Evidence review for tranexamic acid to minimise blood loss

National Guideline Centre (UK)

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Evidence review for tranexamic acid to minimise blood loss

Joint replacement (primary): hip, knee and shoulder

Evidence review G

NICE Guideline, No. 157

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2020 Jun.

ISBN-13: 978-1-4731-3722-6

1. Tranexamic acid

1.1. Review question: In adults having primary elective joint replacement, what is the clinical and cost effectiveness of tranexamic acid (TXA) for minimising blood loss from surgery?

1.2. Introduction

Significant blood loss may occur during joint replacement surgery. Treatments to reduce the blood loss offer advantages to patients, reducing the need for blood products, which are expensive, and reducing recovery time and improving the recovery experience. Tranexamic acid has been utilised both systemically and topically to reduce blood loss in joint replacement surgery. There is currently no agreed national standard on which method of delivery is the best. This review seeks to assess whether tranexamic acid is effective and what the most effective method of delivery is.

1.3. PICO table

For full details see the review protocol in Appendix A:

1.4. Clinical evidence

1.4.1. Included studies

A search was conducted for randomised trials investigating the effectiveness of tranexamic acid for reducing blood loss during primary elective joint replacement surgery.

108 randomised controlled trials were included in the review; ¹^, ⁵^–⁷^, ¹²^, ¹³^, ¹⁸^, ²²^–²⁵^, ²⁷^–³⁰^, ³⁸^, ⁴²^, ⁴⁴^, ⁴⁵^, ⁴⁸^, ⁵⁶^, ⁶⁰^, ⁶⁴^, ⁷⁴^–⁷⁸^, ⁸⁴^, ⁸⁵^, ⁸⁷^, ⁹⁰^–⁹²^, ¹⁰⁴^, ¹⁰⁷^, ¹⁰⁹^, ¹¹¹^, ¹¹⁴^, ¹¹⁶^, ¹¹⁸^, ¹²²^, ¹²⁶^, ¹²⁷^, ¹²⁹^, ¹³¹^, ¹³⁵^, ¹³⁸^, ¹⁴⁰^, ¹⁴²^–¹⁴⁵^, ¹⁴⁷^, ¹⁵⁴^, ¹⁵⁵^, ¹⁶¹^, ¹⁶²^, ¹⁶⁶^, ¹⁶⁷^, ¹⁷⁰^–¹⁷²^, ¹⁷⁵^, ¹⁷⁶^, ¹⁸⁰^, ¹⁸³^, ¹⁹¹^, ¹⁹³^, ¹⁹⁵^–¹⁹⁷^, ²⁰⁰^, ²⁰¹^, ²⁰³^, ²⁰⁶^, ²¹⁰^, ²¹⁴^, ²¹⁵^, ²²⁵^, ²²⁷^, ²³³^, ²⁴¹^, ²⁴⁶^–²⁴⁸^, ²⁵¹^, ²⁵³^–²⁵⁶^, ²⁵⁹^, ²⁶³^, ²⁶⁴^, ²⁷⁰^, ²⁷⁶^, ²⁸⁰^, ²⁸²^, ²⁸⁵^, ²⁸⁷^, ²⁸⁹^, ²⁹¹^, ³⁰²^, ³⁰³^, ³⁰⁵^, ³⁰⁷ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

1.4.2. Excluded studies

See the excluded studies list in Appendix I:

1.4.3. Summary of clinical studies included in the evidence review

See appendix D for full evidence tables.

1.4.4. Quality assessment of clinical studies included in the evidence review

See Appendix F: for full GRADE tables.

1.5. Economic evidence

1.5.1. Included studies

Three health economic studies were identified with the relevant comparison and have been included in this review. ¹²^,¹³^,⁵⁰ These are summarised in the health economic evidence profile below (see Table 16, Table 17 and Table 18) and the health economic evidence tables in Appendix H:

An original network meta-analysis and cost comparison was conducted for this review and can be found in the TXA Network meta-analysis and cost comparison appendix.

1.5.2. Excluded studies

Two economic studies relating to this review question were identified but were selectively excluded due to the availability of more applicable evidence. ²⁴⁹^, ¹¹². Four economic studies were found but excluded due to very serious limitations.³⁹^,⁸⁹^,¹⁷³^,¹⁹⁸

These are listed in Appendix I: with reasons for exclusion given.

See also the health economic study selection flow chart in Appendix G:

1.5.3. Summary of studies included in the economic evidence review

1.5.3.1. Health economic modelling

The committee agreed that new economic analysis of the different ways to administer TXA was the highest priority for the guideline due to other high economic priorities being downgraded or an inability to model. The cost differences between the methods was not considered to be large, however the clinical review showed a difference in transfusion rates, which can have large cost implications. It was felt that a new cost analysis could reduce the uncertainty around the cost of transfusions and different methods of administration.

1.5.3.1.1. Method

A technical report for this analysis including full details of all methods is available in the TXA Network meta-analysis and cost comparison appendix.

A network meta-analysis (NMA) with cost comparison was undertaken in WinBUGs software to compare the costs of different methods of administering TXA when considering the cost of a transfusion. The population was people indicated for primary elective joint replacement, it was assumed that all of these surgeries have a moderate risk of blood loss (500ml-1000ml), as agreed by the committee. The time horizon was initial inpatient stay.

The comparators selected for the model were:

Topical (Intra-articular) (IA) TXA, (monotherapy)
Intra-venous (IV) TXA, (monotherapy)
Oral TXA, (monotherapy)
IA and IV TXA, (combination therapy)
IA and oral TXA, (combination therapy

The outcome selected for the model was:

Transfusion events

As agreed with the committee, placebo and no treatment were not included as comparators as it is established practice that administration of some form of TXA is clinically and cost-effective in comparison. Following a review of all of the studies included in the clinical review, 36 reported transfusion as an outcome with 2 or more relevant comparators. Four of these studies were 3- arm trials such that there were 44 pairwise comparisons in total. All of the included studies were for a hip or knee replacement population, No relevant studies were found for a shoulder replacement population.

Baseline model

One study was chosen to inform the baseline model⁷. The study was chosen as it was the only European study that was graded as having a low risk of bias. Therefore it was considered best to represent a UK population. As only one study was included in the baseline model there was no need to account for between study heterogeneity and therefore, the fixed effects baseline model was chosen.

Main model

For the main model both a random and fixed effects model was run. No meaningful difference was found in the sum of residual deviances or DIC between the two models. Therefore fixed effect model results were used as this is the simplest model available.

Inconsistency

To determine if there is evidence of inconsistency, the selected consistency model (fixed or random effects) was compared to an “inconsistency”, or unrelated mean effects, model.⁵³^, ⁵⁵ The posterior mean of the residual deviance, which measures the magnitude of the differences between the observed data and the model predictions of the data, was used to assess and compare the goodness of fit of each model.⁵⁴ In addition to assessing how well the models fit the data using the posterior mean of the residual deviance, models were compared using the DIC.

Further checks for evidence of inconsistency were run through node-splitting. This method permits the direct and indirect evidence contributing to an estimate of a relative effect to be split and compared.

Costs

For the cost comparison costs were divided into the intervention costs and the cost of a transfusion. Intervention costs were calculated through an unweighted average intervention cost of each arm in the included studies. The cost for each arm of the included studies was calculated by extracting the dosage of TXA used, the saline volume used (if applicable) and disposables used (if applicable). Unit costs for TXA solution, TXA tablets, saline and syringes were then obtained from eMIT⁴⁶ or NHS Supply Chain Catalogue 2018¹⁸⁸ and multiplied by the relevant resource use for each treatment in each included study.

The cost of a transfusion was calculated from Stokes 2018²³² and the NICE Blood Transfusion guideline.¹⁸⁵ The standard volume of a unit of red blood cells (RBCs) was assumed as 280ml with a range of 220-340ml.

The total NHS cost for each administration method was given by the formula:

P (transfusion.event) \times (C (first.unit) + C (subs.unit)) + C (intervention)

Where the probability of a transfusion event occurring [P(transfusion.event)] is the output of the NMA. The cost of a transfusion event [C(first.unit) + C(subs.unit)] is the cost of transfusing an initial unit and 1 subsequent unit, and C(intervention) is the intervention cost. Results Table 8 shows the base case results, including the probability of a transfusion event occurring for the different administration methods and the NHS cost of each administration method when factoring in the probability of a transfusion occurring.

1.5.3.1.2. Results

Table 19 summarises the fixed effects results of the conventional meta-analyses in terms of risk ratios generated from studies directly comparing different interventions, together with the results of the NMA in terms of risk ratios for every possible treatment comparison. Table 20 shows the base case absolute results, including the probability of a transfusion event occurring for the different administration methods and the NHS cost of each administration method when factoring in the probability of a transfusion occurring.

The inconsistency (FE) model showed no meaningful difference to the consistency model suggesting the consistency (FE) model fits the data well. The fixed effect node split models also found no evidence of inconsistency.

The results indicated that topical (intra-articular) in combination with oral had the lowest probability of a transfusion event and was also the cheapest. However, the committee were keen to note that the intervention was linked to the network by a single study that had a high risk of bias in the clinical review. Furthermore, use of oral tranexamic acid is off label and generally not part of current practice, use of topical (intra-articular) tranexamic acid is also off label but is part of current practice. As both methods of administration are off label, the committee agreed they did not want to make a recommendation for topical (intra-articular) in combination with oral. Although as previously noted, topical (intra-articular) tranexamic acid is off license; its use in combination with IV tranexamic acid is not uncommon in current practice. Given the clinical and economic evidence in favour of this combination, the committee decided to make an offer this combination.

1.5.4. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

1.6. Evidence statements

1.6.1. Clinical evidence statements

One hundred and eight RCTs covering 13 comparisons were included in the evidence review.

Topical (intra-articular) versus no treatment (12 RCTs)

A benefit was found for topical (intra-articular) tranexamic acid in transfusion (n=1078, low quality), total blood loss (n=709, very low quality), surgical bleeding (n=355, very low quality) and postoperative bleeding (n=95, high quality). No difference was seen in terms of DVT (n=850, moderate quality), blood loss via haemoglobin level after surgery (n=906, very low quality), and length of stay (n=312, low quality). No outcomes favoured no treatment.

Oral versus no treatment (1 RCT)

A benefit was found for oral tranexamic acid in transfusion (189, very low quality), blood loss via haemoglobin level after surgery (n=189, moderate quality), and total blood loss (n=189, moderate quality). No difference was found in mortality (n=189, low quality), DVT (n=189, very low quality), or length of stay (n=189, moderate quality). No outcomes favoured no treatment.

IV versus no treatment (16 RCTs)

A benefit was found for IV tranexamic acid in transfusion (n=1324, very low quality), total blood loss (n=873, very low quality), and postoperative bleeding (n=96, high quality). No difference was found for mortality (n=100, very low quality), DVT (n=1135, moderate quality), blood loss through haemoglobin level (n=1038, low quality), surgical bleeding (n=356, very low quality), and length of stay (n=213, low quality). No outcomes favoured no treatment.

Topical (intra-articular) versus placebo (23 RCTs)

A benefit was found for topical (intra-articular) tranexamic acid in transfusion (n=2589, high quality), transfusion (n=2589, high quality), blood loss via haemoglobin level after surgery (n=1853, very low quality), total blood loss (n=1617, low quality), and postoperative bleeding (n=394, moderate quality). No difference was seen in terms of mortality (n=60, very low quality), quality of life (n=190, very low quality), DVT (n=2428, very low quality), surgical bleeding (n=243, very low quality), or length of stay (n=1108, low quality). No outcomes favoured placebo.

Oral versus placebo (3 RCTs)

A benefit was found for oral tranexamic acid in transfusion (n=406, moderate quality), blood loss via haemoglobin level after surgery (n=406, low quality), total blood loss (n=126, moderate quality), and surgical bleeding (n=80, low quality). No difference was seen in terms of DVT (n=406, moderate quality) or length of stay (n=80, moderate quality). No outcomes favoured placebo.

IV versus placebo (43 RCTs)

A benefit was found for IV tranexamic acid in transfusion (n=3383, low quality) blood loss via haemoglobin level after surgery (n=2489, very low quality), total blood loss (n=2624, low quality), surgical bleeding (n=744, very low quality), and postoperative bleeding (n=762, very low quality). No difference was seen in terms of mortality (n=290, moderate quality), DVT (n=3356, moderate quality), acute coronary syndrome (n=230, moderate quality), or length of stay (n=1272, high quality). No outcomes favoured placebo.

IV plus topical (intra-articular) versus placebo (4 RCTs)

A benefit was found for IV tranexamic acid plus IA/topical tranexamic acid in transfusion (n=380, moderate quality) blood loss via haemoglobin level after surgery (n=380, moderate quality), total blood loss (n=380, low quality), surgical bleeding (n=100, moderate quality), and postoperative bleeding (n=200, moderate quality). No difference was seen in terms of DVT (n=380, moderate quality) or length of stay (n=200, moderate quality). No outcomes favoured placebo.

Topical (intra-articular) versus IV (31 RCTs)

None of the 11 outcomes indicated difference between treatment groups: mortality at 30 days (n=269, very low quality), quality of life (mental component score) (n=100, low quality), quality of life (physical component score) (n=100, low quality), transfusion (n=3978, high quality), DVT (n=3833, high quality), acute myocardial infarction (n=89, very low quality), blood loss via haemoglobin level after surgery (n=2558, low quality), total blood loss (n=2806, low quality), surgical bleeding (n=1172, very low quality), postoperative bleeding (n=272, low quality), and length of stay (n=1312, high quality).

Oral versus IV (8 RCTs)

None of the 7 outcomes indicated difference between treatment groups: mortality (n=120, moderate quality), transfusion (n-862, very low quality), DVT (n=945, moderate quality), blood loss via haemoglobin level after surgery (n=945, moderate quality), total blood loss (n=665, moderate quality), surgical bleeding (n=200, moderate quality), and length of stay (n=437, moderate quality).

Topical (intra-articular) versus oral (5 RCTs)

A benefit was found for oral tranexamic in the transfusion (n=787, very low quality) and no outcomes indicated a comparative benefit for topical (intra-articular) tranexamic acid. The other 6 outcomes indicated no difference between treatment groups: mortality (n=384, moderate quality), DVT (n=784, moderate quality), blood loss via haemoglobin level after surgery (n=784, moderate quality), total blood loss (n=504, moderate quality), surgical bleeding (n=384, high quality), and length of stay (n=237, moderate quality).

IV plus topical (intra-articular) versus IV (8 RCTs)

A benefit was found for IV tranexamic acid plus Topical (intra-articular) tranexamic acid in transfusion (n=791, moderate quality), blood loss via haemoglobin level after surgery (n=891, very low quality), total blood loss (n=691, very low quality), and postoperative bleeding (n=200, low quality). No difference was seen in terms of DVT (n=891, moderate quality) or length of stay (n=472, moderate quality). No outcomes favoured IV tranexamic acid alone.

Topical (intra-articular) plus oral versus topical (intra-articular) (1 RCT)

A benefit of topical (intra-articular) tranexamic acid plus oral tranexamic acid was found in transfusion (n=100, very low quality), blood loss via haemoglobin level after surgery (n=100, low quality), total blood loss (n=100, low quality), and postoperative bleeding (n=100, low quality). No difference was found for DVT (n=100, very low quality). No outcomes favoured IV tranexamic acid alone.

IV plus topical (intra-articular) versus topical (intra-articular) (4 RCTs)

A benefit for IV tranexamic acid plus topical (intra-articular) tranexamic acid was found in transfusion (n=320, moderate quality), blood loss via haemoglobin level after surgery (n=420, very low quality), and total blood loss (n=420, very low quality). No clinical difference was seen for quality of life (mental component score) (n=100, low quality), quality of life (physical component score) (n=100, low quality), DVT (n=420, low quality), or length of stay (n=140, very low quality). No outcomes favoured topical (intra-articular) tranexamic acid alone.

1.6.2. Health economic evidence statements

One cost utility analysis found that placebo was not cost effective (£63,429 per QALY gained) compared to topical (intra-articular) tranexamic acid for people undergoing total knee replacement. Topical (intra-articular) tranexamic acid was cost saving but was also less effective than placebo. This study was assessed as partially applicable with potentially serious limitations.

One cost utility analysis found that placebo was cost effective (£11,509 per QALY gained) compared to topical (intra-articular) tranexamic acid. Topical (intra-articular) tranexamic acid was cost saving but was also less effective than placebo. The result should be treated with caution due to a much higher baseline quality of life reported for the intervention arm. This study was assessed as partially applicable with potentially serious limitations.

One comparative cost study found that intravenous tranexamic acid was cost saving (saves a minimum of £68 per person for hip and knee replacements) compared to no tranexamic acid. This study was assessed as partially applicable with potentially serious limitations.

An original network meta-analysis with cost comparison found that when factoring in the cost of a transfusion, using topical (intra-articular) tranexamic acid with oral tranexamic acid was the most cost saving method of administration compared to using either: topical (intra-articular) tranexamic acid with intravenous tranexamic acid; oral, intravenous, or topical (intra-articular) alone. Topical (intra-articular) tranexamic acid with intravenous tranexamic acid was found to be more cost saving than using oral, intravenous or topical (intra-articular) alone. The most cost saving method, topical (intra-articular) tranexamic acid with oral tranexamic acid, was linked to the network by a single study that was graded as having a high risk of bias. This analysis was assessed as partially applicable with minor limitations.

1.7. The committee’s discussion of the evidence

1.7.1. Interpreting the evidence

1.7.1.1. The outcomes that matter most

The critical outcomes chosen by the committee were mortality, adverse events, transfusion, quality of life and surgical bleeding. The important outcomes were postoperative anaemia, postoperative bleeding, and length of stay. The outcomes that represent blood loss are transfusion, surgical bleeding, postoperative anaemia, and postoperative bleeding. Surgical bleeding and postoperative bleeding were often reported within the same outcome, blood loss measured via change in haemoglobin and total blood loss. The adverse events associated with tranexamic acid use are postoperative thrombosis such as deep vein thrombosis (DVT), and acute myocardial infarction. Therefore the evidence review sought to assess the possible positives of tranexamic acid treatment in joint replacement surgery around reduction in blood loss and consequently reduction in transfusions, with the possible negative postoperative thrombosis outcomes.

1.7.1.2. The quality of the evidence

The overall outcome quality ranged from high to very low. More outcomes were assessed as low or very low quality than moderate or high quality.

The outcome quality was often downgraded due to risk of bias because studies that did not state an adequate method of randomisation or gave an adequate description of allocation concealment. This could have led to results that favoured tranexamic acid treatment. There were many studies where participants and surgeons were not blinded to the treatment. This was often not considered a risk of bias where outcomes were assessed objectively.

Many outcomes were found to be inconsistent and also a smaller number showed imprecision in the meta-analysis results. This could be explained by the tranexamic acid treatments in the RCTs which were allocated to intervention groups based on route of administration rather than the specific joint being replaced, timing of administration, and dose. These aspects were investigated singly in subgroup analysis where heterogeneity was found. None were found alone to explain the heterogeneity but there could well have been more complex interactions between these factors that led to not only inconsistency but also imprecision.

1.7.1.3. Benefits and harms

107 studies covering 13 comparisons were found.

All 3 routes of tranexamic acid administration were compared alone or in one case, in combination, to no treatment or placebo. These results consistently found a clinically important benefit of tranexamic acid in the blood loss and also in terms of the number of people requiring transfusions. In all cases there was no clinically important difference in DVT between the treatment groups.

The 3 routes of tranexamic acid administration were compared against each other singly. When topical (intra-articular) and oral were each compared to IV administration, all outcomes indicated no clinically important difference. Topical (intra-articular) versus oral administration found no clinically important difference for all outcomes except for transfusion which indicated 18 fewer people per thousand requiring a transfusion.

The last group of analyses compared multiple routes of administration of tranexamic acid to a single route of administration. IV combined with topical (intra-articular) versus IV alone found no clinical difference for 5 outcomes though the transfusion outcome indicated a benefit for combination treatment. IA/topical combined with oral versus IA/topical alone was reported by 1 RCT and this indicated a clinically important benefit of the combination treatment in terms of 4 blood loss outcomes and no difference in DVT. IV combined with IA/topical versus IA/topical alone found a benefit for combination treatment in blood loss via change in haemoglobin and in number of people transfused but no difference in total blood loss.

103 of the RCTs investigated knee or hip joint replacement and 4 RCTs investigated shoulder joint replacement. These 4 studies covered the IA/topical versus placebo and IV versus placebo comparisons. Thus the 11 other comparisons presented in the evidence review did not have include data from people having shoulder joint replacement. The 4 studies that included people having shoulder joint replacement indicated tranexamic acid was effective versus placebo but did not give an indication of its effectiveness when utilised across multiple routes.

Some benefits and no harms were found when multiple treatment routes were utilised versus single routes. The committee spoke about a reduction in transfusions found in all 3 comparisons to support combination treatment and thought this to be a compelling factor. In terms of the comparisons, all of the combination routes included IA/topical and the committee were mindful of this. The committee made a recommendation to offer IV in combination with IA/topical tranexamic acid in people having primary elective hip or knee joint replacement surgery.

