Transfusion Medicine Reviews xxx (2018) xxx–xxx

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Transfusion Medicine Reviews

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The efficacy and safety of topical tranexamic acid: A systematic reviewand meta-analysis

Joshua Montroy a,b, Brian Hutton a,b, Preveshen Moodley c, Nicholas A. Fergusson a, Wei Cheng a,Alan Tinmouth a, Luke T. Lavallée a,c, Dean A. Fergusson a,b,c, Rodney H. Breau a,c,⁎a Clinical Epidemiology Program, Centre for Practice Changing Research, Ottawa Hospital Research Institute, Ottawa, ON, Canadab University of Ottawa, School of Epidemiology, Community Medicine and Preventive Medicine, Ottawa, ON, Canadac Division of Urology, Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada

a b s t r a c ta r t i c l e i n f o

⁎ Corresponding author at: Rodney H. Breau, MsC, MD,versity of Ottawa, 501 Smyth Rd, Box 222, Ottawa, ON K1

E-mail address: rbreau@toh.on.ca (R.H. Breau).

https://doi.org/10.1016/j.tmrv.2018.02.0030887-7963/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as:Montroy J, et al, TheRev (2018), https://doi.org/10.1016/j.tmrv.2

Available online xxxx

Keywords:Tranexamic acidLysine analogueSurgeryBlood transfusionVenous thromboembolismTopical

Tranexamic acid (TXA) is an effective hemostatic agent used for the reduction of blood loss and transfusion. How-ever, the safety profile of TXA remains in question due to a potential increased risk of venous thromboembolism.By applying TXA topically as opposed to intravenously, systemic absorptionmay be reduced and unwanted side-effects mitigated. The objective of our review is to investigate the efficacy and safety of topically appliedtranexamic acid compared to both placebo, and the intravenous administration. Cochrane Central Register ofControlled Trials, MEDLINE, Embase, ISI Web of Science, PubMed, and Clinicaltrials.gov were searched from in-ception to November, 2016. We included randomized controlled trials that compared topical tranexamic acidto either placebo (or standard care) or intravenous administration, in adult patients. Surgical and non-surgicaltrials were included. Abstract, full-text selection, data extraction and risk of bias assessment were all performedin duplicate. In total, 67 studies involving 6,034 patients met inclusion criteria. The majority of trials evaluatedorthopedic procedures. Compared to placebo, the administration of topical TXA significantly reduced the oddsof receiving a blood transfusion (pooled OR 0.28, 95% CI 0.20 to 0.38; P b 0.001) and significantly reducedmean blood loss (WMD -276.6, 95% CI -327.8 to -225.4; P b 0.0001).When compared to the intravenous administra-tion, there was no difference between the two groups in terms of transfusion requirements (pooled OR 1.03, 95% CI0.72 to 1.46; P=0.88) or blood loss (WMD -21.95, 95% CI -66.61 to 27.71; P=0.34). There was no difference in theodds of developing a venous thromboembolic complication between the topical TXA and control groups (pooledOR=0.78, 95% CI 0.47 to 1.29; P=0.33) or the topical and intravenous groups (pooled OR=0.75, 95% CI 0.39 to1.46; P=0.40). The topical applicationof TXAeffectively reduces both transfusion risk andblood loss compared topla-cebo, without increasing thromboembolic risks. There were no major differences between topical and intravenoustranexamic acid with respect to safety and efficacy, and both were superior to placebo with regards to blood lossand transfusion requirements. Further study of the topical application is required outside of the field of orthopedics.

FRCSC, Surgical Oncology, Division of Urology, Associate SciH8L6, Canada.

efficacy and safety of topical tranexamic acid: A018.02.003

© 2018 Elsevier Inc. All rights reserved.

Contents

Background & Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Literature Search Strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Study Selection Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Data Extraction and Risk of Bias Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Characteristics of Included Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Study Quality and Risk of Bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

entist, Ottawa Hospital Research Institute, The Ottawa Hospital/Uni-

systematic review andmeta-analysis, TransfusMed

2 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

. Effect of topical TXA on transfusion rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to intravenous administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA dose on transfusion rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA on blood loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to intravenous administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA on the rate of venous thromboembolic events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Compared to intravenous administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA on the risk of death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA on the risk of stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Effect of topical TXA on the risk of myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

. Publication Bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conflict of Interest Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix A. Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix A. Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Background & Rationale

Allogenic blood transfusions, although potentially life-saving,may be associated with an increased risk of infection and immunereactions, which may be a major source of morbidity for patients [1,2].A number of strategies are available that limit surgical blood lossand transfusions. Use of hemostatic agents has increased over the lastdecade [3] with antifibrinolytics emerging as popular agents inboth medical and surgical practice. Antifibrinolytic lysine analogueshave been shown to be effective in reducing blood loss during surgeryand trauma as well as non-surgical diseases such as anemia relatedto cancer [4-6]. Tranexamic acid (TXA) is a lysine analogue and is awidely used antifibrinolytic. Systemic use of TXA has been shown inmeta-analyses to be safe and effective at reducing blood loss in cardiac[7], orthopedic [8], pelvic [5], and spinal surgeries [9], among others,and is listed on the World Health Organization’s List of EssentialsMedicines.

Due to the mechanism of action of lysine analogues, there exists atheoretical increased risk of developing venous thromboembolic (VTE)complications such as deep venous thrombosis (DVT) or pulmonaryembolism (PE) [10]. In one of the largest trauma trials to date, theCRASH-2 trial (Clinical Randomisation of an Antifibrinolytic in Signifi-cant Hemorrhage), the efficacy and safety of TXA was assessed in over20,000 adult traumapatients and no increase in thromboembolic eventswas reported. However the precision of the safety estimatewas low andtherefore a potential for increased risk of VTE was not ruled out [6].Many systematic reviews have examined the relationship between ly-sine analogues and VTE risk, with point estimates remaining impreciseand thus unable to rule out a potential increased risk of VTE [5,11-13].Because of the theoretical risk of VTE, lysine analogues have not beenadopted as part of routine practice for most major surgeries except per-haps in cardiac and orthopedic procedures [14-16].

There remains a need to assess safety and efficacy of differentmodesof TXA delivery that may maintain the benefits of systemic administra-tionwhile reducing the risk of VTE [17,18]. The plasma concentration oftopically applied TXA has been shown to be approximately 90% lessthan when the medication is administered intravenously [19,20]. Con-versely, it is possible that high local tissue drug concentrations from top-ical application may increase the risk of adverse events.

A previous systematic review showed that local TXA was effective,but safety could not definitively established [12]. In recent years, therehave been a large number of new trails published assessing the effectof topical TXA. Given the need for safe and effective hemostatic

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

interventions, we performed a systematic review and meta-analysis toevaluate the efficacy and safety of topically administered tranexamicacid.

Methods

Our review was registered on Prospero (no. CRD42016035902). Areview protocol was prepared according to the PRISMA-P checklist[21] and is available upon request. The final report was prepared in ac-cordance with the Preferred Reporting Items for Systematic Reviewsand Meta-analyses (PRISMA) [22].

Eligibility Criteria

We included randomized controlled trials (RCTs) that comparedtopical tranexamic acid to either placebo (or standard care) or intrave-nously administered tranexamic acid in adult patients. Surgical andnon-surgical trials were included. We did not restrict inclusion bydrug dose or timing of administration. Our primary outcome was therisk of blood transfusion defined as the number of patients requiringat least one unit of red blood cells transfused. Our secondary outcomesincluded blood loss and adverse events (mortality, myocardial infarc-tion (MI), stroke, and venous thromboembolic events). We did notimpose any language restrictions.

