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.

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.