For those having elective shoulder replacement the committee made a separate consider recommendation. While there is evidence showing a benefit of tranexamic acid in people having primary elective shoulder replacement there was no evidence for combination treatment. However the committee agreed to extrapolate the advantages of combination therapy found in the hip and knee replacement population to the shoulder replacement population. This decision was based on the basic similarities of each form of joint replacement surgery and despite shoulder replacement not yielding as high blood loss as hip or knee replacement surgery it is important to reduce blood loss where possible. The evidence did not show a reduction in transfusions for shoulder replacement and the committee noted that in their experience there are many fewer transfusions in shoulder replacement surgery. They agreed that reducing bleeding also reduces bruising and postoperative haematoma. There were no adverse events associated with this treatment in any of the evidence and no overt economic pressures given the use of tranexamic acid via a single route is standard care and so the committee agreed to include shoulder replacement surgery in the recommendation. With this in mind the committee agreed to make a consider recommendation.

The BNF states tranexamic acid is indicated for local fibrinolysis via oral or slow intravenous injection with dosage stated. It does not mention usage topically or give a dosage for this. The committee are satisfied it is a safe and effective treatment topically and in combination through the large evidence base and their own experience. The committee agree that topical (intra-articular) could be given after the final washout of the wound and before wound closure.

The committee noted the BNF indicates people with mild to moderate renal impairment require a reduced dose of IV tranexamic acid. The amount of dose reduction is according to serum creatinine level and is listed in the manufacturer’s summary of product characteristics (SPC). The absorption is uncertain via topical (intra-articular) usage and consequently, only IV is recommended for this sub-group. Tranexamic acid is contraindicated for people with severe renal impairment.

1.7.2. Cost effectiveness and resource use

The studies in the economic review included 2 cost utility analyses and 1 cost comparison. The cost utility analyses only differed by site of joint replacement, otherwise they were from the same author and used the same methodology. Neither of these studies presented ICERs, these were calculated from the incremental costs and health related quality of life values presented in the papers. The results from the first cost utility analysis suggested that for people with total knee replacements (TKR) placebo was not cost effective (£63,428 per QALY gained) compared to topical (intra-articular) tranexamic acid. The results from the second cost utility analysis suggested that for people with total hip replacements (THR) placebo was cost effective (£11,509 per QALY gained) compared to topical (intra-articular) tranexamic acid. The interpretation of the ICER for these studies was the cost per QALY of the placebo (as opposed to the intervention) because tranexamic acid was cost saving but also gave less improved outcomes compared to placebo. Therefore the incremental values fall into the south-west quadrant on the cost effectiveness plane, which alters interpretation to the cost per QALY of the comparator compared to the intervention.

The results of the cost utility analyses should be treated with caution due to large differences in baseline quality of life (EQ-5D) between the study arms, despite being within-trial RCTs. For the study that concerned the THR population, the baseline EQ-5D for the placebo group was 0.205 whereas the value was 0.34 (a difference of 0.135) for the tranexamic acid group. The higher baseline value in the tranexamic acid group may have left less room for improvement in health related quality of life compared to the placebo group. Although it was not stated in the paper, it may be for this reason that the ICER was not presented in either paper.

The cost comparison study showed similar results to the 2 cost utility analyses, suggesting that using tranexamic acid over placebo or no tranexamic acid was cost saving. However, there were no studies that compared the cost of administering tranexamic acid by different methods. Additionally, all included studies only covered hip and knee replacements, there were no studies included which looked at the cost of tranexamic acid during shoulder surgery.

Current practice with tranexamic acid is varied, although for hip and knee replacements IV is often used in combination with topical (intra-articular). There was notion that oral is less favoured on the NHS. For shoulder replacements, use of topical (intra-articular) may be less common than for hip and knee replacements. Dosage use, and therefore costs are variable.

Given there was evidence presented for the clinical benefit of combination therapies and there was a lack of economic evidence for them, an original network meta-analysis with cost comparison was conducted. No studies with a primary elective shoulder replacement population were includable. In agreement with the committee, placebo and no treatment were excluded from the analysis given that using any form of tranexamic acid is established as current practice.

The results showed that average intervention costs were cheapest for oral and most expensive for IA and IV (oral, £0.27; IV, £2.25; IA and oral, £2.31; IA, £2.82; IA and IV, £5.34). The committee noted that the median dose used for combination therapy arms was generally greater than the dosage used for single therapies.

The results of the network meta-analysis for blood transfusions confirmed the committee’s thoughts that the combination therapies were associated with a lower probability of a transfusion event occurring. Allogeneic blood transfusions carry a significant cost; transfusing 2 units of blood has an overall cost of £351.30. Once the cost and probability of a transfusion was added onto the cost of each intervention, the combination therapies were the least costly interventions (IA, £31.13; IV, £28.63; oral, £24.70; IA and IV, £14.34; IA and oral, £7.76). A sensitivity analysis showed that the overall costs were most sensitive to the cost of a blood transfusion. However, running the cost comparison with 1 unit transfused per transfusion event (instead of 2 units in the base case analysis), still did not change the order of cost. The results were less sensitive to the mean intervention costs.

The results indicated that topical (intra-articular) in combination with oral had the lowest probability of a transfusion event and was also the cheapest. However, the committee were keen to note that the intervention was linked to the network by a single study that had a high risk of bias in the clinical review. Furthermore, use of oral tranexamic acid is off label and generally not part of current practice, use of topical (intra-articular) tranexamic acid is also off label but it is part of current practice. As both methods of administration are off licence, the committee agreed they did not want to make a recommendation for topical (intra-articular) in combination with oral. Although as previously noted, topical (intra-articular) tranexamic acid is off license; its use in combination with IV tranexamic acid is not uncommon in current practice. Given the clinical and economic evidence in favour of this combination, the committee decided to make an offer for IV in combination with topical (intra-articular). There was discussion about the higher median dosage used in the topical (intra-articular) with intravenous method that was recommended. The median dosage for each tranexamic acid administration method in the network was:

2.00 grams for topical (intra-articular)
1.54 grams for intravenous
3.07 grams for oral
3.02 grams for topical (intra-articular) and intravenous
3.50 grams for topical (intra-articular) and oral

Although there was suggestion that this could have been a contributing factor to the results, the committee still felt the evidence was strong enough to offer topical (intra-articular) in combination with IV. The median dosage was considered over the mean as the mean was skewed towards higher values. The committee discussed the total dosage they use in current practice, which varied between 2-3g when combining IV and topical (intra-articular). The median dosage of topical (intra-articular) in combination with IV study arms included in the network roughly equated to the upper end of dosage discussed by the committee. Therefore the committee agreed that dosage should not exceed 3g in total. It was noted that the dosage of topical (intra-articular) used in the combination arms was generally between 1-2g.

The NMA and cost comparison analysis is directly applicable to hip and knee replacements as the clinical data concerned only these populations. Although no evidence was available for tranexamic acid use for shoulder replacements, the committee agreed that the analysis could support a weaker ‘consider’ recommendation for the shoulder population. This was done on the basis that although blood loss may be slightly less for shoulder replacements, there is still benefit in reducing bleeding. The recommendation is likely to lead to an increase in topical (intra-articular) tranexamic acid use in shoulder replacements. Overall, it is expected that the recommendation will be cost saving for shoulder replacements (although the savings will be relatively less than for hip and knee replacements). This is because avoided transfusions drive cost savings and shoulder replacements generally require less transfusions than knee/hip replacements.

1.7.3. Other considerations

The committee discussed any potential interaction between the use of tranexamic acid and venous thromboembolism (VTE) prophylaxis. They agreed there is no evidence that intra-perative tranexamic acid increases the risk of deep vein thrombosis. Tranexamic acid is only offered during the surgical period and the effects of this will have worn off by the time pharmacological VTE prophylaxis is started postoperatively. The committee are also aware that if VTE prophylaxis is given preoperatively it is stopped ahead of surgery. Therefore, the committee concluded there is unlikely to be a risk of harm with both tranexamic acid and VTE pharmacological prophylaxis being used.

References

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Appendices

Appendix A. Review protocols

Table 23. Review protocol: tranexamic acid (PDF, 216K)

Table 24Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify health economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the clinical review protocol above. Studies must be of a relevant health economic study design (cost–utility analysis, cost-effectiveness analysis, cost–benefit analysis, cost–consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of health economic evaluations. (Recent reviews will be ordered although not reviewed. The bibliographies will be checked for relevant studies, which will then be ordered.) Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	A health economic study search will be undertaken using population-specific terms and a health economic study filter – see appendix B below.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2003, abstract-only studies and studies from low or middle-income countries (e.g. most non-OECD countries) or the USA will also be excluded. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in appendix H of Developing NICE guidelines: the manual (2014).¹⁸⁶ Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’ then it will be included in the guideline. A health economic evidence table will be completed and it will be included in the health economic evidence profile. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’ then it will usually be excluded from the guideline. If it is excluded then a health economic evidence table will not be completed and it will not be included in the health economic evidence profile. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both then there is discretion over whether it should be included. Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question, in discussion with the guideline committee if required. The ultimate aim is to include health economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the committee if required, may decide to include only the most applicable studies and to selectively exclude the remaining studies. All studies excluded on the basis of applicability or methodological limitations will be listed with explanation in the excluded health economic studies appendix below. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the USA will be excluded before being assessed for applicability and methodological limitations. Health economic study type: Cost–utility analysis (most applicable). Other type of full economic evaluation (cost–benefit analysis, cost-effectiveness analysis, cost–consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will be excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2003 or later but that depend on unit costs and resource data entirely or predominantly from before 2003 will be rated as ‘Not applicable’. Studies published before 2003 will be excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the health economic analysis: The more closely the clinical effectiveness data used in the health economic analysis match with the outcomes of the studies included in the clinical review the more useful the analysis will be for decision-making in the guideline.

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.¹⁸⁶

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the searches where appropriate.

Table 25Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (OVID)

1946 – 01 May 2019

Exclusions

Randomised controlled trials

Systematic review studies

Observational studies

Embase (OVID)

1974 – 01 May 2019

Exclusions

Randomised controlled trials

Systematic review studies

The Cochrane Library (Wiley)

Cochrane Reviews to 2019 Issue 5 of 12

CENTRAL to 2019 Issue 5 of 12

None

Medline (Ovid) search terms

1.	arthroplasty/ or arthroplasty, replacement/ or arthroplasty, replacement, hip/ or arthroplasty, replacement, knee/ or arthroplasty, replacement, shoulder/ or hemiarthroplasty/
2.	joint prosthesis/ or hip prosthesis/ or knee prosthesis/ or shoulder prosthesis/
3.	((joint* or knee* or shoulder* or hip) adj5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)).ti,ab.
4.	or/1-3
5.	letter/
6.	editorial/
7.	news/
8.	exp historical article/
9.	Anecdotes as Topic/
10.	comment/
11.	case report/
12.	(letter or comment*).ti.
13.	or/5-12
14.	randomized controlled trial/ or random*.ti,ab.
15.	13 not 14
16.	animals/ not humans/
17.	exp Animals, Laboratory/
18.	exp Animal Experimentation/
19.	exp Models, Animal/
20.	exp Rodentia/
21.	(rat or rats or mouse or mice).ti.
22.	or/15-21
23.	4 not 22
24.	limit 23 to English language
25.	Tranexamic Acid/
26.	(tranexamic or txa or cyklokapron).ti,ab.
27.	or/25-26
28.	24 and 27
29.	randomized controlled trial.pt.
30.	controlled clinical trial.pt.
31.	randomi#ed.ti,ab.
32.	placebo.ab.
33.	randomly.ti,ab.
34.	Clinical Trials as topic.sh.
35.	trial.ti.
36.	or/29-35
37.	Meta-Analysis/
38.	exp Meta-Analysis as Topic/
39.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
40.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
41.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
42.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
43.	(search* adj4 literature).ab.
44.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
45.	cochrane.jw.
46.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
47.	or/37-46
48.	Epidemiologic studies/
49.	Observational study/
50.	exp Cohort studies/
51.	(cohort adj (study or studies or analys* or data)).ti,ab.
52.	((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab.
53.	((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab.
54.	Controlled Before-After Studies/
55.	Historically Controlled Study/
56.	Interrupted Time Series Analysis/
57.	(before adj2 after adj2 (study or studies or data)).ti,ab.
58.	or/48-57
59.	exp case control study/
60.	case control*.ti,ab.
61.	or/59-60
62.	58 or 61
63.	Cross-sectional studies/
64.	(cross sectional and (study or studies or review or analys* or cohort* or data)).ti,ab.
65.	or/63-64
66.	58 or 65
67.	58 or 61 or 65
68.	28 and (36 or 47 or 67)

Embase (Ovid) search terms

1.	arthroplasty/ or replacement arthroplasty/ or hip replacement/ or knee replacement/ or shoulder replacement/ or hemiarthroplasty/
2.	joint prosthesis/ or hip prosthesis/ or knee prosthesis/ or shoulder prosthesis/
3.	((joint* or knee* or shoulder* or hip) adj5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)).ti,ab.
4.	or/1-3
5.	letter.pt. or letter/
6.	note.pt.
7.	editorial.pt.
8.	case report/ or case study/
9.	(letter or comment*).ti.
10.	or/5-9
11.	randomized controlled trial/ or random*.ti,ab.
12.	10 not 11
13.	animal/ not human/
14.	nonhuman/
15.	exp Animal Experiment/
16.	exp Experimental Animal/
17.	animal model/
18.	exp Rodent/
19.	(rat or rats or mouse or mice).ti.
20.	or/12-19
21.	4 not 20
22.	limit 21 to English language
23.	tranexamic acid/
24.	(tranexamic or txa or cyklokapron).ti,ab.
25.	1197-18-8.rn.
26.	or/23-25
27.	22 and 26
28.	random*.ti,ab.
29.	factorial*.ti,ab.
30.	(crossover* or cross over*).ti,ab.
31.	((doubl* or singl) adj blind).ti,ab.
32.	(assign* or allocat* or volunteer* or placebo*).ti,ab.
33.	crossover procedure/
34.	single blind procedure/
35.	randomized controlled trial/
36.	double blind procedure/
37.	or/28-36
38.	systematic review/
39.	meta-analysis/
40.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
41.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
42.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
43.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
44.	(search* adj4 literature).ab.
45.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
46.	cochrane.jw.
47.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
48.	or/38-47
49.	Clinical study/
50.	Observational study/
51.	family study/
52.	longitudinal study/
53.	retrospective study/
54.	prospective study/
55.	cohort analysis/
56.	follow-up/
57.	cohort*.ti,ab.
58.	56 and 57
59.	(cohort adj (study or studies or analys* or data)).ti,ab.
60.	((follow up or observational or uncontrolled or non randomi#ed or epidemiologic*) adj (study or studies or data)).ti,ab.
61.	((longitudinal or retrospective or prospective or cross sectional) and (study or studies or review or analys* or cohort* or data)).ti,ab.
62.	(before adj2 after adj2 (study or studies or data)).ti,ab.
63.	or/49-55,58-62
64.	exp case control study/
65.	case control*.ti,ab.
66.	or/64-65
67.	63 or 66
68.	cross-sectional study/
69.	(cross sectional and (study or studies or review or analys* or cohort* or data)).ti,ab.
70.	or/68-69
71.	63 or 70
72.	63 or 66 or 70
73.	27 and (37 or 48 or 72)

Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Arthroplasty] this term only
#2.	MeSH descriptor: [Arthroplasty, Replacement] this term only
#3.	MeSH descriptor: [Arthroplasty, Replacement, Hip] this term only
#4.	MeSH descriptor: [Arthroplasty, Replacement, Knee] this term only
#5.	MeSH descriptor: [Arthroplasty, Replacement, Shoulder] this term only
#6.	MeSH descriptor: [Hemiarthroplasty] this term only
#7.	(or #1-#6)
#8.	MeSH descriptor: [Joint Prosthesis] this term only
#9.	MeSH descriptor: [Hip Prosthesis] this term only
#10.	MeSH descriptor: [Knee Prosthesis] this term only
#11.	MeSH descriptor: [Shoulder Prosthesis] this term only
#12.	(or #8-#11)
#13.	((joint* or knee* or shoulder* or hip) near/5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)):ti,ab
#14.	(or #7, #12-#13)
#15.	MeSH descriptor: [Tranexamic Acid] this term only
#16.	(tranexamic or txa or cyklokapron):ti,ab
#17.	#15 OR #16
#18.	#14 AND #17

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to the joint replacement population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional health economics searches were run in Medline and Embase.

Table 26Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

2014 – 01 May 2019

Exclusions

Health economics studies

Embase

2014 – 01 May 2019

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - Inception – 01 May 2019

NHSEED - Inception to March 2015

None

Medline (Ovid) search terms

1.	arthroplasty/ or arthroplasty, replacement/ or arthroplasty, replacement, hip/ or arthroplasty, replacement, knee/ or arthroplasty, replacement, shoulder/ or hemiarthroplasty/
2.	joint prosthesis/ or hip prosthesis/ or knee prosthesis/ or shoulder prosthesis/
3.	((joint* or knee* or shoulder* or hip) adj5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)).ti,ab.
4.	or/1-3
5.	letter/
6.	editorial/
7.	news/
8.	exp historical article/
9.	Anecdotes as Topic/
10.	comment/
11.	case report/
12.	(letter or comment*).ti.
13.	or/5-12
14.	randomized controlled trial/ or random*.ti,ab.
15.	13 not 14
16.	animals/ not humans/
17.	exp Animals, Laboratory/
18.	exp Animal Experimentation/
19.	exp Models, Animal/
20.	exp Rodentia/
21.	(rat or rats or mouse or mice).ti.
22.	or/15-21
23.	4 not 22
24.	limit 23 to English language
25.	Economics/
26.	Value of life/
27.	exp “Costs and Cost Analysis”/
28.	exp Economics, Hospital/
29.	exp Economics, Medical/
30.	Economics, Nursing/
31.	Economics, Pharmaceutical/
32.	exp “Fees and Charges”/
33.	exp Budgets/
34.	budget*.ti,ab.
35.	cost*.ti.
36.	(economic* or pharmaco?economic*).ti.
37.	(price* or pricing*).ti,ab.
38.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
39.	(financ* or fee or fees).ti,ab.
40.	(value adj2 (money or monetary)).ti,ab.
41.	or/25-40
42.	24 and 41

Embase (Ovid) search terms

1.	arthroplasty/ or replacement arthroplasty/ or hip replacement/ or knee replacement/ or shoulder replacement/ or hemiarthroplasty/
2.	joint prosthesis/ or hip prosthesis/ or knee prosthesis/ or shoulder prosthesis/
3.	((joint* or knee* or shoulder* or hip) adj5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)).ti,ab.
4.	or/1-3
5.	letter.pt. or letter/
6.	note.pt.
7.	editorial.pt.
8.	case report/ or case study/
9.	(letter or comment*).ti.
10.	or/5-9
11.	randomized controlled trial/ or random*.ti,ab.
12.	10 not 11
13.	animal/ not human/
14.	nonhuman/
15.	exp Animal Experiment/
16.	exp Experimental Animal/
17.	animal model/
18.	exp Rodent/
19.	(rat or rats or mouse or mice).ti.
20.	or/12-19
21.	4 not 20
22.	limit 21 to English language
23.	health economics/
24.	exp economic evaluation/
25.	exp health care cost/
26.	exp fee/
27.	budget/
28.	funding/
29.	budget*.ti,ab.
30.	cost*.ti.
31.	(economic* or pharmaco?economic*).ti.
32.	(price* or pricing*).ti,ab.
33.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
34.	(financ* or fee or fees).ti,ab.
35.	(value adj2 (money or monetary)).ti,ab.
36.	or/23-35
37.	22 and 36

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR arthroplasty
#2.	MeSH DESCRIPTOR arthroplasty, replacement
#3.	MeSH DESCRIPTOR arthroplasty, replacement, hip
#4.	MeSH DESCRIPTOR arthroplasty, replacement, knee
#5.	MeSH DESCRIPTOR arthroplasty, replacement, shoulder
#6.	MeSH DESCRIPTOR hemiarthroplasty
#7.	MeSH DESCRIPTOR joint prosthesis
#8.	MeSH DESCRIPTOR hip prosthesis
#9.	MeSH DESCRIPTOR knee prosthesis
#10.	MeSH DESCRIPTOR shoulder prosthesis
#11.	(((joint* or knee* or shoulder* or hip) adj5 (surger or replace* or prosthe* or endoprosthe* or implant* or artificial or arthroplast* or hemiarthroplast*)))
#12.	(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11) IN NHSEED
#13.	(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11) IN HTA

Appendix C. Clinical evidence selection

Figure 2Flow chart of clinical study selection for the review of tranexamic acid

Appendix D. Clinical evidence tables

Download PDF (3.2M)