Literature Search Strategy

A comprehensive literature search of indexed databases was con-ducted to identify all relevant studies in collaboration with an informa-tion specialist and a clinical expert in the field. We had a separateinformation specialist review the search strategy to check for consis-tency according to the PRESS framework [23]. The following databaseswere searched: Cochrane Central Register of Controlled Trials,MEDLINE, Embase, ISI Web of Science, PubMed, and Clinicaltrials.gov.Grey literature was searched via Google using the same searchterms. We searched from database inception to September 10th 2016(Appendix 1).

Study Selection Process

Citations from the literature search were collated and duplicatestudies removed. Titles and abstracts were screened for inclusion bytwo independent reviewers (JM, PMor NF). Titles and abstracts deemed

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 1. Selection flow diagram.

3J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

potentially relevant were recorded and the full text articles obtained.The same reviewers screened the full text articles for final eligibility,with disagreements settled by consultation of a third party (RB) toachieve consensus. The study selection process was documented andreported using a PRISMA flow diagram (Fig 1) [22].

Data Extraction and Risk of Bias Assessment

Two reviewers (JM, PM or NF) extracted all relevant data from theincluded studies using a standardized and piloted data extraction formin Microsoft Excel (version 15.0, Microsoft Corporation, Seattle,Washington, USA). We collected information related to publicationtraits (year of publication, journal, and authorship list), study popula-tion (e.g, eligibility criteria, age, gender, and comorbidities), the inter-ventions compared (type of comparator, dose, and timing), studydesign (methods, setting, sample size, and number of centres), clinicalendpoints (transfusion, blood loss, death, stroke, myocardial infarction,and venous thromboembolic events; endpoint definitionswere also ab-stracted), and risk of bias details. The risk of biaswas assessed by two in-dependent reviewers using the Cochrane Risk of Bias tool [24].

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

Data Analysis

Studies were pooled using Cochrane Review Manager, version 5.3(Cochrane Collaboration, Oxford, United Kingdom) and Open Meta-Analyst for Windows 10 (http://www.cebm.brown.edu/open_meta).For dichotomous outcomes, odds ratios were calculated using a randomeffects frequentist analysis based on the Der-Simonian Laird model andpresented with accompanying 95% confidence intervals. This methodallows for the inclusion of continuity corrections of 0.5 for all zerocells across outcomes, allowing us to estimate odds ratios for studiesreporting no events. For outcomes with zero events, a sensitivity analy-sis was also performed with a fixed effects meta-analysis using Petoodds ratios. For continuous outcomes, a mean difference and 95% confi-dence intervals are presented. Pooled mean differences were calculatedusing random effects inverse variance meta-analysis.

Statistical heterogeneitywas assessed using the I2 statistic, aswell asthe Chi2 test or the Cochrane Q test, depending on the analysis method.An I2 value of N50%was considered to indicate important heterogeneityrequiring additional exploration. For the Chi2 test and the Cochrane Qtest, a p-value of b0.1 was deemed to indicate heterogeneity requiringadditional exploration. The presence of publication bias was assessedusing funnel plots if more than 6 studies were identified. Where suffi-cient data were available, we conducted subgroup analyses to deter-mine whether the effect of topical TXA on blood transfusion and bloodloss varied by the type of surgical procedure, as well as the baselinerate of transfusion. A sensitivity analysis was performed on outcomeswith sufficient data, to determine if the effect of topical TXA variedwhen analyses were restricted to trials with adequate allocation con-cealment. A random-effects meta-regression was performed to deter-mine if the association between topical TXA and blood transfusionrate was affected by the dose of topical TXA used in the trial.

Results

The electronic search identified 1,245 titles and abstracts after theremoval of duplicates, of which 1,149 were excluded based on irrele-vancy to our study question. Of 96 full-text articles reviewed, 29 didnotmeet eligibility criteria andwere excluded. Sixty-seven trialsmet el-igibility representing 6,034 patients [25-75,76-91](Fig 1). Forty-two tri-als compared topical TXA to placebo, 14 compared topical TXA to IVTXA, and 11were 3 arm trials comparing topical TXA to IV TXA and pla-cebo. Eleven of the 67 articles did not report sufficient information forinclusion in our meta-analyses [25-29,35,43,44,62,79,91].

Characteristics of Included Studies

Included articles were published between 1979 and 2016 from 24different countries (Table 1). Study sample sizes ranged from 30 pa-tients to 333 patients (median = 84). Sixty-six of the studies assessedthe efficacy of topical TXA in surgical patients. Thirty trials involvedknee arthroplasty, 11 hip arthroplasty, 10 cardiac surgery, four dentalsurgery, two otolaryngological surgery, two spinal surgery, twoorthognathic surgery, one transurethral prostate resection, one reduc-tion mammoplasty, one pulmonary resection, one hip and kneearthroplasty, and one shoulder arthroplasty. The sole study whichassessed non-surgical patients studied the efficacy of topical TXA in ep-istaxis patients. Two trials consisted of two distinct topical TXA arms(different doses, administration techniques) and therefore were in-cluded twice in analysis forwhich they contributed data. For these trials,the control group size and events were split in half.

In 32 of the 66 surgical trials, topical TXAwas either poured (woundirrigation) or sprayed directly onto the operative site. In 21 trials involv-ing hip or knee arthroplasty, topical TXAwas administered via an intra-articular injection. Three trials used a combination of these two tech-niques. Another trial assessed both these techniques in two separategroups of patients. In two of the dental surgery trials, the wound was

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Table 1Characteristics of included studies

Study HostCountry(ies)

SampleSize

Procedure Comparator Method of topical TXA Administration Transfusionrisk reported(Y/N)

Blood lossreported(Y/N)

VTE riskreported(Y/N)

Chen (2016) Singapore 100 TKA IV Intra-articular injection Y Y YDrosos (2016) Greece 90 TKA Placebo and

IVN.R. Y Y Y

Goyal (2016) Australia 168 TKA IV Intra-articular injection Y N YKeyhani (2016) Iran 120 TKA Placebo and

IVIntra-articular injection Y Y Y

May (2016) USA 131 TKA IV Intra-articular injection Y Y YNorth (2016) USA 139 THA IV Wound irrigation prior to closure Y Y YPinsornsak (2016) Thailand 60 TKA IV Peri-articular injection Y Y YTzatzairis (2016) Greece 120 TKA Placebo and

IVIntra-articular injection Y Y Y

Xie (2016) China 210 THA IV Intra-articular injection Y Y YZhang (2016) China 75 THA Placebo and

IVIntra-articular injection Y Y Y

Aggarwal (2015) India 70 TKA IV Wound irrigation prior to closure Y Y YAguilera (2015) Spain 150 TKA Placebo and

IVSprayed via syringe onto wound prior to closure Y Y N

Ali Shah (2015) Pakistan 100 Open heartsurgeries

Placebo Wound irrigation prior to closure N Y N

Ausen (2015) Norway 56 Bilateral reductionmammoplasty

Placebo Poured into wound prior to closure N N N

Digas (2015) Greece 85 TKA Placebo andIV

Intra-articular injection Y Y Y

Eftekharian(2015)

Iran 56 Bimaxillaryosteotomy

Placebo Wound irrigation throughout procedure Y Y Y

Gillespie (2015) USA 111 TSA Placebo Wound irrigation prior to closure Y Y YLin (2015) Taiwan 120 TKA Placebo Intra-articular injection Y Y YOztas (2015) Turkey 90 TKA Placebo and

