment for venous thromboembolism (VTE) (deep vein thrombosis (DVT), pulmonary embolisms (PE)) within 6 months of surgery\*
7. History of VTE within 6 months of surgery\*
8. Patients who have had a myocardial infarction (MI) within 12 months\*
9. Cardiac stent within 12 months of surgery\*
10. Patients who have had a stroke (cerebrovascular accident (CVA)) or transient ischemic attack (TIA) within 9 months of surgery\*
11. Use of antiplatelet medication within 7 days of surgery\* (Does not include aspirin if dose \<300mg).
12. Direct thrombin inhibitors within 2 days of surgery\*
13. Factor Xa inhibitors within 2 days of surgery\*
14. The International normalized ratio (INR) level is greater than or equal to 1.5 in a patient who has stopped warfarin in preparation for surgery
15. Hepatic failure\*
16. Patients with epilepsy
17. Patients requiring therapeutic anticoagulation post-operatively e.g. Metallic heart valves.
18. Pregnant women, women who have not yet reached the menopause (no menses for ≥ 12 months without an alternative medical cause) who test positive for pregnancy or are unwilling to take a pregnancy test prior to trial entry
19. Patients who have been using Combined hormonal contraception (which includes combined oral contraception (COC), combined contraceptive transdermal patch and vaginal ring) within 4 weeks of surgery\*.
20. Female patients who are breastfeeding
21. Treated with any other investigational medication or device within 60 days
22. Patients unable to provide informed consent
23. Patients who are unable or unwilling to commit to the study schedule of events
24. Patients unwilling to provide informed consent
25. Patients who present for simultaneous bilateral THA or TKA
26. Patients who are on renal dialysis and have an arteriovenous (AV) fistula
27. Patients who previously have been enrolled in this study

    * These are patients with contra-indications to primary hip or knee replacement.

Primary outcomes:
measure: Total Indirect blood loss
timeFrame: At 48 hours
Secondary outcomes:
measure: Incidence of Post-operative haemoglobin falling below the transfusion trigger
timeFrame: Prior to discharge, up to 48 hours
measure: Effect of body mass index (BMI) on the volume of indirect blood loss
timeFrame: At 48 hours post-surgery
measure: Change in c-reactive protein
timeFrame: Pre-surgery to 48 hours post-surgery
measure: Change in Creatinine level
timeFrame: pre-surgery to 48 hours post-surgery
measure: Mortality
timeFrame: 90 days and 1 year post surgery
Other outcomes:
measure: Comparison of intra-operative blood loss between the groups
timeFrame: At 48 hours post surgery
measure: Number of wound dressing changes in the 48 hours post surgery
timeFrame: 48 hours post-surgery
measure: The number of requests for Post-operative Troponin levels prior to discharge
timeFrame: Tested prior to discharge up to Day 4 post-operative
measure: Length of hospital stay after surgery
timeFrame: Up to 30 days
measure: Incidence of allogenic blood transfusion prior to discharge from hospital
timeFrame: Tested prior to discharge up to Day 4 post-operative
measure: Incidence of allogenic blood transfusion within 90 days of surgery
timeFrame: 90 days post-surgery
measure: Incidence of post-operative haemoglobin falling below transfusion trigger without patient being transfused up until time of discharge
timeFrame: Up to Day 4 post-operative
measure: Incidence of post-operative arrhythmia within 90 days of surgery
timeFrame: within 90 days of surgery
measure: Incidence of Pulmonary Embolism (PE) within 90 days of surgery
timeFrame: within 90 days of surgery
measure: Incidence of proximal Deep Vein Thrombosis (DVT) within 90 days of surgery
timeFrame: within 90 days of surgery
measure: Incidence of myocardial infarction within 90 days of surgery
timeFrame: 90 days post-surgery
measure: Incidence of stroke within 90 days of surgery
timeFrame: 90 days post-surgery
measure: Number of emergency hospital admissions or unplanned critical care admissions within 90 days of surgery
timeFrame: 90 days post-surgery
measure: Number of returns to theatre for wound problems within 90 days of surgery
timeFrame: 90 days post-surgery
measure: Difference in indirect blood loss at 48 hours between patients on aspirin as a VTE prophylaxis compared with those on clexane
timeFrame: at 48 hours
measure: Difference in indirect blood loss at 48 hours between patients placed in flexion in a knee jig for 6 hours post-operatively as opposed to those placed in flexion on a pillow
timeFrame: at 48 hours
measure: Difference in indirect blood loss at 48 hours between patients in whom a tourniquet was used as compared to those in whom a tourniquet was not used during TKA
timeFrame: at 48 hours
measure: Change on Oxford Hip Score (OHS) or Oxford Knee Score (OKS) from pre surgery to 90 days post-surgery
timeFrame: from pre surgery to 90 days post-surgery
measure: Change on Oxford Hip Score (OHS) or Oxford Knee Score (OKS) from pre surgery to 1 year post-surgery
timeFrame: from pre-surgery to 1 year post-surgery
measure: Differences in hospital costs associated with each treatment group
timeFrame: Up to 90 days
Locations:
city: Belfast
country: United Kingdom
facility: Primary Joint Unit, Musgrave Park Hospital, BHSCT
state: Northern Ireland
Study officials:
affiliation: Belfast Health and Social Care Trust
name: David Beverland
role: PRINCIPAL_INVESTIGATOR
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