Appendix E. Forest plots

E.1. IA/topical versus no treatment

Figure 3Transfusion

Figure 4Adverse events: DVT

Figure 5Blood loss via haemoglobin level after surgery

Figure 6Total blood loss

Figure 7Surgical bleeding

Figure 8Length of stay

Figure 9Postoperative bleeding

E.2. Oral versus no treatment

Figure 10Mortality

Figure 11Transfusion

Figure 12Adverse events: DVT

Figure 13Total blood loss

Figure 14Blood loss via haemoglobin level after surgery

Figure 15Length of stay

E.3. IV versus no treatment

Figure 16Mortality

Figure 17Transfusion

Figure 18Adverse events: DVT

Figure 19Blood loss via haemoglobin level after surgery

Figure 20Total blood loss

Figure 21Surgical bleeding

Figure 22Postoperative bleeding

Figure 23Length of stay

E.4. IA/topical versus placebo

Figure 24Mortality

Figure 25Quality of life

Figure 26Transfusion

Figure 27Adverse events: DVT

Figure 28Blood loss via haemoglobin level after surgery

Figure 29Total blood loss

Figure 30Surgical bleeding

Figure 31Postoperative bleeding

Figure 32Length of stay

E.5. IV versus placebo

Figure 33Mortality

Figure 34Transfusion

Figure 35Adverse events: DVT

Figure 36Acute coronary syndrome

Figure 37Blood loss via haemoglobin level after surgery

Figure 38Total blood loss

Figure 39Surgical bleeding

Figure 40Postoperative bleeding

Figure 41Length of stay

E.6. Oral versus placebo

Figure 42Transfusion

Figure 43Adverse events: DVT

Figure 44Blood loss via haemoglobin level after surgery

Figure 45Total blood loss

Figure 46Surgical bleeding

Figure 47Length of stay

E.7. IV plus IA/topical versus placebo

Figure 48Transfusion

Figure 49Adverse events: DVT

Figure 50Blood loss via haemoglobin level after surgery

Figure 51Total blood loss

Figure 52Surgical bleeding

Figure 53Postoperative bleeding

Figure 54Length of stay

E.8. IA/topical versus IV

Figure 55Mortality

Figure 56Quality of life: SF-36 MCS

Figure 57Quality of life: SF-36 PCS

Figure 58Transfusion

Figure 59Adverse events: DVT

Figure 60Adverse events: acute myocardial infarction

Figure 61Blood loss via haemoglobin level after surgery

Figure 62Total blood loss

Figure 63Surgical bleeding

Figure 64Postoperative bleeding

Figure 65Length of stay

E.9. Oral versus IV

Figure 66Mortality

Figure 67Transfusion

Figure 68Adverse events: DVT

Figure 69Blood loss via haemoglobin level after surgery

Figure 70Total blood loss

Figure 71Surgical bleeding

Figure 72Length of stay

E.10. IA/topical versus oral

Figure 73Mortality

Figure 74Transfusion

Figure 75Adverse events: DVT

Figure 76Blood loss via haemoglobin level after surgery

Figure 77Total blood loss

Figure 78Surgical bleeding

Figure 79Length of stay

E.11. IV plus IA/topical versus IV

Figure 80Quality of life: SF-36 MCS

Figure 81Quality of life: SF-36 PCS

Figure 82Transfusion

Figure 83Adverse events: DVT

Figure 84Blood loss via haemoglobin level after surgery

Figure 85Total blood loss

Figure 86Postoperative bleeding

Figure 87Length of stay

E.12. IA/topical plus oral versus IA/topical

Figure 88Transfusion

Figure 89Adverse events: DVT

Figure 90Blood loss via haemoglobin level after surgery

Figure 91Total blood loss

Figure 92Postoperative bleeding

E.13. IV plus IA/topical versus IA/topical

Figure 93Quality of life: SF-36 MCS

Figure 94Quality of life: SF-36 PCS

Figure 95Transfusion

Figure 96Adverse events: DVT

Figure 97Blood loss via haemoglobin level after surgery

Figure 98Total blood loss

Figure 99Length of stay

Appendix F. GRADE tables

Table 27Clinical evidence profile: IA/topical versus no treatment

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IA/topical tranexamic acid	No treatment	Relative (95% CI)	Absolute	Quality	Importance
Transfusion (follow-up ranged from while admitted in hospital to 2 months after surgery)
10	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	88/539 (16.3%)	195/539 (36.2%)	RR 0.46 (0.37 to 0.56)	195 fewer per 1000 (from 159 fewer to 228 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
DVT (follow-up ranged from in hospital period to 1 year after surgery)
8	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	1/394 (0.25%)	3/396 (0.76%)	See comment²	8 fewer per 1000 (from 8 more to 8 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 12 hours to 5 days after surgery; Better indicated by higher values)
9	randomised trials	serious¹	very serious⁴	no serious indirectness	serious⁵	none	453	453	-	MD 0.43 higher (0.11 lower to 0.97 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Total blood loss (follow-up ranges from 1 to 5 days after surgery; Better indicated by lower values)
6	randomised trials	very serious¹	very serious⁴	no serious indirectness	serious⁵	none	352	357	-	SMD 1.5 lower (2.3 to 0.71 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
3	randomised trials	serious¹	very serious⁴	no serious indirectness	very serious⁵	none	177	178	-	SMD 0.65 lower (1.51 lower to 0.2 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up 24 hours after surgery; Better indicated by lower values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	47	48	-	MD 337.96 lower (435.16 to 240.76 lower)	⨁⨁⨁⨁ HIGH	IMPORTANT
Length of stay (Better indicated by lower values)
3	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	156	156	-	MD 0.06 lower (0.28 lower to 0.17 higher)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Risk difference used to analyse data due to very low event rates
3: Risk difference utilised to calculate absolute effect
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 28Clinical evidence profile: Oral versus no treatment

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Oral tranexamic acid	No treatment	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up 30 days after surgery)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	0/94 (0%)	0/95 (0%)	See comment³	0 fewer per 1000 (from 20 fewer to 20 more)⁴	⨁⨁◯◯ LOW	CRITICAL
Transfusion (follow-up unclear)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious⁵	none	1/94 (1.1%)	3/95 (3.2%)	RR 0.34 (0.04 to 3.18)	21 fewer per 1000 (from 30 fewer to 69 more)	⨁◯◯◯ VERY LOW	CRITICAL
DVT (follow-up within 7 days of surgery)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious⁵	none	1/94 (1.1%)	0/95 (0%)	Peto OR 7.47 (0.15 to 376.39)	10 more per 1000 (from 20 fewer to 40 more)⁴	⨁◯◯◯ VERY LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up unclear; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	94	95	-	MD 0.8 higher (0.56 to 1.04 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Total blood loss (follow-up unclear; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	94	95	-	MD 228 lower (293.22 to 162.78 lower)	⨁⨁⨁◯ MODERATE	CRITICAL
Length of stay (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	94	95	-	MD 0.1 higher (0.46 lower to 0.66 higher)	⨁⨁⨁◯ MODERATE

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Downgraded one increment for imprecision as it is a small study with no events.
3: Analysis via risk difference due to low event rate
4: Absolute effect calculated using risk difference
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 29Clinical evidence profile: IV versus no treatment

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IV tranexamic acid	No treatment	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up within 90 days of surgery)
1	randomised trials	very serious¹	no serious inconsistency	serious²	serious³	none	0/50 (0%)	0/50 (0%)	See comment⁴	0 fewer per 1000 (from 40 fewer to 40 more)⁵	⨁◯◯◯ VERY LOW	CRITICAL
Transfusion (follow-up ranged from in-hospital period to 90 days after surgery)
15	randomised trials	very serious¹	very serious⁶	no serious indirectness	no serious imprecision	none	74/699 (10.6%)	192/625 (30.7%)	See comment⁴	140 fewer per 1000 (from 210 fewer to 80 fewer)⁵	⨁◯◯◯ VERY LOW	CRITICAL
DVT (follow-up ranged from 2 days to 1 year after surgery)
14	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	13/571 (2.3%)	7/504 (1.4%)	See comment⁴	0 fewer per 1000 (from 20 fewer to 20 more)⁵	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 1 to 5 days after surgery; Better indicated by higher values)
11	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁷	none	526	512	-	MD 0.53 higher (0.38 to 0.67 higher)	⨁⨁◯◯ LOW	CRITICAL
Total blood loss (follow-up either unclear or 3 days after surgery; Better indicated by lower values)
8	randomised trials	serious¹	very serious⁶	no serious indirectness	no serious imprecision	none	437	436	-	SMD 1.33 lower (2.1 to 0.56 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
3	randomised trials	serious¹	very serious⁶	no serious indirectness	very serious⁷	none	178	178	-	SMD 0.88 lower (2.62 lower to 0.86 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up 24 hours after surgery; Better indicated by lower values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	48	48	-	MD 393.16 lower (483.74 to 302.58 lower)	⨁⨁⨁⨁ HIGH	IMPORTANT
Length of stay (Better indicated by lower values)
3	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	156	156	-	MD 0.03 lower (0.24 lower to 0.19 higher)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Considered indirect due to the study follow-up period extending beyond 30 days
3: Study considered imprecise because it is small and there were no events in either treatment group
4: Results analysed using risk difference due to low event rates
5: Risk difference utilised to calculate absolute effect
6: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
7: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 30Clinical evidence profile: IA/topical versus placebo

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IA/topical tranexamic acid	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up 15 days after surgery)
1	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	serious²	none	0/30 (0%)	0/30 (0%)	See comment³	0 fewer per 1000 (from 60 fewer to 60 more)⁴	⨁◯◯◯ VERY LOW	CRITICAL
Quality of life within 6 weeks (follow-up 3 months after surgery; measured with: EuroQol Index (EQ-5D); Better indicated by higher values)
2	randomised trials	very serious¹	no serious inconsistency	serious⁵	no serious imprecision	none	99	91	-	MD 0.06 lower (0.14 lower to 0.03 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Transfusion (follow-up ranged from 3 days to 3 months of surgery)
24	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	92/1347 (6.8%)	245/1242 (19.7%)	RR 0.36 (0.29 to 0.45)	126 fewer per 1000 (from 108 fewer to 140 fewer)	⨁⨁⨁⨁ HIGH	CRITICAL
DVT (follow-up ranged from 5 days to 3 months after surgery)
23	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious⁶	none	20/1228 (1.6%)	23/1200 (1.9%)	See comment³	0 fewer per 1000 (from 10 fewer to 10 more)⁴	⨁◯◯◯ VERY LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 24 hours to 5 days after surgery; Better indicated by higher values)
18	randomised trials	serious¹	very serious⁷	no serious indirectness	no serious imprecision	none	923	930	-	MD 1.04 higher (0.8 to 1.29 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Total blood loss (follow-up ranges from 1 to 5 days after surgery or until hospital discharge; Better indicated by lower values)
17	randomised trials	serious¹	serious⁷	no serious indirectness	no serious imprecision	none	874	743	-	SMD 0.94 lower (1.16 to 0.72 lower)	⨁⨁◯◯ LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
3	randomised trials	no serious risk of bias	very serious⁷	no serious indirectness	serious⁶	none	121	122	-	SMD 0.25 lower (0.93 lower to 0.44 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up ranges from 36 hours to 4 days after surgery; Better indicated by lower values)
5	randomised trials	no serious risk of bias	serious⁷	no serious indirectness	no serious imprecision	none	197	197	-	SMD 0.94 lower (1.35 to 0.53 lower)	⨁⨁⨁◯ MODERATE	IMPORTANT
Length of stay (Better indicated by lower values)
10	randomised trials	serious¹	serious⁷	no serious indirectness	no serious imprecision	none	554	554	-	MD 0.01 lower (0.2 lower to 0.18 higher)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Study considered imprecise because it is small and there were no events in either treatment group
3: Results analysed using risk difference due to low event rates
4: Risk difference used to calculate absolute effect
5: Considered indirect evidence as the outcome was outside of the specified timepoint
6: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
7: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 31Clinical evidence profile: IV versus placebo

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IV tranexamic acid	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up either during hospital stay or within 15 days of surgery)
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	0/184 (0%)	0/106 (0%)	See comment²	0 fewer per 1000 (from 30 fewer to 30 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Transfusion (follow-up ranged from 24 hours to 6 months after surgery)
44	randomised trials	serious⁴	serious⁵	no serious indirectness	no serious imprecision	none	253/1819 (13.9%)	537/1564 (34.3%)	RR 0.39 (0.32 to 0.49)	209 fewer per 1000 (from 175 fewer to 233 fewer)	⨁⨁◯◯ LOW	CRITICAL
DVT (follow-up ranged from in hospital period to 6 months after surgery)
45	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	28/1777 (1.6%)	26/1579 (1.6%)	See comment²	0 fewer per 1000 (from 10 fewer to 10 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Acute coronary syndrome (follow-up during hospital stay)
2	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁶	none	1/154 (0.65%)	0/76 (0%)	RD 0 (−0.02 to 0.04)²	10 more per 1000 (from 20 fewer to 40 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 1 day after surgery to discharge from hospital; Better indicated by lower values)
32	randomised trials	serious⁴	serious⁵	no serious indirectness	serious⁷	none	1321	1168	-	MD 0.64 higher (0.49 to 0.78 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Total blood loss (follow-up ranges from 1 to 6 days after surgery or until hospital discharge; Better indicated by lower values)
33	randomised trials	serious⁴	serious⁵	no serious indirectness	no serious imprecision	none	1419	1205	-	SMD 0.84 lower (1 to 0.68 lower)	⨁⨁◯◯ LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
13	randomised trials	serious⁴	very serious⁵	no serious indirectness	serious⁷	none	389	355	-	SMD 0.61 lower (0.97 to 0.25 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up ranges from 48 hours of surgery to in-hospital period; Better indicated by lower values)
13	randomised trials	serious⁴	very serious⁵	no serious indirectness	no serious imprecision	none	386	376	-	SMD 1.38 lower (1.87 to 0.89 lower)	⨁◯◯◯ VERY LOW	IMPORTANT
Length of stay (Better indicated by lower values)
14	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	684	588	-	MD 0.09 lower (0.18 to 0.01 lower)	⨁⨁⨁⨁ HIGH	IMPORTANT

1: Outcome considered imprecise due to low event rate
2: Analysis by risk difference due to low events rate
3: Absolute effect calculated using risk difference
4: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
5: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
6: No explanation was provided
7: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 32Clinical evidence profile: Oral versus placebo

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Oral tranexamic acid	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Transfusion (follow-up ranged from in hospital period to 3 months after surgery)
3	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	17/206 (8.3%)	45/200 (22.5%)	RR 0.38 (0.23 to 0.64)	139 fewer per 1000 (from 81 fewer to 173 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
DVT (follow-up ranged from 2 weeks to 3 months after surgery)
3	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	1/206 (0.49%)	2/200 (1%)	See comment²	10 fewer per 1000 (from 30 fewer to 20 more)³	⨁⨁⨁◯ MODERATE	center
Blood loss via haemoglobin level after surgery (follow-up ranges from 1 to 3 days after surgery; Better indicated by lower values)
3	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁴	none	206	200	-	MD 0.47 higher (0.37 to 0.57 higher)	⨁⨁◯◯ LOW	CRITICAL
Total blood loss (follow-up 3 days after surgery; Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	60	-	SMD 1.13 lower (1.51 to 0.75 lower)	⨁⨁⨁◯ MODERATE	CRITICAL
Surgical bleeding (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁴	none	40	40	-	MD 21.5 lower (34.91 to 8.09 lower)	⨁⨁◯◯ LOW	CRITICAL
Length of stay (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	40	40	-	MD 0.1 lower (0.69 to 0.49 lower)	⨁⨁⨁◯ MODERATE	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Analysed using risk difference due to low events rates
3: Absolute effect calculated using risk difference
4: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 33Clinical evidence profile: IV plus IA/topical versus placebo

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IV+IA/topical tranexamic acid	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Transfusion (follow-up while admitted in hospital)
4	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	3/190 (1.6%)	49/190 (25.8%)	RR 0.08 (0.03 to 0.22)	237 fewer per 1000 (from 201 fewer to 250 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
DVT (follow-up ranged from 2 weeks to 6 months after surgery)
4	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	3/190 (1.6%)	1/190 (0.53%)	See comment²	10 more per 1000 (from 20 fewer to 40 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up 3 days after surgery; Better indicated by lower values)
4	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	190	190	-	MD 1.45 higher (1.19 to 1.7 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Total blood loss (follow-up 3 days after surgery or in-hospital period; Better indicated by lower values)
4	randomised trials	serious¹	serious⁴	no serious indirectness	no serious imprecision	none	190	190	-	MD 294.44 lower (405.92 to 182.97 lower)	⨁⨁◯◯ LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	50	50	-	MD 94.4 lower (132.77 to 56.03 lower)	⨁⨁⨁◯ MODERATE	CRITICAL
Postoperative bleeding (follow-up 3 days after surgery; Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	100	100	-	SMD 0.92 lower (1.21 to 0.63 lower)	⨁⨁⨁◯ MODERATE	IMPORTANT
Length of stay (Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	100	100	-	MD 0.33 lower (0.76 lower to 0.1 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Analysed via risk difference due to low event rates
3: Absolute effect calculated using risk difference
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 34Clinical evidence profile: IA/topical versus IV

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IA/topical tranexamic acid	IV tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up ranged from 15 to 30 days after surgery)
3	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	serious²	none	1/137 (0.73%)	0/132 (0%)	See comment³	10 more per 1000 (from 20 fewer to 40 more)⁴	⨁◯◯◯ VERY LOW	CRITICAL
Quality of life (mental component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁵	none	50	50	-	MD 2.5 lower (6.87 lower to 1.87 higher)	⨁⨁◯◯ LOW	CRITICAL
Quality of life (physical component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁵	none	50	50	-	MD 2.26 lower (6.18 lower to 1.66 higher)	⨁⨁◯◯ LOW	CRITICAL
Transfusion (follow-up ranged from in hospital period to 3 months after surgery)
32	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	147/2051 (7.2%)	123/1927 (6.4%)	See comment³	10 more per 1000 (from 10 fewer to 20 more)⁴	⨁⨁⨁⨁ HIGH	CRITICAL
DVT (follow-up ranged from within 96 hours of surgery to 1 year after surgery)
29	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	18/1897 (0.95%)	26/1876 (1.4%)	See comment³	0 fewer per 1000 (from 10 fewer to 0 more)⁴	⨁⨁⨁⨁ HIGH	CRITICAL
Acute myocardial infarction (follow-up unclear)
1	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	very serious⁵	none	1/47 (2.1%)	0/42 (0%)	Peto OR 6.64 (0.13 to 336.89)	-	⨁◯◯◯ VERY LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 12 hours to 5 days after surgery; Better indicated by lower values)
19	randomised trials	serious¹	serious⁶	no serious indirectness	no serious imprecision	none	1302	1256	-	MD 0.03 higher (0.09 lower to 0.14 higher)	⨁⨁◯◯ LOW	CRITICAL
Total blood loss (follow-up ranges from 1 to 5 days after surgery; Better indicated by lower values)
26	randomised trials	serious¹	serious⁶	no serious indirectness	no serious imprecision	none	1386	1420	-	SMD 0.12 lower (0.27 lower to 0.04 higher)	⨁⨁◯◯ LOW	CRITICAL
Surgical bleeding (Better indicated by lower values)
6	randomised trials	serious¹	very serious⁶	no serious indirectness	very serious⁵	none	585	587	-	SMD 0.1 higher (0.73 lower to 0.92 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up ranges from 24 to 96 hours after surgery; Better indicated by lower values)
3	randomised trials	no serious risk of bias	serious⁶	no serious indirectness	serious⁵	none	135	137	-	SMD 0.09 higher (0.33 lower to 0.5 higher)	⨁⨁◯◯ LOW	IMPORTANT
Length of stay (Better indicated by lower values)
11	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	652	660	-	MD 0.04 higher (0.05 lower to 0.12 higher)	⨁⨁⨁⨁ HIGH	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Outcome considered imprecise because of the small number of participants and a single event
3: Results analysed using risk difference due to low event rates
4: Absolute effect calculated using risk difference
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
6: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 35Clinical evidence profile: Oral versus IV

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Oral tranexamic acid	IV tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up 30 days after surgery)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	0/60 (0%)	0/60 (0%)	Not estimable²	0 fewer per 1000 (from 30 fewer to 30 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Transfusion (follow-up ranged from in hospital period to 1 month after surgery)
7	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	very serious⁵	none	26/428 (6.1%)	28/434 (6.5%)	RR 0.94 (0.56 to 1.56)	4 fewer per 1000 (from 28 fewer to 36 more)	⨁◯◯◯ VERY LOW	CRITICAL
DVT (follow-up ranged from 30 days to 3 months after surgery)
7	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	1/468 (0.21%)	5/477 (1%)	See comment²	10 fewer per 1000 (from 20 fewer to 10 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 1 day after surgery to hospital discharge; Better indicated by lower values)
8	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	468	477	-	MD 0.01 higher (0.07 lower to 0.09 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Total blood loss (follow-up ranges from 1 to 3 days after surgery or until hospital discharge; Better indicated by lower values)
7	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	328	337	-	SMD 0.0 higher (0.16 lower to 0.15 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Surgical bleeding (Better indicated by lower values)
2	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	100	100	-	MD 0.46 higher (6.43 lower to 7.34 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Length of stay (Better indicated by lower values)
5	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	214	223	-	MD 0.02 lower (0.17 lower to 0.12 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT

1: Results considered imprecise due to zero events in both intervention groups
2: Analysis using risk difference due to low event rates
3: Absolute effect calculate through risk difference
4: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 36Clinical evidence profile: IA/topical versus oral

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IA/topical tranexamic acid	Oral tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days (follow-up 30 days after surgery)
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	0/192 (0%)	0/192 (0%)	See comment²	0 fewer per 1000 (from 20 fewer to 20 more)³	⨁⨁⨁◯ MODERATE	CRITICAL
Transfusion (follow-up ranged from in hospital period to 2 weeks after surgery)
5	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	very serious⁵	none	32/393 (8.1%)	25/394 (6.3%)	RR 1.28 (0.78 to 2.11)	18 more per 1000 (from 14 fewer to 70 more)	⨁◯◯◯ VERY LOW	CRITICAL
DVT (follow-up ranged from 2 weeks to 3 months after surgery)
5	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	serious⁶	none	0/391 (0%)	2/393 (0.51%)	See comment²	10 fewer per 1000 (from 20 fewer to 10 more)³	⨁⨁◯◯ LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 2 days after surgery until hospital discharge; Better indicated by lower values)
5	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	391	393	-	MD 0.04 lower (0.13 lower to 0.05 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Total blood loss (follow-up ranges from 3 days after surgery or until hospital discharge; Better indicated by lower values)
4	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	251	253	-	SMD 0.15 higher (0.02 lower to 0.33 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Surgical bleeding (Better indicated by lower values)
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	193	191	-	SMD 0.06 higher (0.15 lower to 0.26 higher)	⨁⨁⨁⨁ HIGH	CRITICAL
Length of stay (Better indicated by lower values)
2	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	118	119	-	MD 0.07 higher (0.16 lower to 0.29 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT

1: Outcome considered very imprecise because of the small number of participants and zero events
2: Analysis via risk difference due to low event rates
3: Absolute effect calculated using risk difference
4: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
6: Outcome considered imprecise because of the small number of participants and two events

Table 37Clinical evidence profile: IV plus IA/topical versus IV

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IV+IA/topical tranexamic acid	IV tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Quality of life (mental component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 1.32 lower (5.86 lower to 3.22 higher)	⨁⨁◯◯ LOW	CRITICAL
Quality of life (physical component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 1.22 lower (5.27 lower to 2.83 higher)	⨁⨁◯◯ LOW	CRITICAL
Transfusion (follow-up ranged from while admitted in hospital to 6 weeks after surgery)
7	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	7/393 (1.8%)	24/398 (6%)	Peto OR 0.32 (0.16 to 0.67)	41 fewer per 1000 (from 20 fewer to 51 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
DVT (follow-up ranged from in hospital period to 6 months after surgery)
8	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	16/443 (3.6%)	16/448 (3.6%)	See comment³	0 fewer per 1000 (from 20 fewer to 30 more)⁴	⨁⨁⨁◯ MODERATE	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 3 to 5 days after surgery; Better indicated by lower values)
8	randomised trials	serious¹	very serious⁵	no serious indirectness	serious²	none	444	447	-	MD 0.39 lower (0.69 to 0.09 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Total blood loss (follow-up ranges from 3 to 5 days after surgery; Better indicated by lower values)
6	randomised trials	serious¹	very serious⁵	no serious indirectness	serious²	none	343	348	-	SMD 0.76 lower (1.33 to 0.19 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Postoperative bleeding (follow-up ranges from within 3 days of surgery to during in hospital period; Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	100	100	-	SMD 0.18 lower (0.46 lower to 0.1 higher)	⨁⨁◯◯ LOW	IMPORTANT
Length of stay (Better indicated by lower values)
4	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	234	238	-	MD 0.19 lower (0.38 to 0.01 lower)	⨁⨁⨁◯ MODERATE	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Data analysed using risk difference due to low event rates
4: Absolute effect calculated using risk difference
5: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 38Clinical evidence profile: IA/topical plus oral versus IA/topical

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IA/topical+oral tranexamic acid	IA/topical tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Transfusion (follow-up within 3 days of surgery)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	0/50 (0%)	3/50 (6%)	OR 0.13 (0.01 to 1.28)	52 fewer per 1000 (from 59 fewer to 16 more)	⨁◯◯◯ VERY LOW	CRITICAL
DVT (follow-up 1 year after surgery)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious³	none	0/50 (0%)	0/50 (0%)	See comment⁴	0 fewer per 1000 (from 40 fewer to 40 more)⁵	⨁⨁◯◯ LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up 3 days after surgery; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 0.9 higher (0.37 to 1.43 higher)	⨁⨁◯◯ LOW	CRITICAL
Total blood loss (follow-up 3 days after surgery; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 103 lower (169.02 to 36.98 lower)	⨁⨁◯◯ LOW	CRITICAL
Postoperative bleeding (follow-up 3 days after surgery; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 47 lower (67.16 to 26.84 lower)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Outcome considered imprecise because of the small number of participants and zero events
4: Analysed via risk difference due to low event rate
5: Absolute effect calculated using risk difference

Table 39Clinical evidence profile: IV plus IA/topical versus IA/topical

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	IV+IA/topical tranexamic acid	IA/topical tranexamic acid	Relative (95% CI)	Absolute	Quality	Importance
Quality of life (mental component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 1.18 higher (2.84 lower to 5.2 higher)	⨁⨁◯◯ LOW	CRITICAL
Quality of life (physical component score) within 6 weeks (follow-up unclear; measured with: SF-36; range of scores: 0-100; Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	50	50	-	MD 1.04 higher (2.57 lower to 4.65 higher)	⨁⨁◯◯ LOW	CRITICAL
Transfusion (follow-up while admitted in hospital or within 5 days of surgery)
3	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	0/160 (0%)	6/160 (3.8%)	OR 0.13 (0.03 to 0.66)	32 fewer per 1000 (from 12 fewer to 36 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
DVT (follow-up 3 or 6 months after surgery)
4	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious³	none	12/210 (5.7%)	8/210 (3.8%)	See comment⁴	20 more per 1000 (from 20 fewer to 60 more)⁵	⨁⨁◯◯ LOW	CRITICAL
Blood loss via haemoglobin level after surgery (follow-up ranges from 3 to 5 days after surgery; Better indicated by lower values)
3	randomised trials	serious¹	very serious⁶	no serious indirectness	serious²	none	210	210	-	MD 0.54 higher (0.21 to 0.87 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Total blood loss (follow-up ranges from 3 to 5 days after surgery or until hospital discharge; Better indicated by lower values)
3	randomised trials	serious¹	serious⁶	no serious indirectness	serious²	none	210	210	-	SMD 0.60 lower (0.8 to 0.41 lower)	⨁◯◯◯ VERY LOW	CRITICAL
Length of stay (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	70	70	-	MD 0.15 higher (0.24 lower to 0.54 higher)	⨁◯◯◯ VERY LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Outcome considered imprecise due to small number of participants and low event rate
4: Analysis using risk difference due to low event rate
5: Absolute effect calculated using risk difference
6: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Appendix G. Health economic evidence selection

Figure 100Flow chart of health economic study selection for the guideline

a) Non-relevant population, intervention, comparison, design or setting; non-English language

b) One study was applicable to both Q3.1 and Q3.2

Appendix H. Health economic evidence tables

Download PDF (215K)

Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 40Studies excluded from the clinical review

Study	Exclusion reason
Abildgaard 2016²	Incorrect study design
Abrisham 2018³	Not in English
Abrishami 2009⁴	Unclear whether the population was people having primary joint replacement surgery
Ahmed 2018⁸	Unclear whether the population was people having primary joint replacement surgery
Akgul 2016⁹	Incorrect study design
Alipour 2013¹⁰	Unclear if the population is undergoing primary joint replacement surgery
Alshryda 2011¹⁴	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Alshryda 2014¹⁵	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Alvarez 2008¹⁷	Unclear if the population is undergoing primary joint replacement surgery
Alvarez 2019¹⁶	Not in English
Arora 2018¹⁹	Incorrect study design
Bagsby 2015²⁰	Incorrect study design
Balasubramanian 2016²¹	Unclear if the population is undergoing primary joint replacement surgery
Box 2018²⁶	Systematic review does not include knee or hip joint replacement. Included studies checked for this review.
Cao 2015³²	Not in English
Cao 2018³¹	Incorrect interventions
Castro-menendez 2016³³	Incorrect study design
Çavuşoğlu 2015³⁴	Not in English
Chai 2015³⁵	Not in English
Charoencholvanich 2011³⁶	Unclear whether the population was people having primary joint replacement surgery
Chen 2016⁴⁰	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Chen 2016⁴³	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Chen 2017⁴¹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Chen 2018³⁷	Not in English
Cui 2015⁴⁷	Not in English
Dai 2018⁴⁹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
De Napoli 2016⁵¹	Unable to acquire
Dhillon 2011⁵²	Inappropriate comparison
Drosos 2016⁵⁷	Unclear whether the population was people having primary joint replacement surgery
Duan 2017⁵⁸	Not in English
Durgut 2019⁵⁹	Incorrect study design
Ellis 2004⁶¹	Unclear whether the population was people having primary joint replacement surgery
Engel 2001⁶²	Unclear whether the population was people having primary joint replacement surgery
Fernandez-cortinas 2017⁶³	Not in English
Fillingham 2018⁶⁵	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Fillingham 2018⁶⁶	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Franchini 2018⁶⁷	Systematic with a different population. Included studies checked for this review.
Fraval 2017⁶⁸	Unclear whether the population was people having primary joint replacement surgery
Friedman 2016⁶⁹	Incorrect study design
Fu 2013⁷⁰	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Fu 2016⁷¹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Gandhi 2013⁷²	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Gao 2015⁷³	incorrect comparison
Georgiev 2018⁸⁰	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Ghijselings 2015⁸¹	Unable to acquire
Gianakos 2018⁸²	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Gill 2009⁸³	Not review population
Gomez-barbero 2019⁸⁶	Not in English
Guo 2018⁹³	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Hanna 2016⁹⁴	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
He 2015⁹⁶	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
He 2017⁹⁵	Systematic review does not include hip or knee joint replacement. Included studies checked for this review.
Hegde 2013⁹⁷	Incorrect study design
Hiippala 1995⁹⁸	Unclear how tranexamic acid was administered
Hiippala 1997⁹⁹	Unclear whether the population was people having primary joint replacement surgery
Hill 2018¹⁰⁰	Study protocol
Ho 2003¹⁰¹	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Hou 2017¹⁰²	Not in English
Hourlier 2015¹⁰³	Inappropriate comparison
Hu 2018¹⁰⁵	Not in English
Huang 2015¹⁰⁸	Not in English
Huang 2016¹⁰⁶	Unclear whether the population was people having primary joint replacement surgery
Hynes 2003¹¹⁰	Incorrect study design
Iseki 2018¹¹³	Incorrect study design
Ishii 2015¹¹⁵	Incorrect study design
Jansen 1999¹¹⁷	Unclear how tranexamic acid was administered
Jiang 2016¹¹⁹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Johansson 2005¹²⁰	Unclear whether the population was people having primary joint replacement surgery
Jordan 2019¹²¹	Unclear whether the population was people having primary joint replacement surgery
Kang 2017¹²³	Incorrect study design
Karaaslan 2014¹²⁴	Abstract
Karam 2014¹²⁵	Incorrect study design
Kelley 2014¹²⁸	Incorrect study design
Kim 2017¹³³	Incorrect study design
Kim 2017¹³⁰	Incorrect study design
Kim 2018¹³²	All people received both interventions randomised by knee
Konig 2013¹³⁴	Incorrect study design
Kuo 2018¹³⁶	Systematic review does not include hip or knee joint replacement. Included studies checked for this review.
Kwok 2018¹³⁷	Incorrect study design
Lanoiselee 2018¹³⁹	Inappropriate comparison
Lee 2017¹⁴¹	Incorrect study design
Lei 2017¹⁴⁶	Not review population
Li 2016¹⁴⁹	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Li 2017¹⁴⁸	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Li 2017¹⁵⁰	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Li 2017¹⁵¹	Not in English
Lin 2011¹⁵³	Incorrect study design
Lin 2016¹⁵²	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Liu 2017¹⁵⁷	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Liu 2017¹⁵⁸	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Liu 2018¹⁵⁶	Unclear whether the population was people having primary joint replacement surgery
Lopez-hualda 2018¹⁵⁹	Not in English
Lopez-picado 2017¹⁶⁰	Incorrect study design
Ma 2014¹⁶³	Not in English
Macgillivray 2011¹⁶⁴	Unclear whether the population was people having primary joint replacement surgery
Machin 2014¹⁶⁵	Incorrect study design
March 2013¹⁶⁸	Incorrect study design
Marra 2016¹⁶⁹	Incorrect study design
Meena 2017¹⁷⁴	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Mi 2017¹⁷⁸	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Mi 2017¹⁷⁷	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Min 2015¹⁷⁹	Not in English
Moskal 2016¹⁸¹	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Moskal 2018¹⁸²	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Mutsuzaki 2012¹⁸⁴	Incorrect study design
Ni 2016¹⁸⁹	Not in English
Nielsen 2016¹⁹⁰	Unclear whether the population was people having primary joint replacement surgery
Oremus 2014¹⁹⁴	Incorrect interventions
Panteli 2013¹⁹⁹	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Peng Zhang 2017²⁰²	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Perreault 2017²⁰⁴	Incorrect study design
Pertlíček 2015²⁰⁵	Not in English
Pinzon-florez 2015²⁰⁷	Not in English
Pongcharoen 2016²⁰⁸	Incorrect study design
Prabhu 2015²⁰⁹	Unclear how tranexamic acid was administered
Prakash 2018²¹¹	Unclear whether the population was people having primary joint replacement surgery
Rajesparan 2009²¹²	Incorrect study design
Raviraj 2012²¹³	Unclear whether the population was people having primary joint replacement surgery
Sadigursky 2016²¹⁶	Incorrect study design
Sadigursky 2018²¹⁷	Literature review. Studies checked for inclusion in this review.
Sanz-reig 2018²¹⁸	Incorrect study design
Sarzaeem 2014²¹⁹	Unclear whether the population was people having primary joint replacement surgery
Seo 2013²²⁰	Unclear whether the population was people having primary joint replacement surgery
Seol 2016²²¹	Incorrect study design
Shang 2016²²²	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Shen 2015²²³	Unclear whether the population was people having primary joint replacement surgery
Shin 2017²²⁴	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Singh 2010²²⁶	Incorrect study design
Soni 2014²²⁸	Unclear whether the population was people having primary joint replacement surgery
Sridharan 2017²²⁹	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Sridharan 2018²³⁰	NMA does not include knee or shoulder joint replacement. Included studies checked for this review.
Sridharan 2018²³¹	NMA does not include hip or shoulder joint replacement. Included studies checked for this review.
Subramanyam 2018²³⁴	Unclear whether the population was people having primary joint replacement surgery
Sukeik 2011²³⁵	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Sun 2016²³⁷	Not in English
Sun 2016²³⁸	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Sun 2017²³⁶	Systematic review does not include knee or hip joint replacement. Included studies checked for this review.
Sun 2017²³⁹	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Tan 2013²⁴⁰	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Tavares Sanchez-monge 2018²⁴²	Not English language
Thipparampall 2017²⁴³	Not review population
Tzatzairis 2016²⁴⁴	Unclear whether the population was people having primary joint replacement surgery
Ueno 2016²⁴⁵	Incorrect study design
Volquind 2016²⁵⁰	Inclusion included those with RA
Wang 2014²⁵⁷	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Wang 2015²⁵⁸	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Wang 2015²⁶⁰	Not in English
Wang 2015²⁵²	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Wang 2017²⁶²	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Wang 2017²⁶¹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Wei 2015²⁶⁵	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Weng 2016²⁶⁶	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Wind 2013²⁶⁷	Incorrect study design
Wind 2014²⁶⁸	Incorrect study design
Wong 2009²⁶⁹	Unclear whether the population was people having primary joint replacement surgery
Wu 2015²⁷²	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Wu 2017²⁷¹	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Wu 2017²⁷³	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Wu 2018²⁷⁴	Incorrect interventions
Xie 2017²⁷⁵	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Xu 2015²⁷⁷	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Yamasaki 2005²⁷⁸	Unclear whether the population was people having primary joint replacement surgery
Yang 2012²⁸¹	Systematic review does not include hip or shoulder joint replacement. Included studies checked for this review.
Yang 2017²⁷⁹	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Yu 2015²⁸⁴	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Yu 2017²⁸³	Systematic review does not include knee or hip joint replacement. Included studies checked for this review.
Yuan 2016²⁸⁶	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Yue 2015²⁸⁸	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Zhang 2007²⁹³	Not in English
Zhang 2014³⁰¹	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Zhang 2015²⁹²	Not in English
Zhang 2016²⁹⁸	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Zhang 2017²⁹⁵	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Zhang 2017²⁹⁹	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Zhang 2017³⁰⁰	Systematic review with different interventions. Included studies checked for this review.
Zhang 2017²⁹⁶	Systematic review does not include shoulder joint replacement. Included studies checked for this review.
Zhang 2017²⁹⁷	Not review population
Zhang 2017²⁹⁴	Systematic review does not include shoulder or knee joint replacement. Included studies checked for this review.
Zhao-Yu 2014³⁰⁴	Systematic review does not include shoulder or hip joint replacement. Included studies checked for this review.
Zhao 2016³⁰⁶	Not in English
Zhou 2013³⁰⁸	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Zhu 2017³⁰⁹	Systematic review does not include knee or shoulder joint replacement. Included studies checked for this review.
Zohar 2004³¹⁰	Unclear whether the population was people having primary joint replacement surgery

I.2. Excluded health economic studies

Table 41Studies excluded from the health economic review

Reference	Reason for exclusion
Irisson 2012¹¹²	More applicable UK analyses were available, ¹² ¹³ ⁵⁰ so this study was selectively excluded.
Vigna-Taglianti 2014²⁴⁹	More applicable UK analyses were available, ¹² ¹³ ⁵⁰ so this study was selectively excluded.
Chen 2015³⁹	Inadequate adjustment of data
Goyal 2016⁸⁹	Inadequate adjustment of data
McGoldrick 2015¹⁷³	Inadequate adjustment of data
Panchmatia 2012¹⁹⁸	Inadequate adjustment of data

Figures

Figure 1TXA transfusion event NMA structure. Blue shapes indicate a monotherapy and red shapes indicate a combination therapy. Numbers show the amount of studies comparing the relevant interventions

Tables

Table 1PICO characteristics of review question

Population	Adults having primary elective joint replacement
Interventions	Perioperative use of topical/intra-articular tranexamic acid Perioperative use of intravenous tranexamic acid Perioperative use of oral tranexamic acid Perioperative use of topical/intra-articular and intravenous tranexamic acid Perioperative use of topical/intra-articular and oral tranexamic acid Perioperative use of intravenous and oral tranexamic acid Perioperative use of topical/intra-articular, intravenous and oral tranexamic acid
Comparison	Comparison versus interventions or versus placebo or no treatment.
Outcomes	Critical Mortality: 30 day (dichotomous) Blood (allogeneic or autologous) transfusion (dichotomous) Adverse events Acute myocardial infarction (dichotomous) Postoperative thrombosis (dichotomous) Quality of life within 6 weeks (continuous) Surgical bleeding (continuous) Important Postoperative anaemia (dichotomous) Postoperative bleeding (continuous) Length of stay (continuous)
Study design	Randomised controlled trials If no well-conducted RCTs are available, then observational studies with multivariate analysis will be investigated.