IVIntra-articular injection Y Y Y

Taheriazam(2015)*

Iran 80 THA IV Wound irrigation N N N

Vandesande(2015)*

Belgium 63 THA Placebo N.R. Y Y N

Wang, C (2015) China 60 TKA Placebo Intra-articular injection Y Y YWang, G (2015) China 100 TKA Placebo Intra-articular injection Y Y YXu (2015) China 224 THA Placebo Intra-articular injection Y Y YYang (2015) China 80 TKA Placebo Intra-articular injection Y Y YEmara (2014) Egypt 60 Hemiarthroplasty

surgeriesPlacebo andIV

Wound irrigation prior to closure Y Y Y

Gomez-Barrena(2014)

Spain 78 TKA IV Wound irrigation prior to closure andintra-articular injection

Y Y Y

Hosseini (2014) Iran 71 off-pump CABG Placebo Wound irrigation prior to closure N Y YMartin (2014) USA 100 TKA/THA Placebo Wound irrigation prior to closure Y N YPatel (2014) USA 89 TKA IV Wound irrigation prior to closure Y N YSarzaeem (2014) Iran 200 TKA Placebo and

IVWound irrigation prior to closure (grp 2)Intra-articular injection (grp 3)

Y Y Y

Soni (2014) India 80 TKA IV Wound irrigation prior to closure Y Y YWei (2014) China 333 THA Placebo and

IVIntra-operative wound irrigation andintra-articular injection

Y Y Y

Yue (2014) China 103 Unilateral total hipreplacement

Placebo TXA soaked gauze inserted into woundintra-operatively and intra-articular injection

Y Y Y

Alshryda(TRANX-K)(2013)

UnitedKingdom

157 TKA Placebo Solution sprayed onto wound prior to closure Y Y Y

Alshryda(TRANX-H)(2013)

UnitedKingdom

173 Unilateral total hipreplacement

Placebo Solution sprayed onto wound prior to closure Y Y Y

Georgiadis (2013) USA 101 TKA Placebo Wound irrigation prior to closure Y Y YNouraei (2013) Iran 80 Cardiac surgery Placebo Wound irrigation prior to closure Y Y YSa-ngasoonsgsong(2013)

Thailand 135 TKA Placebo Intra-articular injection Y Y Y

Van Elst (2013)* Belgium 67 THA Placebo Intra-articular injection N N YAbdullah (2012)* Pakistan 52 Transurethral

resection of theprostate

Placebo Bladder irrigation N N N

Canata (2012)* N.R. 96 TKA Placebo Infiltration of TXA N N NDell’Amore (2012) Italy 89 Pulmonary

resectionPlacebo Wound irrigation prior to closure Y Y Y

Maniar (2012) India 206 TKA IV Wound irrigation prior to closure Y Y YRoy (2012) India 50 TKA Placebo Intra-articular injection Y Y YSeo (2012) South

Korea150 TKA Placebo and

IVIntra-articular injection Y Y Y

Baric (2011)* Croatia 60 Elective cardiac Placebo and “Administered topically” Y Y N

4 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tranexamic acid: A systematic review andmeta-analysis, TransfusMedRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

Table 1 (continued)

Study HostCountry(ies)

SampleSize

Procedure Comparator Method of topical TXA Administration Transfusionrisk reported(Y/N)

Blood lossreported(Y/N)

VTE riskreported(Y/N)

surgery IVIshida (2011) Japan 100 TKA Placebo Intra-articular injection Y Y NKaewpradub(2011)

Thailand 40 Bimaxillaryosteotomy

Placebo Wound irrigation, intra-operatively N Y N

Kurt (2011) Turkey 100 Cardiac surgery Placebo Wound irrigation prior to closure N Y NSa-ngasoonsgsong(2011)

Thailand 48 TKA Placebo Intra-articular injection Y Y Y

Girgin (2010)* Turkey 60 Non-emergentcoronary bypass

IV Wound irrigation Y Y Y

Saberi (2010) Iran 100 Spinal surgery Placebo Wound irrigation prior to closure Y Y NWong (2010) Canada 124 TKA Placebo Wound soaked in TXA for 5 minutes prior to

closureY Y Y

Fawzy (2009) SaudiArabia

38 Isolated CABG Placebo Wound irrigation prior to closure Y Y N

Athanasiadis(2007)

Australia 30 Sinus surgery Placebo Solution sprayed into nasal cavity N N N

Baric (2007) Croatia 300 Elective cardiacsurgery

Placebo Wound irrigation prior to closure Y Y N

Abul-Azm (2006) Egypt 200 Elective openheart surgery

Placebo Wound irrigation prior to closure N Y N

Jabalameli (2006) Iran 56 Sinus surgery Placebo “Administered topically” N Y NYasim (2005) Turkey 300 TKA Placebo Wound irrigation prior to closure N Y NKrohn (2002) Norway 30 Spinal surgery Placebo Wound irrigation prior to closure Y Y NDe Bonis (2000) Italy 40 Primary coronary

artery surgeryPlacebo Wound irrigation prior to closure Y Y N

Blinder (1999) Israel 150 Dental extraction Placebo Mouthwash rinsed for 2 minutes, 4 times/day for 4days post-op

N N N

Tibbelin (1995) Sweden 68 Epistaxis Placebo TXA gel applied to nasal cavity N N NRamstrom (1993) Denmark

& Sweden93 Dental surgery Placebo Wound irrigation prior to closure and mouthwash

rinsed for 2 minutes, 4 times/day for 7 dayspost-op

N N N

Sindet-Pedersen(1989)

Denmark& Sweden

45 Oral surgery Placebo Wound irrigation prior to closure and mouthwashrinsed for 2 minutes, 4 times/day for 7 dayspost-op

N N N

Gersel-Pedersen(1979)

Denmark 120 Bilateral molarextraction

Placebo TXA soaked cones applied to wound prior toclosure

N N N

• = abstract only.

5J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

irrigated and the patients were given amouthwash to use for a numberof days post-operatively. Post-operative mouthwash alonewas given inone dental surgery trial. In the last dental surgery trial, TXA soakedcones were applied to each tooth socket. Three trials were vague intheir method of topical TXA application describing their technique as“administered topically” and “infiltration of TXA”. Two trials did not re-port their technique. In the one non-surgical trial, TXA gel was appliedto the nasal cavity of epistaxis patients.

Study Quality and Risk of Bias

Figure 2 summarizes the risk of bias using the Cochrane risk of biastool. The majority of studies had an unclear risk of bias for at least one

Fig 2. Risk of bia

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

methodological criterion. Themajority of studies described an adequaterandomization technique, although two trials were deemed to be athigh risk of bias as one trial allocated patients into groups according tothe day of the week and one trial alternately assigned patients intogroups [29,40]. Less than half of the trials adequately described their al-location concealment technique,with the same two trials being deemedto be at high risk of bias in this domain.

The majority of trials were deemed to have adequately blinded theirparticipants and personnel, as well as their outcome assessment fortransfusion rate and were therefore at a low risk for both performancebias and detection bias. The majority of studies had complete data orhad adequately described their reasons for missing data, with onestudy being deemed to be at high risk of attrition bias [38]. A small

s summary.

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

6 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

portion of studies were deemed to have a low risk of reporting bias, asnot many studies were registered on clinicaltrials.gov or had an avail-able study protocol. The majority of studies were found to have a lowrisk of other potential biases. A breakdown of the risk of bias found ineach study can be found in Appendix 2.

