Clinical Outcomes Following Use of Tranexamic Acid in High Tibial Osteotomy: A Systematic Review

This study aimed to evaluate the clinical outcomes following administration of tranexamic acid (TXA) in patients undergoing high tibial osteotomy (HTO) through a systematic review of current available evidence. A systematic database search of PubMed, Embase and Cumulative Index of Nursing and Allied Health Literature (CINAHL) was performed from inception up to December 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Inclusion criteria were (i) randomised control trials, cohort studies or case-control studies that had more than 10 patients; (ii) studies reporting outcomes after TXA administration, of any route, before or after HTO, compared to placebo, control and different doses or routes; and (iii) studies reporting blood loss, including haemoglobin (Hb) drop, estimated blood loss, transfusion requirement and complications. Case reports, reviews, abstracts, non-HTO studies, non-human studies and duplicates were excluded. A synthesized comparison of drain output, wound complications, transfusion requirement and pooled analyses of blood loss and Hb drop was performed. Eleven studies involving 974 patients were included. Nine studies had placebo comparison, and two used single-dose TXA versus multiple doses. All studies reported on postoperative hemoglobin and nine on blood loss. In the six TXA versus placebo studies reporting on total blood loss, the TXA group had a pooled, estimated standardised mean difference (SMD) in blood loss of -2.37 (95% confidence interval (CI) -3.67, -1.07; P = 0.0004). For the Hb drop, on postoperative days (PODs) one, two, and five, the SMDs were -0.97 (95% CI -1.19, -0.75; P < 0.00001) for POD1, -0.74 (95% CI -1.03, -0.46; P < 0.00001) for POD2 and -0.87 (95% CI -1.10, -0.64; P < 0.00001) for POD5. TXA administration in HTO significantly reduces perioperative blood loss. This can greatly improve recovery, reduce complications and shorten length of stay. This is especially pertinent given supply shortages of NHS blood resources.


Introduction And Background
The prevalence of knee osteoarthritis (OA) has doubled since the middle of the twentieth century, due to an increase in both life expectancy and body mass index (BMI) of the general population [1].Medial opening wedge high tibial osteotomy (MOWHTO) has been gaining popularity as a therapy for OA, owing to the improved postoperative activity levels compared to unicompartmental or total knee arthroplasty surgery [2].MOWHTO is primarily utilised as an early surgical intervention for younger patients with unicompartmental KOA [3], preventing progression of disease burden and reducing both the physical cost to patient and long-term financial costs to the NHS.As of 2018, OA and rheumatoid arthritis cost the NHS £10.2 billion per annum with an expectation to surpass £118.6 billion within the next 10 years [4].Furthermore, such musculoskeletal conditions are the leading cause of disability, accounting for 30.5% of years lived with a disability [4].
While MOWHTO is a suitable procedure for patients with unicompartmental KOA, however, this procedure is not without risks.One of the most common risks include bleeding from the metaphyseal cancellous bone at the site of the osteotomy.This, combined with tissue manipulation, can potentially lead to significant blood loss, clinically demonstrated by a drop in the postoperative haemoglobin (Hb) [3].This may cause an increase in both the length of stay (LoS) and the risk of blood transfusion postoperatively.To reduce risks of bleeding in MOWHTO surgery, several methods have been explored and researched.One of these is the use of tranexamic acid (TXA) intraoperatively through various routes of administration [5][6][7][8][9][10][11][12][13][14][15].TXA is a fibrinolytic inhibitor, FDA-approved for menorrhagia and short-term use in haemophilia but with growing popularity and call for approval of intraoperative blood loss.While there are several studies that have been conducted to evaluate the safety and efficacy of TXA in preventing excessive blood loss following MOWHTO, there is no consensus with regard to its routine use.Therefore, we aimed to systematically review the current literature with regard to the safety and efficacy of TXA in MOWHTO.Prior to the initiation of this study, we hypothesised that TXA would be a safe and efficacious intervention in MOWHTO.