Table 2Summary of studies under each comparison in the evidence review

Study	Intervention and comparison	Population	Outcomes	Comments
IA/topical versus no treatment
Aguilera 2015⁷	After prosthesis inserted and cemented, operative field was rinsed and dried. 1g in 10mL solution topically applied by syringe spray to the posterior capsule, surrounding soft tissue, fatty and subcutaneous tissue, exposed surfaces of femur and tibia. versus No treatment	Adults having elective total knee replacement due to OA or RA or other degenerative knee disorders	Transfusion Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Postoperative bleeding Length of stay
Antinolfi 2014¹⁸	500mg injected inside the joint, while no knee flexion or compression was applied versus No treatment	People with primary knee osteoarthritis and scheduled to undergo unilateral primary TKA	Blood loss via haemoglobin level after surgery Total blood loss Adverse events: DVT
Digas 2015⁵⁶	2g after skin closure versus No treatment	People under 85 years old with primary osteoarthritis who we scheduled for total knee arthroplasty.	Transfusion Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Adverse events: DVT
Guerreiro 2017⁹¹	1g in 50ml versus No treatment	People undergoing total knee arthroplasty	Transfusion Blood loss via haemoglobin level after surgery Adverse events: DVT
Keyhani 2016¹²⁹	3g in 100ml normal saline. Half of the solution was used to irrigate the joint before joint closure. The remaining half of the volume was administered in the joint after wound closure by a portovac drain versus No treatment	People with osteoarthritis of the knee scheduled to undergo primary unilateral TKA	Transfusion Blood loss via haemoglobin level after surgery
Lacko 2017¹³⁸	3g in 50 mL of saline, applied directly into surgical wound following the cementing of the implant. versus No treatment	People with primary or secondary osteoarthritis and having unilateral cemented primary total knee replacement	Adverse events: DVT
Laoruengthana 2019¹⁴⁰	15mg/kg poured into knee joint before closure of the arthrotomy. versus No treatment	People with primary osteoarthritis who are scheduled for primary unilateral total knee arthroplasty	Transfusion Length of stay
Mehta 2019¹⁷⁵	2.5g (25ml) in 25ml saline. Equally given to each knee joint after wound closure. versus No treatment	People having primary bilateral total knee arthroplasty due to advanced osteoarthritis of the knee.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
Oztas 2015¹⁹⁶	2g was applied locally on the proximal-medial surface of the patella with intra-articular injection after the joint capsule closure in the final stage of the operation before the tourniquet deflation versus No treatment	People with inflammatory arthritis, history of thromboembolism, myocardial infarction and stroke and allergy to tranexamic acid.	Transfusion Adverse events: DVT Total blood loss Length of stay
Perez-Jimeno, 2018²⁰³	2g administered following skin closure through the deeper drainage tube. versus No treatment	People scheduled for cemented or non-cemented primary elective total hip arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Ugurlu 2017²⁴⁶	3g in 100ml saline. 50ml administered with infiltration to wound lips following suturing of the capsular incision. 50ml administered into the joint. versus No treatment	People undergoing primary total knee arthroplasty for degenerative osteoarthritis.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zhang 2016³⁰²	1g in 100ml saline via the drainage tubes. versus No treatment	Diabetes, bleeding disorders, preoperative anaemia, malignancies, history of thrombosis disease, arteriosclerosis, varicose veins and other cardiovascular diseases, allergy to tranexamic acid, kidney dysfunction.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Oral versus no treatment
Lee 2017a¹⁴²	1g 2 hours before induction of anaesthesia and then two more doses 6 hours and 12 hours postoperatively versus No treatment	People undergoing primary total knee arthroplasty	Mortality Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
IV versus no treatment
Aguilera 2015⁷	2 doses of 1g. 15-30 minutes before tourniquet inflated and again when tourniquet is removed versus No treatment	Adults having elective total knee replacement due to OA or RA or other degenerative knee disorders	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Postoperative bleeding Length of stay
Digas 2015⁵⁶	15mg/kg before deflation of the tourniquet.	People under 85 years old with primary osteoarthritis who we scheduled for total knee arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding
Gautam 2013⁷⁶	10 mg/kg slow injection 10 minutes before deflation of tourniquet. versus No treatment	People having total knee arthroplasty	Total blood loss Adverse events: DVT
Imai 2012¹¹¹	1g administered 10 minutes before surgery and again 6 hours later versus No treatment	People undergoing primary total hip replacement for osteoarthritis of the hip.	Transfusion Adverse events: DVT
Keyhani 2016¹²⁹	500mg in 100cc saline administered at the end of surgery versus No treatment	People with osteoarthritis of the knee scheduled to undergo primary unilateral TKA	Transfusion Blood loss via haemoglobin level after surgery
Kim 2014¹³¹	10mg/kg 30 min before tourniquet deflation, and the same amount was repeated 3 hours later. versus No treatment	People undergoing total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Lacko 2017¹³⁸	2 doses of 10mg/kg. The first dose was administered 20 minutes prior to incision and the second dose was administered three hours after the first dose versus No treatment	People with primary or secondary osteoarthritis and having unilateral cemented primary total knee replacement	Adverse events: DVT
Laoruengthana 2019¹⁴⁰	10mg/kg administered before closure of the arthrotomy. versus No treatment	People with primary osteoarthritis who are scheduled for primary unilateral total knee arthroplasty	Transfusion Length of stay
Mehta 2019¹⁷⁵	1g administered after regional anaesthesia but before tourniquet inflation. versus No treatment	People having primary bilateral total knee arthroplasty due to advanced osteoarthritis of the knee.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
Mcconnell 2011¹⁷²	10 mg/kg at the start of surgery versus No treatment	People who were scheduled to undergo elective primary unilateral cemented hip arthroplasty.	Adverse events: DVT
Melo 2017¹⁷⁶	15mg/kg IV 20 minutes before incision (maximum dose 2g). Half of the people received an extra dose of 10mg/kg using an infusion pump throughout the surgical procedure. versus No treatment	People undergoing primary THA	Blood loss via haemoglobin level after surgery
Molloy 2007¹⁸⁰	500mg five minutes before deflation of the tourniquet and a repeat dose three hours later versus No treatment	People with a pre-operative haemoglobin (Hb) level of 13.0 g/dl or less who were scheduled to undergo a primary TKR	Mortality Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Oztas 2015¹⁹⁶	20mg/kg dose administered 15 minutes before tourniquet inflated. versus No treatment	People with degenerative knee osteoarthritis who did not respond to conservative treatment and underwent unilateral primary TKR	Transfusion Adverse events: DVT Total blood loss Length of stay
Pachauri 2014¹⁹⁷	1g given 1 hour before surgery and a second dose 6 hours later. versus No treatment	People with osteoarthritis scheduled for total knee replacement	No outcomes of interest identified
Ugurlu 2017²⁴⁶	3g in 100ml saline. 50ml administered with infiltration to wound lips following suturing of the capsular incision. 50ml administered into the joint. versus No treatment	People undergoing primary total knee arthroplasty for degenerative osteoarthritis.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zhang 2016³⁰²	1g diluted in 250ml saline and administered via IV infusion 10 minutes before the surgery. versus No treatment	People scheduled for unilateral primary total hip replacement for osteonecrosis of the femoral head and a BMI between 18.5 and 30.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
IA/topical versus placebo
Alshryda 2013a¹²	1g in 50ml saline sprayed into the wound end of the total hip replacement immediately before the wound is dressed. versus Saline placebo	People undergoing primary unilateral total hip replacement.	Quality of life Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Alshryda 2013b¹³	1g in 50ml saline sprayed into the wound end of the total knee replacement immediately before the wound is dressed. versus Saline placebo	People undergoing primary unilateral total knee replacement.	Quality of life Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Georgiadis 2013⁷⁸	2g in 75mLsaline versus Saline placebo	Patients undergoing unilateral primary total knee arthroplasty (TKA)	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Gillespie 2015⁸⁴	2g in 100ml saline poured into surgical wound before closure and left in place for 5 minutes. versus Saline placebo	People undergoing conventional total shoulder arthroplasty or reverse total shoulder arthroplasty.	Transfusion Adverse events: DVT
Ishida 2011¹¹⁴	2g in 20ml into the knee joint versus Saline placebo	People with osteoarthritis scheduled for primary TKA	Transfusion
Lin 2015¹⁵⁵	1g in 20mL normal saline using IA application intraoperatively after joint capsule closure versus Saline placebo	People scheduled for unilateral TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Martin 2014¹⁷⁰	2g in 100 ml of normal saline into the joint space prior to surgical closure. versus Saline placebo	Aged 18 years and older, who were scheduled for a primary TKA or primary THA with or without cement	Transfusion Adverse events: DVT
Onodera 2012¹⁹³	1g in 50ml saline with 50g carbazochrome sodium sulfonate injected through the drain immediately after wound closure. versus Saline placebo	People having primary total knee replacement	Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Prakash 2017²¹⁰	3g in 50ml saline applied to joint cavity 5 minutes before closure. OR 3g in saline retrograde through the drain after closure. versus Saline placebo	People with primary osteoarthritis who were scheduled for primary unilateral total knee arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Roy 2012²¹⁴	Two drain tubes were placed inside the joint through which 500mg in 5ml was administered versus Saline placebo	People under 80 years of age with osteoarthritis scheduled for elective primary unilateral cemented-TKA	Transfusion Blood loss via haemoglobin level after surgery Surgical bleeding Postoperative bleeding
Sa-Ngasoongsong 2011²¹⁵	250mg in 25mL of physiologic saline injected into knee joint after completion of fascial closure. versus Saline placebo	People with primary knee osteoarthritis and undergoing unilateral primary cemented computer-assisted TKR	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Postoperative bleeding
Song 2017²²⁷	1.5g in 50 mL of saline retrograde through the drain after wound closure versus Saline placebo	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Stowers 2017²³³	1.5g in 20mL of saline after implantation of prosthesis and closure of arthrotomy followed by standard closure. versus Saline placebo	Adults undergoing primary unilateral TKA	Transfusion Adverse events: DVT Total blood loss
Wang 2015a²⁵⁶	1g in 50 ml saline and injected after prosthesis implantation and before cavity closed. versus Saline placebo	People undergoing primary unilateral TKA. All patients were treated with patellar medial approach, and the implants were CR knee bone cement prosthesis Gemini MKII	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Wang 2015b²⁵³	Immediately after skin closure, 10mL saline with 0.5g TXA was 7injected into the joint. versus Saline placebo	Primary varus knee osteoarthritis and scheduled for unilateral primary TKA.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Wang 2017²⁵⁹	1g in 50 mL saline was administered right before skin closure. versus Saline placebo	People aged 30 years and older, who were scheduled for primary unilateral TKA for end-stage osteoarthritis	Transfusion Adverse events: DVT Total blood loss Length of stay
Wei 2014²⁶⁴	3g mixed with 100ml saline. During surgery, the acetabulum was bathed in 20ml. Following femoral canal broach preparation, the femoral canal was filled with 20ml. The remaining 60ml was injected into the hip joint following fascia closure. versus Saline placebo	People aged 45–80 years who were scheduled for unilateral cementless primary total hip replacement.	Transfusion Adverse events: DVT Total blood loss Length of stay
Wong 2010²⁷⁰	1.5g OR 3g in saline solution. After all components were cemented in place, the joint was thoroughly irrigated and the solution was applied to the joint surfaces using a bulb syringe and left in contact for 5 minutes. versus Saline placebo	People undergoing total knee arthroplasty.	Transfusion Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Yang 2015²⁸⁰	500mg in 20ml into knee joint cavity after completion of the facial closure. versus Saline placebo	People >60 years old with OA, traumatic arthritis or RA and a BMI <40kg/m².	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Surgical bleeding Postoperative bleeding
Yuan 2017²⁸⁵	3g total 60mL solution administered after the subcutaneous tissue was sutured. Oral and IV placebo used. versus Saline placebo	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Yue 2014²⁸⁷	3g TXA in 150 mL saline was used at three time points. First, after the acetabular preparation then, after femoral canal broach preparation. The remaining 50 mL TXA fluid was injected to the hip joint after fascia closure. versus Saline placebo	People undergoing primary unilateral total hip arthroplasty for OA or ONFH	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding Length of stay
Zekcer 2016²⁸⁹	1.5g in 50 ml of saline which was sprayed over the operated area for 5 minutes, before the tourniquet was released. versus Saline placebo	People scheduled for unilateral TKA due to arthrosis (Albach grades III and IV)	Mortality Transfusion Adverse events: DVT
Zhou 2018³⁰⁷	3g in 60ml saline soaking the hip cavity before the end of surgery. versus Placebo	Adults scheduled to undergo primary unilateral THA	Transfusion Adverse events: DVT Total blood loss Surgical bleeding Postoperative bleeding
IV versus placebo
Almeida 2018¹¹	1g injected before the pneumatic cuff was inflated. versus Placebo	People with primary knee osteoarthrosis who were scheduled for TKA	Transfusion Blood loss via haemoglobin level after surgery Total blood loss
Barrachina 2016²²	IV infusion of 15 mg/kg in 100 mL saline over a 10-minute period after the institution of regional anaesthesia and before the start of surgery. Three hours later they received a second infusion over 10 minutes. In this case half of the people received only saline and half tranexamic acid infusion. versus Saline infusions.	Hip replacement surgery (unilateral, bicompartmental, primary, uncemented, posterolateral, or anterolateral) for arthrosis in adults with ASA physical status I to III and no known allergy to tranexamic acid.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding
Benoni 1996²³	10 mg/kg (maximum 1g) a slow injection towards the end of the operation at a median time of 12 minutes (1 to 40) before deflation of the tourniquet. This dose was repeated after three hours. versus Two placebo infusions	A diagnosis of osteoarthritis or aseptic bone necrosis, but not of rheumatoid arthritis; primary, unilateral, bicompartmental knee arthroplasty	Transfusion Adverse events: DVT Total blood loss
Benoni 2001²⁴	10 mg/kg (maximum 1g) in a slow injection immediately before the operation started versus Saline infusion	People scheduled for a unilateral, primary total hip replacement for osteoarthrosis or osteonecrosis.	Transfusion Adverse events: DVT
Bidolegui 2014²⁵	Two 10-minute infusions of 15mg/kg (diluted in 100 cc of normal saline) versus Placebo	People with osteoarthritis who are scheduled to have primary, unilateral total knee arthroplasty. All people had normal preoperative platelet count, normal prothrombin time, normal partial thromboplastin time, normal international normalized ratio	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Length of stay
Camarasa 2006²⁸	2 doses of 10mg/kg. First during 30 minutes before tourniquet release, second 3 hours after first dose. versus 2 saline doses	People who needed unilateral, bicompartmental, primary, cemented TKR because of osteoarthritis or rheumatoid arthritis and were in the anaesthetic risk groups ASA I–III were invited to participate in the study.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Chen 2016a⁴²	1g in 100 mL 10 minutes before the tourniquet was inflated versus Saline placebo	Patients eligible for simultaneous bilateral cemented total knee arthroplasty (TKAs) with a diagnosis of primary osteoarthritis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Claeys 2007⁴⁴	15mg/kg single slow injection 15 minutes before first incision. versus Saline slow IV injection	People ASA I-II undergoing unilateral elective primary total hip replacement.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding
Clave 2019⁴⁵	2 IV groups. 1 group received 1g at 0 (incision) and then 3, 7 and 11 hours after surgery. The other group had placebo for the later 2 time points. versus Placebo	Adults awaiting primary elective THA	Mortality Transfusion Adverse events: DVT Acute coronary syndrome Total blood loss Length of stay
Cvetanovich 2018⁴⁸	1g diluted in 10mL normal saline 10 minutes before incision versus 10mL of normal saline	Patients undergoing a unilateral primary anatomic or reverse primary total shoulder arthroplasty TSA at a single institution.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Ekback 2000⁶⁰	10 mg/kg before surgical incision. A continuous infusion of 1.0 mg/ kg/h for 10 h was then started immediately after the first dose. A second dose of 10mg/kg body weight was given 3 h later. versus Saline as placebo	Patients undergoing total hip replacement (THR)	Transfusion Adverse events: DVT
Garneti 2004⁷⁴	10mg/kg dose versus Saline placebo	Patients with a diagnosis of primary osteoarthritis of the hip necessitating total hip arthroplasty (THA)	Transfusion Total blood loss Postoperative bleeding
Gautam 2011⁷⁵	10mg/kg approximately half an hour before deflation of tourniquet versus Saline placebo	People scheduled for elective primary unilateral TKR for osteoarthritis	Transfusion Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding
Good 2003⁸⁷	10mg/ kg infusion and dose was repeated after 3 hours. versus placebo	Patients who had elective total primary unilateral tricompartmental knee arthroplasty because of osteoarthrosis, and were all classified as ASA I or II.	Transfusion Adverse events: DVT
Hsu 2015¹⁰⁴	2 doses of 1g in 20ml. The first 10 minutes before incision and the second 3 hours later. versus Saline placebo	People undergoing hip arthroplasty	Adverse events: DVT Surgical bleeding Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding Length of stay
Husted 2003¹⁰⁹	10 mg/kg (maximum 1g) sloq infusion before the incision, followed by a continuous infusion of 1 mg/kg/hour dissolved in 1L of saline for 10 hours (maximum 1 g/10 hours). versus Saline placebo	Patients scheduled for primary total hip arthroplasty due to arthrosis or osteonecrosis of the femoral head.	Transfusion Adverse events: DVT Total blood loss Postoperative bleeding
Kakar 2009¹²²	10mg/kg followed by an infusion of 1mg/kg/hr until skin closure. versus Saline placebo	People undergoing primary cemented unilateral(U/L) or bilateral(B/L) total knee arthroplasties.	Adverse events: DVT
Kazemi 2010¹²⁷	15mg/kg was given slowly for 5 minutes preoperatively versus Saline placebo	People having cementless hip replacement	Adverse events: DVT Blood loss via haemoglobin level after surgery Length of stay
Kundu 2015¹³⁵	20mg/kg diluted to 25cc with normal saline administered before surgery versus Saline placebo	American Society of Anesthesiologists I-II patients scheduled for unilateral total knee replacement (TKR)	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Surgical bleeding Postoperative bleeding
Lee 2013a¹⁴⁵	15 mg/kg administered slowly over 10 minutes before the surgical incision was made then a continuous infusion of 15 mg/kg in saline until skin closure. versus Saline placebo	ASA physical status 1 and 2 patients scheduled to undergo primary unilateral cementless total hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Postoperative bleeding Length of stay
Lee 2013b¹⁴³	2 doses of 10 mg/kg. The first infusion after implantation before tourniquet release and the second infusion 6 hours after the first. versus Placebo	People undergoing elective primary TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Lemay 2004¹⁴⁷	10mg/kg followed by an infusion of 1 mg/kg/hr until skin closure. versus Saline placebo	Patients were eligible for this study if they were ASA classI to III and were undergoing primary total hip replacement (THR)	Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Lin 2012¹⁵⁴	Half the people received 10 mg/kg five minutes before the incision. All people received 10 mg/kg by slow intravenous infusion five minutes before deflation of the tourniquet. versus Saline placebo	People having unilateral minimally invasive primary TKR	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Malhotra 2011¹⁶⁶	15kg/mg 15 minutes before incision. versus Saline placebo	People undergoing unilateral cementless total hip arthroplasty.	Transfusion Adverse events: DVT
Motififard 2015¹⁸³	2 doses of 500mg diluted in saline. First dose was infused in over 10 minutes about 30 minutes before inflation of tourniquet and the second dose after staying in the recovery room for three hours. versus Saline placebo	People with osteoarthritis who were indicated for primary TKA.	Adverse events: DVT Blood loss via haemoglobin level after surgery Surgical bleeding Length of stay
Niskanen 2005¹⁹¹	3 dosesof 10 mg/kg mixed in 100 mL saline. The first injection was given intravenously over 5–10 min, immediately before the operation. The next two doses were given 8 hours and 16 hours after the first injection. versus Saline placebo	Consecutive people who were scheduled for a cemented hip arthroplasty for osteoarthritis.	Transfusion Total blood loss Surgical bleeding
Orpen 2006¹⁹⁵	15mg/kg at the time that cement mixing commenced. versus Saline placebo	People scheduled for total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Postoperative bleeding
Pauzenberger 2017²⁰¹	1g in 100ml saline 30 minutes prior to incision. 1g in 100ml saline during wound closure. versus Saline placebo	People over 40 years old undergoing primary TSA or RTSA	Transfusion Total blood loss
Prakash 2017²¹⁰	10mg/kg administered 3 times. 20 minutes before tourniquet application, 15 minutes before deflation of the tourniquet, 3 hours after the previous dose in the postoperative period. versus Saline placebo	People with primary osteoarthritis who were scheduled for primary unilateral total knee arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Shinde 2015²²⁵	3 doses of 10 mg/kg. The first dose was prior to inflation of the tourniquet after induction, the second dose was 4 hours after the first dose either in the recovery room or in the ward and the third dose was after 12 hours of the first dose. versus Saline placebo	People with tricompartmental osteoarthritis of the knee and scheduled for unilateral total knee replacement were included in the study	Transfusion Adverse events: DVT Surgical bleeding Postoperative bleeding
Song 2017²²⁷	10mg/kg 20 minutes before tourniquet application as a preoperative dose, 10 mg/kg 15 minutes before deflation of the tourniquet as an intraoperative dose, and 10 mg/kg 3 hours after the second dose as a postoperative dose. As placebo, the group received 50 mL of saline retrograde through drain after surgery. versus Saline placebo	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Stowers 2017²³³	1.5g at the before release of tourniquet versus Saline placebo	Adults undergoing primary unilateral TKA	Transfusion Adverse events: DVT Total blood loss
Tanaka 2001²⁴¹	One or two doses: 20mg/kg minutes before surgery and/or 20mg/kg ten minutes before deflation of the tourniquet versus Saline placebo	People with rheumatoid arthritis or osteoarthritis who were scheduled to have a unilateral bicondylar cemented TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Vara 2017²⁴⁷	2 doses of 10mg/kg. Firstly within 60 minutes of surgery. Secondly at wound closure. versus Saline placebo	Adults undergoing primary RTSA for massive cuff deficiency with or without glenohumeral arthrosis.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding
Veien 2002²⁴⁸	10mg/kg given just before release of tourniquet and again 3 hours later. versus Saline placebo	Adults undergoing primary cemented TKR.	Transfusion Adverse events: DVT
Wang 2016²⁵¹	10mg/kg or 15mg/kg before surgery begins. versus Saline placebo	People with OA scheduled to have primary unilateral total hip replacement.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding
Wang 2017²⁵⁹	1g in 50 mL saline was administered right before skin closure. versus Saline placebo	People aged 30 years and older, who were scheduled for primary unilateral TKA for end-stage osteoarthritis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Wei 2014²⁶⁴	3g infusion 10 minutes prior to incision. Physiological saline solution (0.85%) was used as placebo. versus Saline placebo	People aged 45–80 years, without low preoperative hemoglobin, normal international normalized ratio (INR), prothrombin time, partial thromboplastin time (PTT) values, no history of previous hip surgery who were scheduled for unilateral cementless primary total hip replacement.	Transfusion Adverse events: DVT Total blood loss Length of stay
Yi 2016²⁸²	15mg/kg 5 minutes before incision. 20ml normal saline solution used to topically on acetabulum and placed within femoral canal. 60ml normal saline solution injected into hip joint. versus Saline placebo	People undergoing hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding Length of stay
Yuan 2017²⁸⁵	20 mg/kg intravenously 30 minutes before incising the skin, and the same dose 12 hours after TKA. Oral and IA placebo used. versus Saline placebo	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zekcer 2016²⁸⁹	20mg/kg, diluted in 100 ml of saline, infused over a 10-minute period at the same time as anaesthesia was administered. versus Saline placebo	People scheduled for unilateral TKA due to arthrosis (Albach grades III and IV)	Mortality Transfusion Adverse events: DVT
Zhao 2018³⁰⁵	15mg/kg 10 minutes before incision. 4 ascorbic acid tablets used for oral placebo. versus Saline placebo and 4 ascorbic acid tablets used for oral placebo.	People having elective primary unilateral total hip arthroplasty for osteoarthritis of femoral head necrosis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