Effect of topical TXA on transfusion rate

Compared to placeboThirty-seven trials involving 3,408 patients reported blood transfu-

sion data comparing topical TXA to placebo. Compared to placebo, theadministration of topical TXA significantly reduced the odds of receivinga blood transfusion (pooled OR 0.29, 95% CI 0.20 to 0.40; P b 0.001, I2=49.7%) (Fig 3). In subgroup analyses by surgery type, there was a signif-icant reduction in transfusion risk for orthopedic procedures (pooledOR0.22, 95% CI 0.16 to 0.30; Pb0.01). There was no significant difference intransfusion risk for cardiac procedures (pooled OR 0.94, 95% CI 0.60 to1.46; P=0.78), orthognathic procedures (pooled OR 1.00, 95% CI 0.02to 52.15; P=N/A), spinal procedures (pooled OR 0.15, 95% CI 0.02 to1.31; P=0.09), and thoracic procedures (pooled OR 0.73, 95% CI 0.26to 2.08; P=0.53) surgeries, although a small number of studies were

Fig 3. Odds ratio (95% CI) and pooled estimates for ri

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

included in these subgroups. The sensitivity analysis using the fixed-effects Peto odds ratio, revealed similar results (Peto OR 0.32, 95% CI0.27 to 0.39; P b 0.001) (Appendix 3). When the analysis was restrictedto the 20 trials deemed to have adequate allocation concealment, simi-lar resultswere obtained (pooledOR 0.32, 95% CI 0.22 to 0.46; P b 0.001)(Appendix 3). For the subgroup analysis by baseline rate of transfusion,subgroups included baseline risks of b10%, 10-20%, 20-30%, 30-40% andN40%.With the exception of a baseline risk of b10% (pooledOR0.47, 95%CI 0.18 to 1.25; P=0.13), a significant decrease in transfusion risk wasseen across all subgroups (Appendix 3).

Compared to intravenous administrationTwenty-four studies representing 2,154 patients reported blood

transfusion data comparing topical TXA to IV TXA. When compared tothe intravenous administration of TXA, there was no significant differ-ence between the two groups overall (pooled OR 1.03, 95% CI 0.72 to1.46; P=0.88, I2=4.1%), or for orthopedic procedures (OR 0.92, 95% CI0.66 to 1.30; P=0.65). However, in the one cardiac surgery trial in-cluded in the analysis, patients who were administered topical TXAhad a significantly increased odds of receiving a transfusion (OR 11.00,95% CI 2.00 to 60.57; P=0.006) (Fig 4). The sensitivity analysis using

sk of blood transfusion (topical TXA vs placebo).

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 4. Odds ratio (95% CI) and pooled estimates for risk of blood transfusion (topical TXA vs IV TXA).

7J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

the fixed-effects Peto odds ratio, revealed similar results (Peto OR 1.04,95% CI 0.77 to 1.42; P =0.79) (Appendix 3). When the analysis was re-stricted to the 11 trials deemed to have adequate allocation conceal-ment, similar results were obtained (pooled OR 0.99, 95% CI 0.60 to1.61; P=0.96) (Appendix 3).

Effect of topical TXA dose on transfusion rate

Thirty-two of the 36 trials that reported transfusion data comparingtopical TXA to placebo were included in a univariate meta-regressionanalysis. In four trials, we were unable to convert the dose of topicalTXA into the appropriate mg/mL due to a lack of information providedin the related publications [38,63,67,68]. The concentration of topicalTXA used in the trials ranged from 1 mg/mL to 100 mg/mL. Dosage oftopical TXAdid not influence effectiveness of topical TXA used in the tri-als (Coefficient = -0.002, 95% CI -0.015 to 0.011; P = 0.75).

Effect of topical TXA on blood loss

Compared to placeboForty-three trials involving 3,666 patients reported blood loss data

comparing topical TXA to placebo. Topical TXA resulted in a meanblood loss reduction of 276 mL compared to placebo (weighted meandifference (WMD) -273, 95% CI -324. to -223; P b 0.0001) (Fig 5).There was substantial statistical heterogeneity between subgroups(Chi2 = 275.6, df = 5 (P b0.00001); I2 = 98.2%).When the analysiswas restricted to the 22 trials deemed to have adequate allocation con-cealment, similar resultswere seen (WMD-299, 95%CI -370 to -229; P b0.00001) (Appendix 3). Large reductions in blood loss were reported inorthopedic and cardiac surgery trials, while no statistically significantbenefit was reported in the single thoracic surgery trial.

Compared to intravenous administrationTwenty-two trials involving 1,897 patients reported blood loss data

comparing topical TXA to IV TXA. When compared to the intravenousadministration of TXA, there was no significant difference in blood

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loss between groups (WMD -22, 95% CI -67 to 28; p=0.34) (Fig 6).There was substantial statistical heterogeneity between trials (Chi2 =222.47, df = 21 (p b0.00001); I2 = 91%). When the analysis was re-stricted to the 10 trials deemed to have adequate allocation conceal-ment, similar results were seen (WMD -9, 95% CI -77 to 58; P=0.78)(Appendix 3).

Effect of topical TXA on the rate of venous thromboembolic events

Compared to placeboThirty trials involving 2,845 patients reported data on the rate of ve-

nous thromboembolic events (either pulmonary embolism or deep veinthrombosis) in their topical TXA group and placebo group. Nineteen tri-als reported no venous thromboembolic events in either arm of theirtrial. Therewas no difference in the odds of developing a venous throm-boembolic complication between the topical TXA and control groups(pooled OR=0.78, 95% CI 0.47 to 1.29; P=0.33, I2=0%) (Fig 7). In oursensitivity analysis using thefixed-effects Peto odds ratio, similar resultswere obtained (Peto OR=0.79, 95% CI 0.49 to 1.27; P=0.33, I2=0%)(Appendix 3).

Compared to intravenous administrationTwenty-one trials involving 1,965 patients reported data on the rate of

venous thromboembolic events (either pulmonary embolism or deepvein thrombosis) in their topical TXA group and IV groups. Ten of thesetrials reportedno thromboembolic events in either arm. Therewas no sig-nificant difference in the odds of developing a venous thromboemboliccomplication between the topical TXA and IV TXA groups (pooled OR=0.75, 95% CI 0.39 to 1.46; P=0.40, I2=0%) (Fig 8). In our sensitivity anal-ysis using the fixed-effects Peto odds ratio, similar results were obtained(Peto OR=0.73, 95% CI 0.40 to 1.31; P=0.29, I2=0%) (Appendix 3).

Effect of topical TXA on the risk of death

When comparing to placebo, nine trials involving 894 patients re-ported mortality data. Seven of the nine trials reported zero deaths in

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 5.Mean difference (95% CI) for estimated blood loss (topical TXA vs placebo).

8 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

each group. The administration of topical TXA did not increase the riskof death compared to placebo (pooled OR=0.52, 95% CI 0.18 to 1.55;P=0.24, I2=0%) (Fig 9). When comparing topical to intravenous TXA,one study reported mortality data, with one death in the topical group(2.1%), and zero in the IV group.

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Effect of topical TXA on the risk of stroke

Seven trials involving 552 patients reported stroke data comparingtopical TXA to placebo. Six of the seven studies reported zero events inboth arms of their trial. The administration of topical TXA did not

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 6. Mean difference (95% CI) for estimated blood loss (topical TXA vs IV TXA).

Fig 7. Odds ratio (95% CI) and pooled estimates for the incidence of venous thromboembolic events (topical TXA vs placebo).

9J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

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Fig 8. Odds ratio (95% CI) and pooled estimates for the incidence of venous thromboembolic events (topical TXA vs IV TXA).

10 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

increase the risk of strokewhen compared to placebo (pooledOR=0.75,95% CI 0.18 to 3.18; P=0.70, I2=0%) (Fig 10). Two studies involving 180patients reported stroke data comparing topical to intravenous TXA.There was one stroke in the intravenous group (1.1%) and zero in thetopical group.