Eligibility criteria
The inclusion criteria adopted for the study selection were as follows: (i) randomised clinical trials (RCTs), cohort studies or case-control studies of at least 10 patients; (ii) studies reporting clinical outcomes following application of tranexamic acid via any route before or after MOWHTO, compared to placebo, control, different dosing or different routes of TXA administration; (iii) and studies reporting blood loss, measured by Hb drop, estimated blood loss, need for blood transfusion and complications.Case reports, review articles, published abstracts, non-MOWHTO operations, non-human studies and duplicate studies were excluded from this review.Articles in languages other than English were also excluded.

Quality assessment of the included studies
For RCTs, quality was assessed using the Cochrane Collaboration risk-of-bias version 2 (ROB 2) tool whose domains included (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias) and (7) other sources of bias.For non-RCTs, the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool was used.The domains included (1) confounding bias, (2) bias in selection of participants, (3) bias in classification of interventions, (4) bias from deviation in intended interventions, (5) missing data bias, (6) outcome measurement bias and (7) bias in the selection of the reported result.For both ROBINS-I and ROB, the risk was deemed low, moderate or serious.

Data collection
All data from the texts, figures and tables of the included studies were extracted to Microsoft Excel spreadsheet software for analysis and review.The specific information extracted included the following: (i) study details, including study design and level of evidence; (ii) study population details, including number of patients, patient demographics and the size of the control group (if present); (iii) objective of study; (iv) TXA route of administration and dose given; (v) outcomes studied and results; and (vi) any reported complications.

Statistical analysis
To evaluate the efficiency of TXA to reduce blood loss in HTO, either in comparison to placebo or as a multiple-dosing regimen, a fixed-effect model was used for the meta-analysis.The standardised mean difference (SMD) was used to compare the effects of the other variables (transfusion requirement, drain output, Hb drop and wound complications), with calculation of 95% confidence intervals (CIs) of the SMDs.An effect was considered statistically significant with a p-value less than 0.05.These other variables were chosen with the consideration of clinical importance and with reference to previous review articles.

Quality assessment of studies
The quality of the RCTs included in this study was assessed using the Cochrane Collaboration ROB-2 tool.The ROBINS-I tool was used in the evaluation of the quality of evidence for each outcome measure for the non-RCTs.The results of the quality assessment are illustrated in Table 1.

Total blood loss
In the six TXA versus placebo studies reporting on the total blood loss, the TXA group had a pooled, estimated SMD in blood loss of -2.37 (95% CI -3.67, -1.07; P = 0.0004) (Figure 2).

FIGURE 3: Haemoglobin decrease results 1, table and forest plot of pooled estimated standardised mean differences (SMDs).
Results grouped by data availability of postoperative days [7,8,12].