Zhou 2018³⁰⁷	10mg/kg in 100 ml saline by intravenous infusion approximately 15 min before skin incision, and a second identical dose administered 3 hours later. versus Placebo	Adults scheduled to undergo primary unilateral THA	Transfusion Adverse events: DVT Total blood loss Surgical bleeding Postoperative bleeding
Oral versus placebo
Bradshaw 2012²⁷	4 doses of 1500mg encapsulated tranexamic acid. First dose 8 hours before admission, unclear when second dose was given, third dose within 2 hours of surgery, fourth dose 6-8 hours after surgery. versus 4 doses of encapsulated inactive comparator.	People with osteoarthritis undergoing primary total knee replacement.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Yuan 2017²⁸⁵	20mg/kg orally 2 hours before the operation and the same dose 12 hours after TKA. IV and IA placebo used. versus Saline placebo	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zhao 2018³⁰⁵	20mg/kg 2 hours before surgery and 3 hours after surgery. IV saline given to enable blinding with IV group. versus Saline placebo	People having elective primary unilateral total hip arthroplasty for osteoarthritis of femoral head necrosis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
IV plus IA/topical versus placebo
Lin 2015¹⁵⁵	1g IV injection 15 minutes before skin incision and 1g IA application intraoperatively after joint capsule closure. versus Saline placebo	People scheduled for unilateral TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Song 2017²²⁷	10mg/kg 20 minutes before tourniquet application as a preoperative dose and 10 mg/kg as a postoperative dose. 1.5g in 50mL of saline retrograde through the drain after wound closure. As placebo, these patients received 5mL of normal saline at the time of intraoperative dose. versus Saline placebo	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Yi 2016²⁸²	15mg/kg IV 5 minutes before incision. 200mg in 20ml solution used to topically on acetabulum and placed within femoral canal. 600mg in 60ml injected into hip joint. versus Saline placebo	People undergoing hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Postoperative bleeding Length of stay
Zeng 2017²⁹¹	15mg/kg IV in saline. Topical administration 1g in 100ml saline administered during surgery. versus Saline placebo	Adults (18-90 years old) undergoing primary unilateral total hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Surgical bleeding Postoperative bleeding Length of stay
IA/topical versus IV
Abdel 2018¹	3g diluted in 45mL of saline applied to open joint surfaces after cementation of the implant and prior to tourniquet release versus 1g administered prior to tourniquet inflation.	People with osteoarthritis having primary elective unilateral total knee arthroplasty.	Transfusion Adverse events: DVT Total blood loss Surgical bleeding
Aggarwal 2016⁶	15 mg/kg in 100 mL of normal saline solution which was applied to the joint surface and left in contact for 10 minutes. versus 15 mg/kg 30 minutes before tourniquet deflation.	People undergoing bilateral primary TKA for severe arthritis of the knee with tricompartmental involvement.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Aguilera 2015⁷	After prosthesis inserted and cemented, operative field was rinsed and dried. 1g in 10mL solution topically applied by syringe spray to the posterior capsule, surrounding soft tissue, fatty and subcutaneous tissue, exposed surfaces of femur and tibia. versus 2 doses of 1g. 15-30 minutes before tourniquet inflated and again when tourniquet is removed	Adults having elective total knee replacement due to OA or RA or other degenerative knee disorders	Transfusion Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Postoperative bleeding Length of stay
Chen 2016b³⁸	1500mg diluted in 100ml saline was given as an IA wash after cementing the prostheses. versus 1500mg diluted in 100ml saline given as an infusion over 20 minutes after cementing the prostheses.	People aged from 50 to 85 with osteoarthritis of the knee and scheduled for an elective primary TKA	Transfusion Adverse events: DVT Total blood loss
Digas 2015⁵⁶	2g after skin closure versus 15mg/kg before deflation of the tourniquet.	People under 85 years old with primary osteoarthritis who we scheduled for total knee arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding
George 2018⁷⁷	1.5g in 100 mL of saline poured into the joint before wound closure. versus 10mg/kg before tourniquet inflation and again at tourniquet release.	People with osteoarthritis who are scheduled for a primary unilateral cemented TKA	Transfusion Adverse events: DVT Total blood loss
Gomez-Barrena 2014⁸⁵	3g in 100ml of saline. Half administered by irrigation before joint closure. Half administered after joint closure. IV placebo with saline. versus 15mg/kg in 100ml saline slowly infused before tourniquet release. A second identical dose given 3 hours after surgery. IA placebo with saline.	Adults scheduled for primary unilateral total knee replacement with cemented implants.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Goyal 2017⁹⁰	3,000mg (30mL) IA in the knee joint after wound closure. IV saline placebo. versus 1,000mg (10 mL) IV 10 minutes before deflation of the tourniquet (if a tourniquet was used) or 10 minutes before incision (if a tourniquet was not used). IA saline placebo. 2 more 1,000mg (10mL) doses of IV were given at 8 hourly intervals postoperatively.	People having primary total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Length of stay
Laoruengthana 2019¹⁴⁰	15mg/kg poured into knee joint before closure of the arthrotomy. versus 10mg/kg administered before closure of the arthrotomy.	People with primary osteoarthritis who are scheduled for primary unilateral total knee arthroplasty	Transfusion Length of stay
Lee 2017b¹⁴⁴	10 mg/kg 30 minutes before tourniquet deflation; the same dose was repeated 3 hours after surgery. Both doses by slow infusion. versus 2g of in 30mL of normal saline was injected in the joint after closure of the retinaculum and quadriceps tendon but before subcutaneous closure.	“People with osteoarthritis having elective unilateral primary TKA”	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Luo 2018¹⁶²	2g diluted in 150mL of normal saline. Following the acetabular preparation, the acetabulum was soaked with 50mL of solution for 3 minutes. After the femoral canal broach preparation, 50mL solution was injected into the femoral canal and removed by suction 3 minutes later. After reduction of the final hip components, 50mL solution was applied to the wound and allowed to remain undisturbed for 3 minutes, after which it was removed by suction. 100mL saline IV placebo used. versus 20 mg/kg diluted in 100ml normal saline given as an IV bolus 5 minutes before the skin incision	People with osteoarthritis or osteonecrosis of the femoral head and scheduled to undergo cementless primary unilateral THA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Maniar 2012¹⁶⁷	3g diluted in 100 mL normal saline applied locally after cementing the implant and before tourniquet release. versus 10 mg/kg 15 minutes before deflation of the tourniquet as an intraoperative dose. Half of the people received a postoperative dose. Half of the people received a preoperative dose.	People with osteoarthritis scheduled to have primary, unilateral TKA.	Transfusion Adverse events: DVT Total blood loss
May 2016¹⁷¹	2g in 50ml saline. Injected into capsular closure. 100ml saline used as IV placebo. versus 2 doses of 1g in 100ml normal saline. The first dose after anaesthetic induction, the second dose after capsular closure. Saline used for IA placebo.	Adults over 18 years old undergoing primary unilateral total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Mehta 2019¹⁷⁵	2.5g (25ml) in 25ml saline. Equally given to each knee joint after wound closure. versus 1g administered after regional anaesthesia but before tourniquet inflation.	People having primary bilateral total knee arthroplasty due to advanced osteoarthritis of the knee.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
Oztas 2015¹⁹⁶	2g was applied locally on the proximal-medial surface of the patella with intra-articular injection after the joint capsule closure in the final stage of the operation before the tourniquet deflation versus 15mg/kg given 1 hour before the inflation of the tourniquet and 1 hour after the deflation of the tourniquet, and 10 mg/kg in saline given through one-hour infusion.	People with degenerative knee osteoarthritis who did not respond to conservative treatment and underwent unilateral primary TKR	Transfusion Adverse events: DVT Total blood loss Length of stay
Patel 2014²⁰⁰	2g in 100 ml of normal saline put directly into the surgical site and bathed in the solution, undisturbed for 2 minutes prior to tourniquet release versus 10mg/kg 10 minutes prior to tourniquet deflation.	Adults with osteoarthritis undergoing elective unilateral primary TKA	Mortality Transfusion Adverse events: acute myocardial infarction Blood loss via haemoglobin level after surgery
Pinsornsak 2016²⁰⁶	750mg in 15 mL saline injected into the soft tissue around medial capsule (5 ml), lateral capsule (5 ml) and around the quadriceps muscle (5 ml). versus 750mg in 15ml saline.	Adults with osteoarthritis scheduled for TKA.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Length of stay
Prakash 2017²¹⁰	10mg/kg administered 3 times. 20 minutes before tourniquet application, 15 minutes before deflation of the tourniquet, 3 hours after the previous dose in the postoperative period. Topical saline as placebo. versus 3g in 50ml saline applied to joint cavity 5 minutes before closure OR 3g in saline retrograde through the drain after closure. IV saline as placebo.	People with primary osteoarthritis who were scheduled for primary unilateral total knee arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Song 2017²²⁷	1.5g in 50 mL of saline retrograde through the drain after wound closure, and as placebo, saline utilised at the same points as the IV treatment. versus 10mg/kg 20 minutes before tourniquet application as a preoperative dose, 10 mg/kg 15 minutes before deflation of the tourniquet as an intraoperative dose, and 10 mg/kg 3 hours after the second dose as a postoperative dose. As placebo, the group received 50 mL of saline retrograde through drain after surgery.	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Stowers 2017²³³	1.5g in 20mL of saline after implantation of prosthesis and closure of arthrotomy followed by standard closure. Saline IV placebo used. versus 1.5g intravenously at the same time before release of tourniquet. IA saline used as placebo.	Adults undergoing primary unilateral TKA	Transfusion Adverse events: DVT Total blood loss
Ugurlu 2017²⁴⁶	3g in 100ml saline. 50ml administered with infiltration to wound lips following suturing of the capsular incision. 50ml administered into the joint. versus 20mg/kg dose administered 15 minutes before tourniquet inflated.	People undergoing primary total knee arthroplasty for degenerative osteoarthritis.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Wang 2017²⁵⁹	1g in 50 mL saline was administered right before skin closure. versus 1g IV in 50 mL saline was administered right before skin closure.	People aged 30 years and older, who were scheduled for primary unilateral TKA for end-stage osteoarthritis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Wang 2018b²⁵⁴	2g in 100 mL of saline solution, administered intra-articularly at two time points. Oral and IV placebos used. versus 20mg/kg dose in 100 mL of normal saline solution administered 5 minutes prior to incision. Oral and IA placebos used.	Adults with primary knee osteoarthritis who were scheduled for elective primary unilateral total knee replacement	Mortality Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Wei 2014²⁶⁴	3g mixed with 100ml saline. During surgery, the acetabulum was bathed in 20ml. Following femoral canal broach preparation, the femoral canal was filled with 20ml. The remaining 60ml was injected into the hip joint following fascia closure. versus 3g infusion 10 minutes prior to incision. Saline placebo used.	People aged 45–80 years, without low preoperative haemoglobin, normal international normalized ratio (INR), prothrombin time, partial thromboplastin time (PTT) values, no history of previous hip surgery who were scheduled for unilateral cementless primary total hip replacement.	Transfusion Adverse events: DVT Total blood loss Length of stay
Wei 2018²⁶³	1g diluted in 50ml of normal saline, injected into the surgical site (posterior and anterior capsule, medial and lateral retinaculum), and the surgical site was soaked in the solution for 5 min before deflation of the tourniquet. versus 10mg/kg 10 min after placement of a loose tourniquet.	Adults with knee osteoarthritis and an American Society of Anesthesiologists (ASA) score 3 or under who are scheduled for unilateral primary TKA	Adverse events: DVT Blood loss via haemoglobin level after surgery Postoperative bleeding Surgical bleeding
Xie 2016²⁷⁶	3g in 150ml saline was utilised. Gauze with 50ml used to soak the acetabulum for 3 minutes and gauze with 50ml used to soak the femoral canal for 3 minutes. Remaining 50ml injected into joint space through the drainage tube after fascia closure. versus 1.5g 15 minutes before skin incision.	People undergoing hip replacement surgery	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Yuan 2017²⁸⁵	3g total 60 mL solution administered after the subcutaneous tissue was sutured. Oral and IV placebo used. 20 mg/kg 30 minutes before incising the skin, and the same dose 12 hours after surgery. IA and oral placebo used.	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zekcer 2016²⁸⁹	1.5g in 50 ml of saline which was sprayed over the operated area for 5 minutes, before the tourniquet was released. versus 20mg/kg, diluted in 100 ml of saline, infused over a 10-minute period at the same time as anaesthesia was administered.	People scheduled for unilateral TKA due to arthrosis (Albach grades III and IV)	Mortality Transfusion Adverse events: DVT
Zhang 2016³⁰²	After skin sutures closed, the IA group were injected with 1g in 100ml saline via the drainage tubes. versus 1g diluted in 250ml saline and administered via IV infusion 10 minutes before the surgery.	People scheduled for unilateral primary total hip replacement for osteonecrosis of the femoral head and a BMI between 18.5 and 30.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zhang 2019³⁰³	Articular injection of 3.0g after it was sutured versus IV injection of 20mg/kg TXA before the incision	People 40 to 80 years old scheduled for TKA	Quality of life Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Zhou 2018³⁰⁷	3g in 60ml saline soaking the hip cavity before the end of surgery. versus 10mg/kg in 100 ml saline by intravenous infusion approximately 15 min before skin incision, and a second identical dose administered 3 hours later.	Adults scheduled to undergo primary unilateral THA	Transfusion Adverse events: DVT Total blood loss Surgical bleeding Postoperative bleeding
Oral versus IV
Cao 2018³⁰	20mg/kg IV administered 5-10 minutes before first incision. 2g given orally in 4 tablets at 4 hours, 10 hours and 16 hours after surgery. IV saline given at the same time points as the higher IV dose group. versus 20mg/kg IV administered 5-10 minutes before fist incision. 1g given IV in saline 6 hours, 12 hours and 18 hours after surgery. Oral placebo taken at the corresponding time points.	People undergoing primary unilateral total hip arthroplasty for osteoarthritis, osteonecrosis of the femoral head and developmental dysplasia of the hip.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss	Oral group received small IV dose and the study was considered indirect evidence.
Fillingham 2016⁶⁴	1950 mg (3 tablets of 650 mg) approximately 2 hours before incision and given an IV placebo of 10-mL normal saline immediately before wound closure. versus 1g in 10 mL saline immediately before wound closure and received 750 mg of placebo (ascorbic acid in 3 tablets of 250 mg) approximately 2 hours before incision	People scheduled to undergo unilateral primary TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Jaszczyk 2015¹¹⁸	1950mg in 3 tablets 2 hours before incision and an IV placebo dose of saline immediately before incision. versus 1g in 10mL saline as bolus immediately before incision. Placebo tablets 2 hours before incision.	People undergoing primary total hip arthroplasty.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Kayupov 2017¹²⁶	1960mg given in 3 tablets 2 hours before incision. IV saline given immediately prior to incision versus 1g in saline given immediately prior to incision, placebo for oral group in ascorbic acid given 2 hours before incision.	People having cementless primary hip arthroplasty	Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Luo 2018¹⁶²	2g approximately 2 hours before the incision. 100mL saline IV placebo infusion administered 5 minutes before the skin incision. versus 20 mg/kg diluted in 100ml normal saline given as an IV bolus 5 minutes before the skin incision.4 placebo tablets, identical in appearance with no active ingredient, were administered	People with osteoarthritis or osteonecrosis of the femoral head and scheduled to undergo cementless primary unilateral THA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Wang 2018b²⁵⁴	2g in 500mg tablets taken approximately 2 hours before incision. IA and IV placebos used. versus 20mg/kg dose in 100 mL of normal saline solution administered 5 minutes prior to incision. Oral and IA placebos used.	Adults with primary knee osteoarthritis who were scheduled for elective primary unilateral total knee replacement	Mortality Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Yuan 2017²⁸⁵	20mg/kg orally 2 hours before the operation and the same dose 12 hours after surgery. IV and IA placebo used. versus 20 mg/kg intravenously 30 minutes before incising the skin, and the same dose 12 hours after surgery. Oral and IA placebo used.	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Zhao 2018³⁰⁵	20mg/kg 2 hours before surgery and 3 hours after surgery. IV saline placebo used. versus 15mg/kg 10 minutes before incision. 4 ascorbic acid tablets used for placebo.	People having elective primary unilateral total hip arthroplasty for osteoarthritis of femoral head necrosis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
IA/topical versus oral
Luo 2018a¹⁶¹	3g diluted in 150ml saline utilised. 50ml to soak the acetabulum for 3 minutes. After the femoral canal broach preparation, 50ml injected into the femoral canal and removed 3 minutes later. After reduction of femoral components, 50ml was soaked and removed 3 minutes later. Placebo tablets used to keep blinding. versus 2g administered 2 hours before surgery. 2 1g doses were administered postoperatively with a 6 hour interval. Saline IA wash was used to keep blinding.	People undergoing hip replacement surgery	Mortality Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Length of stay
Luo 2018b¹⁶²	2g diluted in 150mL of normal saline. Following the acetabular preparation, the acetabulum was soaked with 50mL of solution for 3 minutes. After the femoral canal broach preparation, 50mL solution was injected into the femoral canal and removed by suction 3 minutes later. After reduction of the final hip components, 50mL solution was applied to the wound and allowed to remain undisturbed for 3 minutes, after which it was removed by suction. 100mL saline IV placebo used. 4 placebo tablets, identical in appearance with no active ingredient, were administered versus 2g approximately 2 hours before the incision.. IA saline placebo used.	People with osteoarthritis or osteonecrosis of the femoral head and scheduled to undergo cementless primary unilateral THA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Wang 2018a²⁵⁵	2g 2 hours before incision. A postoperative dose of 1g was repeated 6 and 12 hours after surgery. Saline IA placebo. versus 3g in 100 mL of saline solution administered is 2 doses. After all components have been cemented and the joint was thoroughly irrigated, the first half is applied to soak the open joint surface and tissue for 5 min and the second half administered using a needle to achieve tissue impregnation. Placebo pills identical to oral TXA in appearance were given 2 hours before incision.	People scheduled for primary unilateral total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Surgical bleeding Mortality
Yuan 2017²⁸⁵	3g total 60mL solution administered after the subcutaneous tissue was sutured. Oral and IV placebo utilised. versus 20mg/kg orally 2 hours before the operation and the same dose 12 hours after surgery. IV placebo joint injection of saline. IA placebo of saline	People with osteoarthritis or rheumatoid arthritis who were scheduled for primary unilateral TKA were enrolled.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery
Wang 2018b²⁵⁴	2g in 500mg tablets taken approximately 2 hours before incision. IA and IV placebos used. versus 2g in 100 mL of saline solution, administered intra-articularly at two time points. Oral and IV placebos used.	Adults with primary knee osteoarthritis who were scheduled for elective primary unilateral total knee replacement	Mortality Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
IV plus IA/topical versus IV
Adravanti 2018⁵	1g IV 30 minutes before induction of anaesthesia, then at 3 and 9 hours after surgery. 3g topical injected into the joint after closure of the capsule. versus 1g IV 30 minutes before induction of anaesthesia and then at 3 and 9 hours after surgery	Adults 18 to 95 years old undergoing primary TKA.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Postoperative bleeding
Gulabi 2019⁹²	1g in saline given as a slow IV injection 30 minutes before incision. Dose repeated 3 hours later. 3g diluted in isotonic saline and applied intra-articularly. versus 1g in saline given as a slow IV injection 30 minutes before incision. Dose repeated 3 hours later.	Adults scheduled for elective primary unilateral THA.	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Huang 2014¹⁰⁷	1.5g dissolved in 50 mL saline was irrigated in the wound after implantation of the components and 1.5g IV was administered before inflation of the tourniquet versus 3g administered before inflation of the tourniquet.	Adults scheduled for a primary TKA for end-stage osteoarthritis	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Jain 2016¹¹⁶	3 IV doses: 15 mg/kg 30 minutes before skin incision. 10mg/kg repeated 3 and 6 hours after surgery. 2g diluted in 30 mL saline applied IA for about 5minutes before closure of arthrotomy. versus 3 doses: 15 mg/kg 30 minutes before skin incision. 10mg/kg repeated 3 and 6 hours after surgery. Saline IA placebo.	People with primary osteoarthritis undergoing elective unilateral primary TKAs	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Song 2017²²⁷	10mg/kg 20 minutes before tourniquet application as a preoperative dose and 10 mg/kg as a postoperative dose. 1.5g in 50mL of saline retrograde through the drain after wound closure. As placebo, these patients received 5mL of normal saline at the time of intraoperative dose. versus 10mg/kg 20 minutes before tourniquet application as a preoperative dose, 10 mg/kg 15 minutes before deflation of the tourniquet as an intraoperative dose, and 10 mg/kg 3 hours after the second dose as a postoperative dose. As placebo, the group received 50 mL of saline retrograde through drain after surgery.	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Xie 2016²⁷⁶	1g IV dose 15 minutes before skin incision. 2g in 150ml physiological saline was utilised. Gauze with 50ml used to soak the acetabulum for 3 minutes and gauze with 50ml used to soak the femoral canal for 3 minutes. Remaining 50ml injected into joint space through the drainage tube after fascia closure. versus 1.5g IV dose 15 minutes before skin incision.	People undergoing hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Yi 2016²⁸²	15mg/kg IV 5 minutes before incision. 200mg in 20ml solution used to topically on acetabulum and placed within femoral canal. 600mg in 60ml injected into hip joint. versus 15mg/kg IV 5 minutes before incision. Saline IA placebo used.	People undergoing hip replacement	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Postoperative bleeding Length of stay
Zhang 2019³⁰³	IV injection of 20mg/kg before the incision and articular injection of 3g TXA after it was sutured. versus IV injection of 20mg/kg TXA before the incision	People 40 to 80 years old scheduled for TKA	Quality of life Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
IA/topical plus oral versus IA/topical
Cankaya 2017²⁹	Oral 25mg/kg (maximum 2g) given 2 hours before surgery. 1.5g in saline administered to the joint cavity during surgery. versus 1.5g in saline administered to the joint cavity during surgery.	People 55 to 85 years old with knee osteoarthrosis, undergoing primary total knee arthroplasty	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Postoperative bleeding
IV plus IA/topical versus IA/topical
Lin 2015¹⁵⁵	1g IV injection 15 minutes before skin incision and 1g IA application intraoperatively after joint capsule closure. versus 1g in 20 mL normal saline using IA application intraoperatively after joint capsule closure	People scheduled for unilateral TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Song 2017²²⁷	10mg/kg 20 minutes before tourniquet application as a preoperative dose and 10 mg/kg as a postoperative dose. 1.5g in 50mL of saline retrograde through the drain after wound closure. versus 1.5g in 50 mL of saline retrograde through the drain after wound closure, and as placebo, saline utilised at the same points as the IV treatment.	People with primary osteoarthritis of knee awaiting navigation assisted TKA	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss
Xie 2016²⁷⁶	1g IV dose 15 minutes before skin incision. 2g in 150ml physiological saline was utilised. Gauze with 50ml used to soak the acetabulum for 3 minutes and gauze with 50ml used to soak the femoral canal for 3 minutes. Remaining 50ml injected into joint space through the drainage tube after fascia closure. versus 3g in 150ml physiological saline was utilised. Gauze with 50ml used to soak the acetabulum for 3 minutes and gauze with 50ml used to soak the femoral canal for 3 minutes. Remaining 50ml injected into joint space through the drainage tube after fascia closure.	People undergoing hip replacement surgery	Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss Length of stay
Zhang 2019³⁰³	IV injection of 20mg/kg before the incision and articular injection of 3g TXA after it was sutured. versus Articular injection of 3.0g after it was sutured	People 40 to 80 years old scheduled for TKA	Quality of life Transfusion Adverse events: DVT Blood loss via haemoglobin level after surgery Total blood loss