Effect of topical TXA on the risk of myocardial infarction

Six trials involving 362 patients reported myocardial infarction datacomparing topical TXA to placebo. Four of the six studies reported zeroevents in both arms of their trial. The administration of topical TXA didnot increase the risk of myocardial infarction (pooled OR=0.58, 95% CI0.13 to 2.57; P=0.47) (Fig 11). Three studies involving 368 patients re-ported myocardial infarction data comparing topical to intravenousTXA. There was no significant difference in the odds of developing anMI between topical and intravenous TXA groups (pooled OR=1.94,95% CI 0.34 to 11.06; P=0.45) (Fig 12).

Publication Bias

Publication bias was assessed for clinical outcomes of transfusionrisk, blood loss and thromboembolic events (Appendix 3). Slight asym-metry was seen in the funnel plots for transfusion risk and blood loss

Fig 9. Odds ratios (95% CI) and pooled estimates for th

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comparing topical TXA to placebo, with the plots suggesting the pres-ence of small study effects favouring topical TXA. No asymmetry wasseen in the funnel plot for thromboembolic events, suggesting low riskof bias. No asymmetry was seen in the funnel plots for the comparisonof topical and intravenous TXA (Appendix 3).

Discussion

There is considerable interest in topical TXA, given thepotential ben-efits and theoretical decreased risk of adverse events compared to sys-temic TXA. We performed a systematic review and meta-analysiscomparing the safety and efficacy of topically applied TXA to both pla-cebo and the intravenous application. The results of our review suggestthat the topical application of tranexamic acid during surgery is highlyeffective in reducing both blood loss and the subsequent rate of bloodtransfusions compared to placebo. However, when compared to the in-travenous application of TXA, the topical application did not provide anyfurther benefits in terms of blood loss reduction or a reduction in trans-fusion requirements. In addition, we observed no difference in the riskof thromboembolic events, stroke, myocardial infarction, or mortalitycompared to either placebo or the intravenous administration.

Thirty-seven randomized controlled trials involving 3,408 patientsin our review reported on transfusion rate compared to placebo, and

e incidence of mortality (topical TXA vs placebo).

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 10. Odds ratios (95% CI) and pooled estimates for the incidence of stroke (topical TXA vs placebo).

11J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

we found a 71% reduction in the odds of receiving a blood transfusion inpatients who had received TXA topically. In a systematic review andmeta-analysis of 129 randomized controlled trials involving a total of10,488 patients treated with TXA by any form of administration, Kerat al. reported a 30% reduction in the need for transfusion [13], a similarmagnitude of effect has been noted in reviews of pelvic and orthopedicsurgeries [5,8]. The potential for differences between the two methodsof application was explored, with 24 studies involving 2,154 patientsreporting transfusion data comparing topical TXA to IV TXA, and wesaw no difference in the odds of receiving a blood transfusion (pooledOR 1.03, 95% CI 0.72 to 1.46; P=0.88).

In theory, topical application of TXA may be safer than intravenousadministration because topically applied TXA results in a 90% reductionin plasma concentration compared to intravenous [19,20]. None of thetrials included in our analysis were adequately powered to detect a dif-ference in thromboembolic events, or other adverse events, betweengroups. Moreover, the pooled analysis also suggests there is no signifi-cant increased risk of thromboembolic events associated with topicalTXA compared to placebo (pooled OR=0.78, 95% CI 0.47 to 1.29; P=0.33, I2=0%). Despite these reassuring data, it is worth noting the con-fidence interval remains wide for safety estimates and only abouttwo-thirds (42/67) of the studies in our review reported on thrombo-embolic events. High-quality randomized controlled trials designedand powered to detect differences in adverse events are needed to de-finitively establish the safety of TXA, especially in understudied andhigh risk populations such as cancer patients [11].

There is no accepted standard dose of TXA for systemic or topical use[92,93]. The studies included in our analysis used a wide range of dosesof topical TXA (1mg/mL to 100mg/mL). According to our meta-regression analysis, the relationship between topical TXA administra-tion and transfusion risk reductionwas not dose-dependent, suggestingtopical TXA remains effective at small doses or low concentrations. Fur-ther study to identify optimal drug doses are needed, in both intrave-nous and topical applications.

Of note, the majority of studies (about two-thirds) evaluated ortho-pedic procedures. In subgroup analysis of non-orthopedic procedures,

Fig 11. Odds ratios (95% CI) and pooled estimates for the inci

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no significant benefit of topical TXA was observed. Only two non-orthopedic studies compared topical to intravenous TXA [80,91]. Inone of these studies [91] no difference in transfusion was observed,while the other [80] observed a significantly higher risk of transfusionin the topical TXA arm. Outside of orthopedics, it is clear that more evi-dence is needed to determine if topical TXA is as effective as IV TXA inreduction of blood loss and transfusion.

This review is limited by the quality of the published studies, manyof which had unclear risk of bias due to under reporting of methodolog-ical details. We found substantial statistical heterogeneity in our clinicaloutcomes of blood transfusion and blood loss. This heterogeneityremained within the blood loss subgroups and in the sensitivity analy-ses. There are a number of factors which could explain this heterogene-ity. Transfusion in clinical practice can vary within healthcare systemsand even within hospitals. Considering the wide range of studies, it islikely that transfusion thresholds varied from study to study. Surgicalquality across studies is another factor which could influence the mag-nitude of effect observed. With respect to blood loss, this is a difficultoutcome tomeasure accurately and consistently. Differences inmeasur-ing techniques across studies could explain some of the heterogeneityobserved. It is important to note that the variation seen in these out-comes were in the magnitude of effect, and not the direction. Finally,few trials reported data on the rate of mortality, stroke or MI, makingthe effect estimates for these outcomes very imprecise and preclude de-finitive conclusions.

Conclusion

The topical application of tranexamic acid effectively reduces bothtransfusion risk and blood loss compared to placebo. This effect doesnot appear to be dose-dependent. Our review suggests the lack of a re-lationship between topical TXA administration and an increased risk ofadverse events including thromboembolism, although more high-quality evidence from trials designed and powered to detect differencesin safety outcomes are needed before definitive conclusions can bedrawn. There were no major differences between topical and

dence of myocardial infarction (topical TXA vs placebo).

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

Fig 12. Odds ratios (95% CI) and pooled estimates for the incidence of myocardial infarction (topical TXA vs IV TXA).

12 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

intravenous tranexamic acid with respect to safety and efficacy, andboth were superior to placebo with regards to blood loss and transfu-sion requirements. Outside of orthopedic surgery, the comparison oftopically administered tranexamic acid to intravenously administeredtranexamic acid warrants further exploration.

Funding

This research did not receive any specific grant from funding agen-cies in the public, commercial, or not-for-profit sectors.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.tmrv.2018.02.003.

References

[1] Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood2008;112:2617–26. https://doi.org/10.1182/blood-2008-07-077370.

[2] Mannucci PM, Levi M. Prevention and Treatment of Major Blood Loss. N Engl J Med2007;356:2301–11. https://doi.org/10.1056/NEJMra067742.

[3] Wright JD, Ananth CV, Lewin SN, Burke WM, Siddiq Z, Neugut AI, et al. Patterns ofuse of hemostatic agents in patients undergoing major surgery. J Surg Res 2014;186:458–66. https://doi.org/10.1016/j.jss.2013.07.042.

[4] Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastro-intestinal bleeding. In: Gluud LL, editor. Cochrane Database Syst. Rev. Chichester,UK: John Wiley & Sons, Ltd; 2014. p. CD006640. https://doi.org/10.1002/14651858.CD006640.pub3.

