Investigating the Effect of Intravenous and Oral Tranexamic Acid on Blood Loss After Primary Hip and Knee Arthroplasty
Condition: Primary Total Knee Arthroplasty; Primary Total Hip Arthroplasty
MeSH terms: Hemorrhage
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Tranexamic Acid 100 MG/ML; Tranexamic Acid 500 MG
Intervention type(s): Drug; Drug
Intervention description(s): Tranexamic Acid: 100 MG/ML Solution for injection; Tranexamic Acid: Tranexamic Acid 500mg Tablets
Other intervention name(s): TXA; TXA
Intervention MeSH terms: Tranexamic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A Phase IV, single centred, open label, parallel group, randomised controlled trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Tranexamic Acid