Table 3Clinical evidence summary: IA/topical versus no treatment

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with No treatment	Risk difference with IA/topical tranexamic acid (95% CI)
Mortality	Not reported
Transfusion	1078 (10 studies) ranged from while admitted in hospital to 2 months after surgery	MODERATE¹ due to risk of bias	RR 0.46 (0.37 to 0.56)	362 per 1000	195 fewer per 1000 (from 159 fewer to 228 fewer)
Acute myocardial infarction	Not reported
DVT	850 (9 studies) ranged from in hospital period to 1 year after surgery	MODERATE¹ due to risk of bias	RD −0.00 (−0.02 to 0.01)³	7 per 1000	0 fewer per 1000 (from 20 fewer to 10 more)²
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	906 (9 studies) ranges from 12 hours to 5 days after surgery	VERY LOW¹^,⁴^,⁵ due to risk of bias, inconsistency, imprecision		The mean blood loss via haemoglobin level after surgery in the control groups was 9	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.43 higher (0.11 lower to 0.97 higher)
Total blood loss	709 (6 studies) ranges from 1 to 5 days after surgery	VERY LOW¹^,⁴^,⁵ due to risk of bias, inconsistency, imprecision		The mean total blood loss in the control groups was 1200 mL	The mean total blood loss in the intervention groups was 1.5 standard deviations lower (2.3 to 0.71 lower)
Surgical bleeding	355 (3 studies)	VERY LOW¹^,⁴^,⁵ due to risk of bias, inconsistency, imprecision		The mean surgical bleeding in the control groups was 500 mL	The mean surgical bleeding in the intervention groups was 0.65 standard deviations lower (1.51 lower to 0.2 higher)
Postoperative bleeding	95 (1 study) 24 hours after surgery	HIGH		The mean postoperative bleeding in the control groups was 538.06 mL	The mean postoperative bleeding in the intervention groups was 337.96 lower (435.16 to 240.76 lower)
Length of stay	312 (3 studies)	LOW¹ due to risk of bias		The mean length of stay in the control groups was 5 days	The mean length of stay in the intervention groups was 0.06 lower (0.28 lower to 0.17 higher)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Risk difference utilised to calculate absolute effect
3: Risk difference used to analyse data due to very low event rates
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 4Clinical evidence summary: Oral versus no treatment

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with No treatment	Risk difference with Oral tranexamic acid (95% CI)
Mortality at 30 days	189 (1 study) 30 days after surgery	LOW³^,⁴ due to risk of bias, imprecision	RD 0 (−0.02 to 0.02)²	0 per 1000	0 fewer per 1000 (from 20 fewer to 20 more)¹
Transfusion	189 (1 study) unclear	VERY LOW³^,⁴ due to risk of bias, imprecision	RR 0.34 (0.04 to 3.18)	32 per 1000	21 fewer per 1000 (from 30 fewer to 69 more)
Acute myocardial infarction	Not reported
DVT	189 (1 study) within 7 days of surgery	VERY LOW³^,⁴ due to risk of bias, imprecision	Peto OR 7.47 (0.15 to 376.39)	0 per 1000	10 more per 1000 (from 20 fewer to 40 more)¹
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	189 (1 study) unclear	MODERATE³ due to risk of bias		The mean blood loss via haemoglobin level after surgery in the control groups was −2.5 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.8 higher (0.56 to 1.04 higher)
Total blood loss	189 (1 study) unclear	MODERATE³ due to risk of bias		The mean total blood loss in the control groups was 626 mL	The mean total blood loss in the intervention groups was 228 lower (293.22 to 162.78 lower)
Length of stay	189 (1 study)	MODERATE³ due to risk of bias		The mean length of stay in the control groups was 5.8 days	The mean length of stay in the intervention groups was 0.1 higher (0.46 lower to 0.66 higher)

1: Absolute effect calculated using risk difference
2: Analysis via risk difference due to low event rate
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
4: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 5Clinical evidence summary: IV versus no treatment

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with No treatment	Risk difference with IV tranexamic acid (95% CI)
Mortality at 30 days	100 (1 study) within 90 days of surgery	VERY LOW³^,⁵^,⁶ due to risk of bias, indirectness, imprecision	RD 0 (−0.04 to 0.04)²	0 per 1000	0 fewer per 1000 (from 40 fewer to 40 more)¹
Transfusion	1324 (15 studies) ranged from in-hospital period to 90 days after surgery	VERY LOW³^,⁴ due to risk of bias, inconsistency	RD −0.14 (−0.21 to −0.08)²	307 per 1000	140 fewer per 1000 (from 210 fewer to 80 fewer)¹
Acute myocardial infarction	Not reported
DVT	1135 (15 studies) ranged from 2 days to 1 year after surgery	MODERATE³ due to risk of bias	RD 0 (−0.02 to 0.01)²	13 per 1000	0 fewer per 1000 (from 20 fewer to 10 more)¹
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	1038 (11 studies)⁷ ranges from 1 to 5 days after surgery	LOW³^,⁵ due to risk of bias, imprecision		The mean blood loss via haemoglobin level after surgery in the control groups was 9.5	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.53 higher (0.38 to 0.67 higher)
Total blood loss	873 (8 studies) either unclear or 3 days after surgery	VERY LOW³^,⁴ due to risk of bias, inconsistency		The mean total blood loss in the control groups was 1250 mL	The mean total blood loss in the intervention groups was 1.33 standard deviations lower (2.1 to 0.56 lower)
Surgical bleeding	356 (3 studies)	VERY LOW³^,⁴^,⁵ due to risk of bias, inconsistency, imprecision		The mean surgical bleeding in the control groups was 500 mL	The mean surgical bleeding in the intervention groups was 0.88 standard deviations lower (2.62 lower to 0.86 higher)
Postoperative bleeding	96 (1 study) 24 hours after surgery	HIGH		The mean postoperative bleeding in the control groups was 538.06	The mean postoperative bleeding in the intervention groups was 393.16 lower (483.74 to 302.58 lower)
Length of stay	312 (3 studies)	LOW³ due to risk of bias		The mean length of stay in the control groups was 5 days	The mean length of stay in the intervention groups was 0.03 lower (0.24 lower to 0.19 higher)

1: Risk difference utilised to calculate absolute effect
2: Results analysed using risk difference due to low event rates
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.
6: Considered indirect due to the study follow-up period extending beyond 30 days
7: Two intervention groups reported in Melo 2017. The numbers of people in the control groups have been halved to prevent double counting.

Table 6Clinical evidence summary: IA/topical versus placebo

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Placebo

Risk difference with IA/topical tranexamic acid (95% CI)

Mortality at 30 days

(1 study)

15 days after surgery

VERY LOW³^,⁴

due to risk of bias, imprecision

RD 0 (−0.06 to 0.06)²

0 per 1000

0 fewer per 1000

(from 60 fewer to 60 more)¹

Transfusion

2589

(24 studies)

ranged from 3 days to 3 months of surgery

HIGH

RR 0.36 (0.29 to 0.45)

197 per 1000

126 fewer per 1000

(from 108 fewer to 140 fewer)

Acute myocardial infarction

Not reported

DVT

2428

(23 studies)

ranged from 5 days to 3 months after surgery

VERY LOW³^,⁶

due to risk of bias, imprecision

RD 0 (−0.01 to 0.01)²

19 per 1000

0 fewer per 1000

(from 10 fewer to 10 more)¹

Quality of life within 6 weeks

EuroQol Index (EQ-5D)

190

(2 studies)

3 months after surgery

VERY LOW³^,⁵

due to risk of bias, indirectness

The mean quality of life within 6 weeks in the control groups was

0.75

The mean quality of life within 6 weeks in the intervention groups was

0.06 lower

(0.14 lower to 0.03 higher)

Blood loss via haemoglobin level after surgery

1853

(18 studies)

ranges from 24 hours to 5 days after surgery

VERY LOW³^,⁷

due to risk of bias, inconsistency

The mean blood loss via haemoglobin level after surgery in the control groups was

9 g/dL

The mean blood loss via haemoglobin level after surgery in the intervention groups was

1.04 higher

(0.8 to 1.29 higher)

Total blood loss

1617

(17 studies)

ranges from 1 to 5 days after surgery or until hospital discharge

LOW³^,⁷

due to risk of bias, inconsistency

The mean total blood loss in the control groups was

1100 mL

The mean total blood loss in the intervention groups was

0.94 standard deviations lower

(1.16 to 0.72 lower)

Surgical bleeding

243

(3 studies)

VERY LOW⁶^,⁷

due to inconsistency, imprecision

The mean surgical bleeding in the control groups was

200 mL

The mean surgical bleeding in the intervention groups was

0.25 standard deviations lower

(0.93 lower to 0.44 higher)

Postoperative bleeding

394

(5 studies)

ranges from 36 hours to 4 days after surgery

MODERATE⁷

due to inconsistency

The mean postoperative bleeding ranged across control groups from

55 to 400

The mean postoperative bleeding in the intervention groups was

0.94 standard deviations lower

(1.35 to 0.53 lower)

Length of stay

1108

(10 studies)

LOW³^,⁷

due to risk of bias, inconsistency

The mean length of stay in the control groups was

5 days

The mean length of stay in the intervention groups was

0.01 lower

(0.2 lower to 0.18 higher)

1: Risk difference used to calculate absolute effect
2: Results analysed using risk difference due to low event rates
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
4: Study considered imprecise because it is small and there were no events in either treatment group
5: Considered indirect evidence as the outcome was outside of the specified time point
6: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
7: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 7Clinical evidence summary: IV versus placebo

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Placebo	Risk difference with IV tranexamic acid (95% CI)
Mortality at 30 days	290 (3 studies) either during hospital stay or within 15 days of surgery	MODERATE⁵ due to imprecision	RD 0 (−0.03 to 0.03)²	See comment	0 fewer per 1000 (from 30 fewer to 30 more)¹
Transfusion	3383 (44 studies) ranged from 24 hours to 6 months after surgery	LOW³^,⁴ due to risk of bias, inconsistency	RR 0.39 (0.32 to 0.49)	343 per 1000	209 fewer per 1000 (from 175 fewer to 233 fewer)
Acute coronary syndrome	230 (2 studies) during hospital stay	MODERATE⁵ due to imprecision	RD 0 (−0.02 to 0.04)²		10 more per 1000 (from 20 fewer to 40 more)¹
DVT	3356 (45 studies) ranged from in hospital period to 6 months after surgery	MODERATE³ due to risk of bias	RD 0 (−0.01 to 0.01)²	16 per 1000	0 fewer per 1000 (from 10 fewer to 10 more)¹
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	2489 (32 studies) ranges from 1 day after surgery to discharge from hospital	VERY LOW³^,⁴^,⁶ due to risk of bias, inconsistency, imprecision		The mean blood loss via haemoglobin level after surgery in the control groups was 9.5 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.64 higher (0.49 to 0.78 higher)
Total blood loss	2624 (33 studies) ranges from 1 to 6 days after surgery or until hospital discharge	LOW³^,⁴ due to risk of bias, inconsistency		The mean total blood loss ranged across control groups from 590 to 2393 mL	The mean total blood loss in the intervention groups was 0.84 standard deviations lower (1 to 0.68 lower)
Surgical bleeding	744 (13 studies)	VERY LOW³^,⁴^,⁶ due to risk of bias, inconsistency, imprecision		The mean surgical bleeding ranged across control groups from 140 to 790	The mean surgical bleeding in the intervention groups was 0.61 standard deviations lower (0.97 to 0.25 lower)
Postoperative bleeding	762 (13 studies) ranges from 48 hours of surgery to in-hospital period	VERY LOW³^,⁴ due to risk of bias, inconsistency		The mean postoperative bleeding ranged across control groups from 244 to 1074 mL	The mean postoperative bleeding in the intervention groups was 1.38 standard deviations lower (1.87 to 0.89 lower)
Length of stay	1272 (14 studies)	HIGH		The mean length of stay in the control groups was 7 days	The mean length of stay in the intervention groups was 0.09 lower (0.18 to 0.01 lower)

1: Absolute effect calculated using risk difference
2: Analysis by risk difference due to low events rate
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.
5: No explanation was provided
6: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 8Clinical evidence summary: Oral versus placebo

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Placebo	Risk difference with Oral tranexamic acid (95% CI)
Mortality	Not reported
Transfusion	406 (3 studies) ranged from in hospital period to 3 months after surgery	MODERATE¹ due to risk of bias	RR 0.38 (0.23 to 0.64)	225 per 1000	139 fewer per 1000 (from 81 fewer to 173 fewer)
Acute myocardial infarction	Not reported
DVT	406 (3 studies) ranged from 2 weeks to 3 months after surgery	MODERATE¹ due to risk of bias	RD 0 (−0.03 to 0.02)³	10 per 1000	10 fewer per 1000 (from 30 fewer to 20 more)²
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	406 (3 studies) ranges from 1 to 3 days after surgery	LOW¹^,⁴ due to risk of bias, imprecision		The mean blood loss via haemoglobin level after surgery in the control groups was −3	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.47 higher (0.37 to 0.57 higher)
Total blood loss	126 (2 studies) 3 days after surgery	MODERATE¹ due to risk of bias		The mean total blood loss in the control groups was 948.5 mL	The mean total blood loss in the intervention groups was 1.13 standard deviations lower (1.51 to 0.75 lower)
Surgical bleeding	80 (1 study)	LOW¹^,⁴ due to risk of bias, imprecision		The mean surgical bleeding in the control groups was 156.3 mL	The mean surgical bleeding in the intervention groups was 21.5 lower (34.91 to 8.09 lower)
Length of stay	80 (1 study)	MODERATE¹ due to risk of bias		The mean length of stay in the control groups was 1.9 days	The mean length of stay in the intervention groups was 0.1 lower (0.69 to 0.49 lower)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Absolute effect calculated using risk difference
3: Analysed using risk difference due to low events rates
4: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 9Clinical evidence summary: IV plus IA/topical versus placebo

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Placebo	Risk difference with IV+IA/topical tranexamic acid (95% CI)
Mortality	Not reported
Transfusion	380 (4 studies) while admitted in hospital	MODERATE¹ due to risk of bias	RR 0.08 (0.03 to 0.22)	258 per 1000	237 fewer per 1000 (from 201 fewer to 250 fewer)
Acute myocardial infarction	Not reported
DVT	380 (4 studies) ranged from 2 weeks to 6 months after surgery	MODERATE¹ due to risk of bias	RD 0.01 (−0.02 to 0.04)³	5 per 1000	10 more per 1000 (from 20 fewer to 40 more)²
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	380 (4 studies) 3 days after surgery	MODERATE¹ due to risk of bias		The mean blood loss via haemoglobin level after surgery in the control groups was −4 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 1.45 higher (1.19 to 1.7 higher)
Total blood loss	380 (4 studies) 3 days after surgery or in-hospital period	LOW¹^,⁴ due to risk of bias, inconsistency		The mean total blood loss in the control groups was 1100 ml	The mean total blood loss in the intervention groups was 294.44 lower (405.92 to 182.97 lower)
Surgical bleeding	100 (1 study)	MODERATE¹ due to risk of bias		The mean surgical bleeding in the control groups was 288.2 mL	The mean surgical bleeding in the intervention groups was 94.4 lower (132.77 to 56.03 lower)
Postoperative bleeding	200 (2 studies) 3 days after surgery	MODERATE¹ due to risk of bias		The mean postoperative bleeding in the control groups was 243 mL	The mean postoperative bleeding in the intervention groups was 0.92 standard deviations lower (1.21 to 0.63 lower)
Length of stay	200 (2 studies)	MODERATE¹ due to risk of bias		The mean length of stay in the control groups was 6.6 days	The mean length of stay in the intervention groups was 0.33 lower (0.76 lower to 0.1 higher)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Absolute effect calculated using risk difference
3: Analysed via risk difference due to low event rates
4: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 10Clinical evidence summary: IA/topical versus IV

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with IV tranexamic acid

Risk difference with IA/topical tranexamic acid (95% CI)

Mortality at 30 days

269

(3 studies)

ranged from 15 to 30 days after surgery

VERY LOW³^,⁴

due to risk of bias, imprecision

RD 0.01 (−0.02 to 0.04)²

0 per 1000

10 more per 1000

(from 20 fewer to 40 more)¹

Transfusion

3978

(32 studies)

ranged from in hospital period to 3 months after surgery

HIGH

RD 0.01 (−0.01 to 0.02)²

64 per 1000

10 more per 1000

(from 10 fewer to 20 more)¹

Acute myocardial infarction

(1 study)

unclear

VERY LOW³^,⁵

due to risk of bias, imprecision

Peto OR 6.64 (0.13 to 336.89)