[5] Breau RH, Kokolo MB, Punjani N, Cagiannos I, Beck A, Niznick N, et al. The effects oflysine analogs during pelvic surgery: a systematic review and meta-analysis.Transfus Med Rev 2014;28:145–55. https://doi.org/10.1016/j.tmrv.2014.05.002.

[6] CRASH-2 trial collaboratorsShakur H, Roberts I, Bautista R, Caballero J, Coats T, et al.Effects of tranexamic acid on death, vascular occlusive events, and blood transfusionin trauma patients with significant haemorrhage (CRASH-2): a randomised,placebo-controlled trial. Lancet 2010;376:23–32. https://doi.org/10.1016/S0140-6736(10)60835-5.

[7] Hutton B, Joseph L, Fergusson D, Mazer CD, Shapiro S, Tinmouth A. Risks of harmsusing antifibrinolytics in cardiac surgery: systematic review and network meta-analysis of randomised and observational studies. BMJ 2012;345:e5798. https://doi.org/10.1136/bmj.e5798.

[8] Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use ofantifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic sur-gery: A systematic review of randomized trials. Thromb Res 2009;123:687–96.https://doi.org/10.1016/j.thromres.2008.09.015.

[9] Li Z-J, Fu X, Xing D, Zhang H-F, Zang J-C, Ma X-L. Is tranexamic acid effective and safein spinal surgery? A meta-analysis of randomized controlled trials. Eur Spine J 2013;22:1950–7. https://doi.org/10.1007/s00586-013-2774-9.

[10] White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolismafter different elective or urgent surgical procedures. Thromb Haemost 2010;90:446–55. https://doi.org/10.1160/TH03-03-0152.

[11] Montroy J, Fergusson NA, Hutton B, Lavallée LT, Morash C, Cagiannos I, et al. TheSafety and Efficacy of Lysine Analogues in Cancer Patients: A Systematic Reviewand Meta-Analysis. Transfus Med Rev 2017. https://doi.org/10.1016/j.tmrv.2017.03.002.

[12] Ker K, Beecher D, Roberts I. Topical application of tranexamic acid for the reductionof bleeding. In: Ker K, editor. Cochrane Database Syst. Rev. Chichester, UK: JohnWiley & Sons, Ltd; 2013. p. CD010562. https://doi.org/10.1002/14651858.CD010562.pub2.

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

[13] Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgicalbleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.

[14] Punjani N, Lavallée LT, Momoli F, Fergusson D,Witiuk K, Mallick R, et al. Blood trans-fusion and hemostatic agents used during radical cystectomy. Can Urol Assoc J 2013;7:E275-0. https://doi.org/10.5489/cuaj.1002.

[15] Jawa RS, Singer A, Mccormack JE, Huang EC, Rutigliano DN, Vosswinkel JA.Tranexamic Acid Use in United States Trauma Centers: A National Survey. AmSurg 2016;82:439–47.

[16] Truong JL, Cyr DP, Lam-mcculloch J, Cleary SP, Karanicolas PJ. Consensus and Contro-versy in Hepatic Surgery: A Survey of Canadian Surgeons. J Surg Oncol 2014;110:947–51. https://doi.org/10.1002/jso.23748.

[17] Ipema HJ, Tanzi MG. Use of Topical Tranexamic Acid or Aminocaproic Acid to Pre-vent Bleeding After Major Surgical Procedures. Ann Pharmacother 2012;46:97–107. https://doi.org/10.1345/aph.1Q383.

[18] Abrishami A, Chung F, Wong J. Topical application of antifibrinolytic drugs for on-pump cardiac surgery: a systematic review and meta-analysis. Can J Anaesth2009;56:202–12. https://doi.org/10.1007/s12630-008-9038-x.

[19] Abrishami A, Wong J, El-Beheiry H, Hasan SM, Chung F. Intra-articular application oftranexamic acid for perioperative blood loss in total knee arthroplasty: a random-ized controlled trial. Can J Anesth 2009;56.

[20] McCormack PL. Tranexamic acid: a review of its use in the treatment ofhyperfibrinolysis. Drugs 2012;72:585–617. https://doi.org/10.2165/11209070-000000000-00000.

[21] Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferredreporting items for systematic review and meta-analysis protocols (PRISMA-P)2015 statement. Syst Rev 2015;4:1. https://doi.org/10.1186/2046-4053-4-1.

[22] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting itemsfor systematic reviews andmeta-analyses: The PRISMA statement. Int J Surg 2010;8:336–41. https://doi.org/10.1016/j.ijsu.2010.02.007.

[23] McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS PeerReview of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol2016;75:40–6. https://doi.org/10.1016/j.jclinepi.2016.01.021.

[24] Higgins, JPT, Altman DG, Sterne, JAC (editors). Chapter 8: Assessing risk of bias in in-cluded studies. In: Higgins, JPT, Green S (editors). Cochrane Handbook for System-atic Reviews of Interventions Version 5.1.0 (updated March 2011). The CochraneCollaboration. http://handbook.cochrane.org/chapter_8/8_assessing_risk_of_bias_in_included_studies.html.

[25] Gersel-Pedersen N. Tranexamic acid in alveolar sockets in the prevention of alveoli-tis sicca dolorosa. Int J Oral Surg 1979;8:421–9.

[26] Sindet-Pedersen S, Ramström G, Bernvil S, Blombäck M. Hemostatic Effect ofTranexamic Acid Mouthwash in Anticoagulant-Treated Patients Undergoing Oral Sur-gery. N Engl J Med 1989;320:840–3. https://doi.org/10.1056/NEJM198903303201305.

[27] Ramström G, Sindet-Pedersen S, Hall G, Blombäck M, Alander U. Prevention of post-surgical bleeding in oral surgery using tranexamic acid without dose modification oforal anticoagulants. J Oral Maxillofac Surg 1993;51:1211–6.

[28] Tibbelin A, Aust R, Bende M, Holgersson M, Petruson B, Rundcrantz H, et al. Effect oflocal tranexamic acid gel in the treatment of epistaxis. ORL J Otorhinolaryngol RelatSpec 1995;57:207–9.

[29] Blinder D, Manor Y, Martinowitz U, Taicher S, Hashomer T. Dental extractions in pa-tients maintained on continued oral anticoagulant: comparison of local hemostaticmodalities. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:137–40.

[30] De Bonis M, Cavaliere F, Alessandrini F, Lapenna E, Santarelli F, Moscato U, et al. Top-ical use of tranexamic acid in coronary artery bypass operations: a double-blind,prospective, randomized, placebo-controlled study. J Thorac Cardiovasc Surg 2000;119:575–80.

[31] Krohn CD, Sorensen R, Lange JE, Riise R, Bjornsen S, Brosstad F. Tranexamic acidgiven into the wound reduces postoperative blood loss by half in major orthopaedicsurgery. Eur J Surg 2002(Suppl. 588):57–61.

[32] Yasim A, Aşik R, Atahan E. Effects of topical applications of aprotinin and tranexamicacid on blood loss after open heart surgery. Anadolu Kardiyol Derg 2005;5:36–40.

[33] Abul-Azm A, Abdullah KM. Effect of topical tranexamic acid in open heart surgery.Eur J Anaesthesiol 2006;23:380–4. https://doi.org/10.1017/S0265021505001894.

[34] Jabalameli M, Zakeri K. Evaluation of Topical Tranexamic Acid on IntraoperativeBleeding in Endoscopic Sinus Surgery. IJMS Iran J Med Sci 2006;31.