Wound complications
The prevalence of wound complications was not significantly significant; nine studies saw a pooled estimated SMD of 0.49 (95% CI 0.22, 1.10; P = 0.08) (Figure 7).MOWHTO is known to be a procedure that risks high blood loss.This is due to a variety of reasons, including intraoperative exposure of highly vascularised cancellous bone [11].In addition, MOWHTO typically involves torniquet use to optimise surgical view of the operative field [15].Studies have demonstrated an abnormal increase in fibrinolytic activity in patients undergoing torniquet procedures, which has the potential to perpetuate bleeding for at least 15 minutes [16].Perioperative blood loss increases the risk of haematoma formation around the incision site, anaemia and blood transfusion rates [11,17].Orthopaedic literature has reported that blood transfusion is an independent predictor for increased length of inpatient stay [18].In addition, transfusion requirement is of particular significance in light of the recent reduction in the availability of blood due to limited stock resulting in the necessity to use alternative means when appropriate, including TXA [19].A previous systematic review has confirmed that TXA can reduce the relative risk of requiring a blood transfusion by 45% in MOWHTO [20].
In our study, a decrease in total blood loss was seen in all 11 studies.This result can be explained by the mechanism of TXA; acting as a competitive inhibitor, TXA binds lysine sites on plasminogen, preventing the enzymatic breakdown of fibrin meshwork [21].Previous literature corroborated this effect; Ma et al. (2021) found that TXA reduced blood loss, decreased Hb and reduced wound complications [22].Similarly, TXA has successfully reduced blood loss in an RCT focusing on total knee replacements [23].
Due to its antifibrinolytic effect, there remains understandable concern that TXA has the potential to increase rates of deep vein thrombosis (DVT).However, it has been demonstrated that preoperative TXA does not increase the rates of either DVT or pulmonary embolism (PE) in total knee replacements [24].The study mentioned was prospective and single-blinded with TXA infusion post-total knee replacement.Follow-up occurred at three months postoperatively, and no thromboembolic events were observed in the TXA group.Although an interesting result, further investigation is recommended, largely due to both a small sample size and absence of control group.A further trial has demonstrated that the rate of DVT is not increased by TXA whether used IV or s/c for TKA [25].A 2021 meta-analysis of studies between 1976 and 2020 also disproved the theory, demonstrating that TXA did not increase thromboembolic events and did reduce bleeding-associated mortality [26].However, it did mention a high degree of variation between both follow-up and postoperative care between included studies.There remain patient groups where TXA is advised to be used with caution, including renal impairment due to excretion by glomerular filtration [27].
Cases of ophthalmological disturbance following TXA usage have been reported in the literature, including altered colour perception and retinal artery occlusion [28].However, it has been emphasised that further literature is required in this area and the relationship between the two is not considered directly causal; a future systematic review of this effect would likely be of value.Currently, TXA is approved and considered safe for clinical use in post-partum haemorrhage, acute traumatic blood loss, cardiothoracic surgery and bleeding disorders [21].
While none of the studies included in this review reported the effect of TXA use on the length of stay, the senior authors in their high-volume osteotomy practice have found that the length of stay in patients undergoing MOWHTO has significantly decreased with the use of TXA.This is likely due to reduced rate of transfusions.While the literature surrounding MOWHTO on TXA effect on the length of stay is lacking, there is strong evidence from TKA studies that we can extrapolate from [29].

Conclusions
MOWHTO is a popular early surgical intervention for OA, but it risks blood loss.This systematic review and meta-analysis has determined that TXA is a safe and effective therapy to reduce blood loss in MOWHTO surgery.This result could demonstrate a substantial improvement in postoperative outcomes, which consequently impact patient the length of stay and thus overall NHS expenditure.However, to establish this effect, we believe that larger, randomised trials would be of value to the literature.In addition, there remains opportunity for review articles determining both the impact of intraoperative TXA use upon overall inpatient length of stay and lesser reported side effects of TXA, including ophthalmological disturbances.

Appendices
Conference 2023, BOA Annual Conference 2023 and accepted for future presentation at BOTA Annual Conference 2023.Review Information sources and study selection An electronic search was performed by two independent authors (C.O'D and H.D) in PubMed, Embase, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases to identify all relevant studies, with the most recent search conducted in December 2022.The following search strategy was used to query citation titles and abstracts: ((osteotomy) OR (high tibial osteotomy) OR (hto) OR (knee) OR (proximal tibia)) AND ((tranexamic acid) OR (txa)).Our detailed search strategy for each of the databases is presented in Annex A. Reference lists of relevant systematic reviews were manually searched.This review was not registered on the International Prospective Register of Systematic Reviews (PROSPERO) database.The search workflow was in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and is illustrated in Figure 1.To identify studies to be included in the final review, the articles were independently assessed by two authors (C.O'D and H.D), to determine eligibility for inclusion in the analysis.Any disagreements were resolved by consensus discussion among the authors.A total of 11 studies were included in the final review.

TABLE 4 :
Search strategies by database NCBI: ational Center for Biotechnology Information, CINAHL: Cumulative Index of Nursing and Allied Health Literature