0 per 1000

20 more per 1000

(from 40 fewer to 80 more)¹

DVT

3833

(30 studies)

ranged from within 96 hours of surgery to 1 year after surgery

HIGH

RD 0 (−0.01 to 0)²

14 per 1000

0 fewer per 1000

(from 10 fewer to 0 more)¹

Quality of life (mental component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

LOW³^,⁵

due to risk of bias, imprecision

The mean quality of life (mental component score) within 6 weeks in the control groups was

The mean quality of life (mental component score) within 6 weeks in the intervention groups was

2.5 lower

(6.87 lower to 1.87 higher)

Quality of life (physical component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

LOW³^,⁵

due to risk of bias, imprecision

The mean quality of life (physical component score) within 6 weeks in the control groups was

The mean quality of life (physical component score) within 6 weeks in the intervention groups was

2.26 lower

(6.18 lower to 1.66 higher)

Blood loss via haemoglobin level after surgery

2558

(19 studies)

ranges from 12 hours to 5 days after surgery

LOW³^,⁶

due to risk of bias, inconsistency

The mean blood loss via haemoglobin level after surgery in the control groups was

10 g/dL

The mean blood loss via haemoglobin level after surgery in the intervention groups was

0.03 higher

(0.09 lower to 0.14 higher)

Total blood loss

2806

(26 studies)

ranges from 1 to 5 days after surgery

LOW³^,⁶

due to risk of bias, inconsistency

The mean total blood loss ranged across control groups from

456 to 1626

The mean total blood loss in the intervention groups was

0.12 standard deviations lower

(0.27 lower to 0.04 higher)

Surgical bleeding

1172

(6 studies)

VERY LOW³^,⁵^,⁶

due to risk of bias, inconsistency, imprecision

The mean surgical bleeding ranged across control groups from

123 to 685 mL

The mean surgical bleeding in the intervention groups was

0.1 standard deviations higher

(0.73 lower to 0.92 higher)

Postoperative bleeding

272

(3 studies)

ranges from 24 to 96 hours after surgery

LOW⁵^,⁶

due to inconsistency, imprecision

The mean postoperative bleeding in the control groups was

135 mL

The mean postoperative bleeding in the intervention groups was

0.09 standard deviations higher

(0.33 lower to 0.5 higher)

Length of stay

1312

(11 studies)

HIGH

The mean length of stay in the control groups was

4.5 days

The mean length of stay in the intervention groups was

0.04 higher

(0.05 lower to 0.12 higher)

1: Absolute effect calculated using risk difference
2: Results analysed using risk difference due to low event rates
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
4: Outcome considered imprecise because of the small number of participants and a single event
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
6: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 11Clinical evidence summary: Oral versus IV

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with IV tranexamic acid	Risk difference with Oral tranexamic acid (95% CI)
Mortality at 30 days	120 (1 study) 30 days after surgery	MODERATE³ due to imprecision	RD 0 (−0.03 to 0.03)²	0 per 1000	0 fewer per 1000 (from 30 fewer to 30 more)¹
Transfusion	862 (7 studies) ranged from in hospital period to 1 month after surgery	VERY LOW⁴^,⁵ due to risk of bias, imprecision	RR 0.94 (0.56 to 1.56)	65 per 1000	4 fewer per 1000 (from 28 fewer to 36 more)
Acute myocardial infarction	Not reported
DVT	945 (7 studies) ranged from 30 days to 3 months after surgery	MODERATE⁴ due to risk of bias	RD −0.01 (−0.02 to 0.01)²	10 per 1000	10 fewer per 1000 (from 20 fewer to 10 more)¹
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	945 (8 studies) ranges from 1 day after surgery to hospital discharge	MODERATE⁴ due to risk of bias		The mean blood loss via haemoglobin level after surgery in the control groups was −3.2 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.01 higher (0.07 lower to 0.09 higher)
Total blood loss	665 (7 studies) ranges from 1 to 3 days after surgery or until hospital discharge	MODERATE⁴ due to risk of bias		The mean total blood loss ranged across control groups from 692 to 1301 mL	The mean total blood loss in the intervention groups was 0.0 standard deviations higher (0.16 lower to 0.15 higher)
Surgical bleeding	200 (2 studies)	MODERATE⁴ due to risk of bias		The mean surgical bleeding in the control groups was 140 mL	The mean surgical bleeding in the intervention groups was 0.46 higher (6.43 lower to 7.34 higher)
Length of stay	437 (5 studies)	MODERATE⁴ due to risk of bias		The mean length of stay in the control groups was 3 days	The mean length of stay in the intervention groups was 0.02 lower (0.17 lower to 0.12 higher)

1: Absolute effect calculate through risk difference
2: Analysis using risk difference due to low event rates
3: Results considered imprecise due to zero events in both intervention groups
4: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
5: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs

Table 12Clinical evidence summary: IA/topical versus oral

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Oral tranexamic acid	Risk difference with IA/topical tranexamic acid (95% CI)
Mortality at 30 days	384 (3 studies) 30 days after surgery	MODERATE⁴ due to imprecision	RD 0 (−0.02 to 0.02)²	0 per 1000	0 fewer per 1000 (from 20 fewer to 20 more)¹
Transfusion	787 (5 studies) ranged from in hospital period to 2 weeks after surgery	VERY LOW³^,⁴ due to risk of bias, imprecision	RR 1.28 (0.78 to 2.11)	63 per 1000	18 more per 1000 (from 14 fewer to 70 more)
Acute myocardial infarction	Not reported
DVT	784 (5 studies) ranged from 2 weeks to 3 months after surgery	LOW³^,⁵ due to risk of bias, imprecision	RD −0.01 (−0.02 to 0.01)²	5 per 1000	10 fewer per 1000 (from 20 fewer to 10 more)¹
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	784 (5 studies) ranges from 2 days after surgery until hospital discharge	MODERATE³ due to risk of bias		The mean blood loss via haemoglobin level after surgery in the control groups was −3 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.04 lower (0.13 lower to 0.05 higher)
Total blood loss	504 (4 studies) ranges from 3 days after surgery or until hospital discharge	MODERATE³ due to risk of bias		The mean total blood loss in the control groups was 900 mL	The mean total blood loss in the intervention groups was 0.15 standard deviations higher (0.02 lower to 0.33 higher)
Surgical bleeding	384 (3 studies)	HIGH		The mean surgical bleeding in the control groups was 175 mL	The mean surgical bleeding in the intervention groups was 0.06 standard deviations higher (0.15 lower to 0.26 higher)
Length of stay	237 (2 studies)	MODERATE³ due to risk of bias		The mean length of stay in the control groups was 3.5 days	The mean length of stay in the intervention groups was 0.07 higher (0.16 lower to 0.29 higher)

1: Absolute effect calculated using risk difference
2: Analysis via risk difference due to low event rates
3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
4: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
5: Outcome considered imprecise because of the small number of participants and two events

Table 13Clinical evidence summary: IV plus IA/topical versus IV

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with IV tranexamic acid

Risk difference with IV+IA/topical tranexamic acid (95% CI)

Transfusion

791

(7 studies)

ranged from while admitted in hospital to 6 weeks after surgery

MODERATE¹

due to risk of bias

Peto OR 0.32 (0.16 to 0.67)

60 per 1000

41 fewer per 1000

(from 20 fewer to 51 fewer)

Acute myocardial infarction

Not reported

DVT

891

(8 studies)

ranged from in hospital period to 6 months after surgery

MODERATE¹

due to risk of bias

RD 0 (−0.02 to 0.03)⁴

36 per 1000

0 fewer per 1000

(from 20 fewer to 30 more)³

Quality of life (mental component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

LOW¹^,²

due to risk of bias, imprecision

The mean quality of life (mental component score) within 6 weeks in the control groups was

63.3

The mean quality of life (mental component score) within 6 weeks in the intervention groups was

1.32 lower

(5.86 lower to 3.22 higher)

Quality of life (physical component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

LOW¹^,²

due to risk of bias, imprecision

The mean quality of life (physical component score) within 6 weeks in the control groups was

The mean quality of life (physical component score) within 6 weeks in the intervention groups was

1.22 lower

(5.27 lower to 2.83 higher)

Blood loss via haemoglobin level after surgery

891

(8 studies)

ranges from 3 to 5 days after surgery

VERY LOW¹^,²^,⁵

due to risk of bias, inconsistency, imprecision

The mean blood loss via haemoglobin level after surgery in the control groups was

The mean blood loss via haemoglobin level after surgery in the intervention groups was

0.39 lower

(0.69 to 0.09 lower)

Total blood loss

691

(6 studies)

ranges from 3 to 5 days after surgery

VERY LOW¹^,²^,⁵

due to risk of bias, inconsistency, imprecision

The mean total blood loss in the control groups was

850 mL

The mean total blood loss in the intervention groups was

0.76 standard deviations lower

(1.33 to 0.19 lower)

Postoperative bleeding

200

(2 studies)

ranges from within 3 days of surgery to during in hospital period

LOW¹^,²

due to risk of bias, imprecision

The mean postoperative bleeding in the control groups was

500 mL

The mean postoperative bleeding in the intervention groups was

0.18 standard deviations lower

(0.46 lower to 0.1 higher)

Length of stay

472

(4 studies)

MODERATE¹

due to risk of bias

The mean length of stay in the control groups was

6 days

The mean length of stay in the intervention groups was

0.19 lower

(0.38 to 0.01 lower)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Absolute effect calculated using risk difference
4: Data analysed using risk difference due to low event rates
5: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 14Clinical evidence summary: IA/topical plus oral versus IA/topical

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with IA/topical tranexamic acid	Risk difference with IA/topical+oral tranexamic acid (95% CI)
Mortality	Not reported
Transfusion	100 (1 study) within 3 days of surgery	VERY LOW¹^,² due to risk of bias, imprecision	OR 0.13 (0.01 to 1.28)	60 per 1000	52 fewer per 1000 (from 59 fewer to 16 more)
Acute myocardial infarction	Not reported
DVT	100 (1 study) 1 year after surgery	LOW¹^,⁵ due to risk of bias, imprecision	RD 0 (−0.04 to 0.04)⁴	0 per 1000	0 fewer per 1000 (from 40 fewer to 40 more)³
Quality of life	Not reported
Blood loss via haemoglobin level after surgery	100 (1 study) 3 days after surgery	LOW¹^,² due to risk of bias, imprecision		The mean blood loss via haemoglobin level after surgery in the control groups was 9.9 g/dL	The mean blood loss via haemoglobin level after surgery in the intervention groups was 0.9 higher (0.37 to 1.43 higher)
Total blood loss	100 (1 study) 3 days after surgery	LOW¹^,² due to risk of bias, imprecision		The mean total blood loss in the control groups was 731 mL	The mean total blood loss in the intervention groups was 103 lower (169.02 to 36.98 lower)
Postoperative bleeding	100 (1 study) 3 days after surgery	LOW¹^,² due to risk of bias, imprecision		The mean postoperative bleeding in the control groups was 128 mL	The mean postoperative bleeding in the intervention groups was 47 lower (67.16 to 26.84 lower)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Absolute effect calculated using risk difference
4: Analysed via risk difference due to low event rate
5: Outcome considered imprecise because of the small number of participants and zero events

Table 15Clinical evidence summary: IV plus IA/topical versus IA/topical

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with IA/topical tranexamic acid

Risk difference with IV+IA/topical tranexamic acid (95% CI)

Mortality

Not reported

Transfusion

320

(3 studies)

while admitted in hospital or within 5 days of surgery

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

OR 0.13 (0.03 to 0.66)

38 per 1000

32 fewer per 1000

(from 12 fewer to 36 fewer)

Acute myocardial infarction

Not reported

DVT

420

(4 studies)

3 or 6 months after surgery

⊕⊕⊝⊝

LOW¹^,⁵

due to risk of bias, imprecision

RD 0.02 (−0.02 to 0.06)⁴

38 per 1000

20 more per 1000

(from 20 fewer to 60 more)³

Quality of life (mental component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean quality of life (mental component score) within 6 weeks in the control groups was

The mean quality of life (mental component score) within 6 weeks in the intervention groups was

1.18 higher

(2.84 lower to 5.2 higher)

Quality of life (physical component score) within 6 weeks

SF-36. Scale from: 0 to 100.

100

(1 study)

unclear

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean quality of life (physical component score) within 6 weeks in the control groups was

The mean quality of life (physical component score) within 6 weeks in the intervention groups was

1.04 higher

(2.57 lower to 4.65 higher)

Blood loss via haemoglobin level after surgery

420

(3 studies)

ranges from 3 to 5 days after surgery

⊕⊝⊝⊝

VERY LOW¹^,²^,⁶

due to risk of bias, inconsistency, imprecision

The mean blood loss via haemoglobin level after surgery in the control groups was

−3 g/dL

The mean blood loss via haemoglobin level after surgery in the intervention groups was

0.54 higher

(0.21 to 0.87 higher)

Total blood loss

420

(3 studies)

ranges from 3 to 5 days after surgery or until hospital discharge

⊕⊝⊝⊝

VERY LOW¹^,²^,⁶

due to risk of bias, inconsistency, imprecision

The mean total blood loss in the control groups was

900 mL

The mean total blood loss in the intervention groups was

0.60 standard deviations lower

(0.8 to 0.41 lower)

Length of stay

140

(1 study)

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

The mean length of stay in the control groups was

4 days

The mean length of stay in the intervention groups was

0.15 higher

(0.24 lower to 0.54 higher)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.
2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs
3: Absolute effect calculated using risk difference
4: Analysis using risk difference due to low event rate
5: Outcome considered imprecise due to small number of participants and low event rate
6: Downgraded by 1 or 2 increments because the point estimate varies widely across studies, unexplained by subgroup analysis. Random effects (DerSimonian and Laird) model was employed.

Table 16Health economic evidence profile: Topical (intra-articular) tranexamic acid versus Placebo (knee replacements)

Study

Applicability

Limitations

Other comments

Incremental cost

Incremental effects

Cost effectiveness

Uncertainty

Alshryda 2013¹³ [UK]

Partially applicable^(a)

Potentially serious limitations^(b)

A cost utility within-trial analysis (TRANX-K RCT) of tranexamic acid in knee replacements.

Analysed patient level outcomes (transfusion, OKS and EQ-5D) and resource use over 3 months. Unit costs applied.

Tranexamic acid saves £333 per person

Tranexamic acid gave 0.0053 less QALYs per person^(c)

Placebo costs £63,429 per QALY gained compared to tranexamic acid^(d)

Costs were bootstrapped due to skewness of the cost data. The results showed a similar cost saving of £333 for the use of tranexamic acid.

: Abbreviations: OKS: Oxford Knee Score; QALY: quality-adjusted life years; RCT: randomised controlled trial; TRANX-K: Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total knee replacement: a randomized controlled trial
(a): A within trial analysis with cost consequence which included relevant costs and outcomes. EQ-5D recorded but not used as part of the cost effectiveness calculations.
(b): Costs of complications during the trial were not accounted for. Unit costs are not referenced. Outcomes are from a single RCT rather than a systematic review.
(c): Quality of life is reported amongst other outcomes but the difference in baseline values mean inference should be treated with caution
(d): ICER was not reported in the study

Table 17Health economic evidence profile: Topical (intra-articular) tranexamic acid versus Placebo (hip replacements)

Study

Applicability

Limitations

Other comments

Incremental cost

Incremental effects

Cost effectiveness

Uncertainty

Alshryda 2013¹² [UK]

Partially applicable^(a)

Potentially serious limitations^(b)

A cost utility within-trial analysis (TRANX-H RCT) of tranexamic acid in hip replacements.

Analysed patient level outcomes (transfusion, OHS and EQ-5D) and resource use over 3 months. Unit costs applied.

Tranexamic acid saves £305 per person

Tranexamic acid gave 0.027 less QALYs per person^(c)

Placebo costs £11,509 per QALY gained compared to tranexamic acid^(d)

Costs were bootstrapped due to skewness of the cost data. The results showed a similar cost saving of £305 for the use of tranexamic acid.

: Abbreviations: OHS: Oxford Hip Score; QALY: quality-adjusted life years; RCT: randomised controlled trial; TRANX-H: Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total hip replacement: a randomized controlled trial
(a): A within trial analysis with cost consequence which included relevant costs and outcomes. EQ-5D recorded but not used as part of the cost effectiveness calculations.
(b): Costs of complications during the trial were not accounted for. Unit costs are not referenced. Outcomes are from a single RCT rather than a systematic review.
(c): Quality of life is reported amongst other outcomes but the difference in baseline values mean inference should be treated with caution.
(d): ICER was not reported in the study

Table 18Health economic evidence profile: Intravenous tranexamic acid versus No tranexamic acid

Study	Applicability	Limitations	Other comments	Incremental cost	Incremental effects	Cost effectiveness	Uncertainty
Davies 2018⁵⁰ [UK]	Partially applicable ^(a)	Potentially serious limitations^(b)	Cost comparison of intravenous tranexamic acid versus no tranexamic acid in lower limb joint replacement. The study is a retrospective cohort analysis with multivariate regression.	Tranexamic acid saves £67.89 (min) and £155.90 (max)	N/A	Tranexamic acid is cost saving	Two estimates of cost difference are given to account for the minimum and maximum cost of a bed day. Tranexamic acid was cost saving in both analyses.

: Abbreviations: N/A; not applicable
(a): Cost comparison from a UK perspective with a relevant intervention and comparator. No QALYs or health outcomes
(b): Observational data from a single study used, although data is adjusted; no health outcomes or adverse events are factored into cost calculations.

Table 19Risk ratios for transfusion events; direct pairwise meta-analysis results and NMA results

Comparator	Intervention	Direct (95% confidence interval)	Fixed effects NMA - median (95% credible interval)
IA	IV	Presented as risk difference in clinical review	0.925 (0.732, 1.161)
	Oral	0.781 (0.474, 1.282)^(a)	0.840 (0.518, 1.319)
	IA + IV	Presented as Peto odds ratio in clinical review	0.294 (0.126, 0.611)
	IA + Oral	Presented as Peto odds ratio in clinical review	0.070 (0.000, 1.102)
IV	Oral	1.01 (0.59, 1.73)	0.909 (0.561, 1.432)
	IA + IV	0.27 (0.11, 0.67)	0.318 (0.140, 0.642)
	IA + Oral	n/a	0.076 (0.000, 1.208)
Oral	IA + IV	n/a	0.350 (0.137, 0.816)
Oral	IA + Oral	n/a	0.083 (0.000, 1.377)
IA + IV	IA + Oral	n/a	0.239 (0.000, 4.311)

(a): The inverse risk ratio to the one presented in the evidence review is presented here for comparison

Table 20Absolute outcomes and ranking of interventions

Transfusions
	Probability of a transfusion event - median (95% CrIs)	Intervention rank - median (95% CrIs) 1=least transfusions, 5=most	Probability that intervention is best (least transfusions)
IA	0.072 (0.025, 0.187)	5 (3, 5)	0.00%
IV	0.066 (0.023, 0.178)	4 (3, 5)	0.00%
Oral	0.060 (0.019, 0.175)	3 (2, 5)	0.06%
IA + IV	0.021 (0.005, 0.74)	2 (1, 2)	20.14%
IA + Oral	0.005 (0.000, 0.098)	1 (1, 5)	79.80%
NHS cost
	Cost of each intervention including transfusion costs – mean (95% CrIs)	Intervention rank - median (95% CrIs) 1=least cost, 5=most cost	Probability that intervention is best (least cost)
IA	£31.13 (11.76, 68.36)	5 (3, 5)	0.00%
IV	£28.63 (10.22, 64.65)	4 (3, 5)	0.00%
Oral	£24.70 (6.92, 61.65)	3 (2, 5)	1.15%
IA + IV	£14.34 (7.23, 31.42)	2 (1, 3)	12.23%
IA + Oral	£7.76 (2.31, 36.82)	1 (1, 5)	86.62%

Table 21UK unit costs of tranexamic acid

Resource	Dose	Unit cost
Oral tranexamic acid (tablet)	500 mg	£0.05
Intravenous/Intra-articular tranexamic acid solution	500 mg/5ml	£0.55
Syringe^(a)	-	£0.35
Saline ampoule (20ml of 0.9%)^(a)	-	£0.11

: Source: eMIT ⁸⁸ and NHS Supply chain Catalogue ¹⁸⁸
(a): Required for administration of intravenous/intraarticular tranexamic acid

Table 22UK costs of blood transfusion

Resource	Unit cost
Administration of first unit of RBCs	£57.19
Administration of subsequent unit of RBCs	£36.13
Unit of RBCs (first and subsequent)	£128.99
Total cost of first RBC unit	£186.18
Total cost of a subsequent RBC unit	£165.12

: Source: Stokes 2018²³², NHSBT 2017/18¹⁸⁷

Final

Intervention evidence review underpinning recommendations 1.4.1 and 1.4.2 in the NICE guideline

This evidence review was developed by the National Guideline Centre, hosted by the Royal College of Physicians

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian.

Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK561388PMID: 32881462