[35] Athanasiadis T, Beule AG, Wormald PJ. Effects of topical antifibrinolytics in endo-scopic sinus surgery: A pilot randomized controlled trial. Am J Rhinol 2007;21:737–42. https://doi.org/10.2500/ajr.2007.21.3097.

[36] Baric D, Biocina B, Unic D, Sutlic Z, Rudez I, Vrca VB, et al. Topical use ofantifibrinolytic agents reduces postoperative bleeding: a double-blind, prospective,randomized study. Eur J Cardiothorac Surg 2007;31:366–71.

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

13J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

[37] Fawzy H, Elmistekawy E, Bonneau D, Latter D, Errett L. Can local application ofTranexamic acid reduce post-coronary bypass surgery blood loss? A randomizedcontrolled trial. J Cardiothorac Surg 2009;4:25. https://doi.org/10.1186/1749-8090-4-25.

[38] Wong J, Abrishami A, El Beheiry H, Mahomed NN, Roderick Davey J, Gandhi R, et al.Topical application of tranexamic acid reduces postoperative blood loss in total kneearthroplasty: a randomized, controlled trial. J Bone Joint Surg Am 2010;92:2503–13.

[39] Kaewpradub P, Apipan B, Rummasak D. Does tranexamic acid in an irrigating fluidreduce intraoperative blood loss in orthognathic surgery? A double-blind, random-ized clinical trial. J Oral Maxillofac Surg 2011;69:e186-. https://doi.org/10.1016/j.joms.2010.11.041.

[40] Ishida K, Tsumura N, Kitagawa A, Hamamura S, Fukuda K, Dogaki Y, et al. Intra-articular injection of tranexamic acid reduces not only blood loss but also kneejoint swelling after total knee arthroplasty. Int Orthop 2011;35:1639–45. https://doi.org/10.1007/s00264-010-1205-3.

[41] Kurt T. Evaluation of the effects of systemic or topical use of tranexamic acid andaprotinin on the blood loss and the used amount of blood products following cardio-pulmonary bypass surgery. Anatol J Clin Investig 2011;5:116–21.

[42] Sa-ngasoongsong P, Channoom T, Kawinwonggowit V, Woratanarat P, ChanplakornP, Wibulpolprasert B, et al. Postoperative blood loss reduction in computer-assistedsurgery total knee replacement by low dose intra-articular tranexamic acid injectiontogether with 2-hour clamp drain: a prospective triple-blinded randomized con-trolled trial. Orthop Rev (Pavia) 2011;3:12. https://doi.org/10.4081/or.2011.e12.

[43] Abdullah AJA. Does topical tranexamic acid reduce post-turp hematuria: A doubleblind randomized control trial. Urology 2012;80:S221–222.

[44] Canata GL, Casale V, Chiey A. Management of postoperative pain and bleeding inknee replacement. Orthop Traumatol 2012;13:S25–55.

[45] Dell’Amore A, Caroli G, Nizar A, Cassanelli N, Luciano G, Greco D, et al. Can topical ap-plication of tranexamic acid reduce blood loss in thoracic surgery? A prospectiverandomised double blind investigation. Heart Lung Circ 2012;21:706–10. https://doi.org/10.1016/j.hlc.2012.06.016.

[46] Roy SP, Tanki UF, Dutta A, Jain SK, Nagi ON. Efficacy of intra-articular tranexamic acidin blood loss reduction following primary unilateral total knee arthroplasty. KneeSurg Sports Traumatol Arthrosc 2012;20:2494–501. https://doi.org/10.1007/s00167-012-1942-5.

[47] Seo J-G, Moon Y-W, Park S-H, Kim S-M, Ko K-R. The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total kneearthroplasty. Knee Surg Sports Traumatol Arthrosc 2013;21:1869–74. https://doi.org/10.1007/s00167-012-2079-2.

[48] Alshryda S, Mason J, Sarda P, Nargol A, Cooke N, Ahmad H, et al. Topical (intra-artic-ular) tranexamic acid reduces blood loss and transfusion rates following total hip re-placement: a randomized controlled trial (TRANX-H). J Bone Joint Surg Am2013;95:1969–74. https://doi.org/10.2106/JBJS.L.00908.

[49] Alshryda S, Mason J, Vaghela M, Sarda P, Nargol A, Maheswaran S, et al. Topical(intra-articular) tranexamic acid reduces blood loss and transfusion rates followingtotal knee replacement: a randomized controlled trial (TRANX-K). J Bone Joint SurgAm 2013;95:1961–8. https://doi.org/10.2106/JBJS.L.00907.

[50] Georgiadis AG, Muh SJ, Silverton CD, Weir RM, Laker MW. A Prospective Double-Blind Placebo Controlled Trial of Topical Tranexamic Acid in Total Knee Arthroplasty.J Arthroplast 2013;28:78–82. https://doi.org/10.1016/j.arth.2013.03.038.

[51] Nouraei M, Baradari AG, Ghafari R, Habibi MR, Zeydi AE, Sharifi N. Decreasing bloodloss and the need for transfusion after CABG surgery: a double-blind randomizedclinical trial of topical tranexamic acid. Turk J Med Sci 2013;43:273–8. https://doi.org/10.3906/sag-1206-37.

[52] Sa-Ngasoongsong P, Wongsak S, Chanplakorn P, Woratanarat P, WechmongkolgornS, Wibulpolprasert B, et al. Efficacy of low-dose intra-articular tranexamic acid intotal knee replacement; a prospective triple-blinded randomized controlled trial.BMC Musculoskelet Disord 2013;14:340. https://doi.org/10.1186/1471-2474-14-340.

[53] Van Elst C, Vanbiervliet J, Simon JP, Corten K. The effect of topical application oftranexamic acid in total hip arthroplasty through the direct anterior approach. AmAcad Orthop Surg Annu Meet 2013.

[54] Emara WM, Moez KK, Elkhouly AH. Topical versus intravenous tranexamic acid as ablood conservation intervention for reduction of post-operative bleeding inhemiarthroplasty. Anesth Essays Res 2014;8:48–53. https://doi.org/10.4103/0259-1162.128908.

[55] Hosseini H, Rahimianfar AA, Abdollahi MH, Moshtaghiyoon MH, Haddadzadeh M,Fekri A, et al. Evaluations of topical application of tranexamic acid on post-operative blood loss in off-pump coronary artery bypass surgery. Saudi J Anaesth2014;8:224–8. https://doi.org/10.4103/1658-354X.130724.

[56] Martin JG, Cassatt KB, Kincaid-Cinnamon KA, Westendorf DS, Garton AS, Lemke JH.Topical Administration of Tranexamic Acid in Primary Total Hip and Total KneeArthroplasty. J Arthroplast 2014;29:889–94. https://doi.org/10.1016/j.arth.2013.10.005.

[57] SarzaeemMM, Razi M, Kazemian G,MoghaddamME, Rasi AM, Karimi M. Comparingefficacy of three methods of tranexamic acid administration in reducing hemoglobindrop following total knee arthroplasty. J Arthroplast 2014;29:1521–4. https://doi.org/10.1016/j.arth.2014.02.031.

[58] Wei W, Wei B. Comparison of Topical and Intravenous Tranexamic Acid on BloodLoss and Transfusion Rates in Total Hip Arthroplasty. J Arthroplast 2014;29:2113–6. https://doi.org/10.1016/j.arth.2014.07.019.

[59] Yue C, Kang P, Yang P, Xie J, Pei F. Topical Application of Tranexamic Acid in PrimaryTotal Hip Arthroplasty: A Randomized Double-Blind Controlled Trial. J Arthroplast2014;29:2452–6. https://doi.org/10.1016/j.arth.2014.03.032.

[60] Aguilera X, Martínez-Zapata MJ, Hinarejos P, JordánM, Leal J, González JC, et al. Top-ical and intravenous tranexamic acid reduce blood loss compared to routine

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

hemostasis in total knee arthroplasty: a multicenter, randomized, controlled trial.Arch Orthop Trauma Surg 2015;135:1017–25. https://doi.org/10.1007/s00402-015-2232-8.

[61] Ali Shah MU, Asghar MI, Siddiqi R, Chaudhri MS, Janjua AM, Iqbal A. Topical applica-tion of tranexamic acid reduces postoperative bleeding in open-heart surgery: mythor fact? J Coll Physicians Surg Pak 2015;25:161–5 [doi:03.2015/JCPSP.161165].

[62] Ausen K, Fossmark R, Spigset O, Pleym H. Randomized clinical trial of topicaltranexamic acid after reduction mammoplasty. Br J Surg 2015;102:1348–53.https://doi.org/10.1002/bjs.9878.

[63] Digas G, Koutsogiannis I, Meletiadis G, Antonopoulou E, Karamoulas V, Bikos C. Intra-articular injection of tranexamic acid reduce blood loss in cemented total kneearthroplasty. Eur J Orthop Surg Traumatol 2015;25:1181–8. https://doi.org/10.1007/s00590-015-1664-8.

[64] Eftekharian H, Vahedi R, Karagah T, Tabrizi R. Effect of tranexamic acid irrigation onperioperative blood loss during orthognathic surgery: a double-blind, randomizedcontrolled clinical trial. J Oral Maxillofac Surg 2015;73:129–33. https://doi.org/10.1016/j.joms.2014.07.033.

[65] Gillespie R, Shishani Y, Joseph S, Streit JJ, Gobezie R. Neer Award 2015: A random-ized, prospective evaluation on the effectiveness of tranexamic acid in reducingblood loss after total shoulder arthroplasty. J Shoulder Elb Surg 2015;24:1679–84.https://doi.org/10.1016/j.jse.2015.07.029.

[66] Lin S-Y, Chen C-H, Fu Y-C, Huang P-J, Chang J-K, Huang H-T. The Efficacy of Com-bined Use of Intraarticular and Intravenous Tranexamic Acid on Reducing BloodLoss and Transfusion Rate in Total Knee Arthroplasty. J Arthroplast 2015;30:776–80. https://doi.org/10.1016/j.arth.2014.12.001.

[67] Öztaş S, Öztürk A, Akalin Y, Şahin N, Özkan Y, Otuzbir A, et al. The effect of local andsystemic application of tranexamic acid on the amount of blood loss and allogeneicblood transfusion after total knee replacement. Acta Orthop Belg 2015;81:698–707.

[68] Vandesande W, Haenen F. Topical use of tranexamic acid in total hip arthroplasty. Aprospective randomized controlled trial. Hip Int 2015:S34.

[69] Wang G, Wang D, Wang B, Lin Y, Sun S. Efficacy and safety evaluation of intra-articular injection of tranexamic acid in total knee arthroplasty operation with tem-porarily drainage close. Int J Clin Exp Med 2015;8:14328–34.

[70] Wang C, Sun Z, Liu J, Cao J-G, Li Z. Safety and efficacy of intra-articular tranexamicacid injection without drainage on blood loss in total knee arthroplasty: A random-ized clinical trial. Int J Surg 2015;20:1–7. https://doi.org/10.1016/j.ijsu.2015.05.045.

[71] Yang Y, Lv Y-M, Ding P-J, Li J, Ying-Ze Z. The reduction in blood loss with intra-articular injection of tranexamic acid in unilateral total knee arthroplasty withoutoperative drains: a randomized controlled trial. Eur J Orthop Surg Traumatol 2015;25:135–9. https://doi.org/10.1007/s00590-014-1461-9.

[72] Drosos GI, Ververidis A, Valkanis C, Tripsianis G, Stavroulakis E, Vogiatzaki T, et al. Arandomized comparative study of topical versus intravenous tranexamic acid ad-ministration in enhanced recovery after surgery (ERAS) total knee replacement. JOrthop 2016;13:127–31. https://doi.org/10.1016/j.jor.2016.03.007.

[73] Keyhani S, Esmailiejah AA, Abbasian MR, Safdari F. Which Route of Tranexamic AcidAdministration is More Effective to Reduce Blood Loss Following Total KneeArthroplasty? Arch Bone Jt Surg 2016;4:65–9.

[74] Tzatzairis TK, Drosos GI, Kotsios SE, Ververidis AN, Vogiatzaki TD, Kazakos KI. Intra-venous vs Topical Tranexamic Acid in Total Knee Arthroplasty Without TourniquetApplication: A Randomized Controlled Study. J Arthroplast 2016;31:2465–70.https://doi.org/10.1016/j.arth.2016.04.036.

[75] Zhang Y, Zhang L, Ma X, Jia Y, Wang H, Zhu Y, et al. What is the optimal approach fortranexamic acid application in patients with unilateral total hip arthroplasty?Orthopade 2016;45:616–21. https://doi.org/10.1007/s00132-016-3252-y.

[76] Saberi H, Miri SM, Poordel Namdar M. The effects of topically applied tranexamicacid on reduction of postlaminectomy hemorrhage. Tehran Univ Med J 2010;68:527–33.

[77] Xu X, Li X, Liu W, Wang Z. Longtime soaking of high concentration tranexamic acidin total hip arthroplasty: A prospective randomized controlled trial in 224 patients.Pakistan J Med Sci 2015;31:1306–11.

[78] Aggarwal AK, Singh N, Sudesh P. Topical vs Intravenous Tranexamic Acid in Reduc-ing Blood Loss After Bilateral Total Knee Arthroplasty: A Prospective Study. JArthroplast 2016;31:1442–8. https://doi.org/10.1016/j.arth.2015.12.033.

[79] Taheriazam A, Safdari F. Using Tranexamic Acid to decrease postoperative hemor-rhage: Local versus Intravenous administration. Int Comb Meet Br Hip Soc 2015.

[80] Baric D, Unic D, Rudez V, Bacic-Vrca M, Planinc D, Jonjic D. Systemic usage oftranexamic acid is superior to topical: Randomized placebo-controlled trial. InteractCardiovasc Thorac Surg 2011:S92.

[81] Gomez-Barrena E, Ortega-Andreu M, Padilla-Eguiluz NG, Pérez-Chrzanowska H,Figueredo-Zalve R. Topical Intra-Articular Compared with Intravenous TranexamicAcid to Reduce Blood Loss in Primary Total Knee Replacement. J Bone Joint SurgAm 2014;96:1937–44. https://doi.org/10.2106/JBJS.N.00060.

[82] May JH, Rieser GR, Williams CG, Merkert RJ, Bauman RD, Lawless MW. The Assess-ment of Blood Loss During Total Knee Arthroplasty When Comparing Intravenousvs Intracapsular Administration of Tranexamic Acid. J Arthroplast 2016;31:2452–7.

[83] Xie J, Ma J, Yue C, Kang P, Pei F. Combined use of intravenous and topical tranexamicacid following cementless total hip arthroplasty: a randomised clinical trial. Hip Int2016;26:36–42. https://doi.org/10.5301/hipint.5000291.

[84] Chen JY, Chin PL, Moo IH, Pang HN, Tay DKJ, Chia S-L, et al. Intravenous versus intra-articular tranexamic acid in total knee arthroplasty: A double-blinded randomisedcontrolled noninferiority trial. Knee 2016;23:152–6. https://doi.org/10.1016/j.knee.2015.09.004.

[85] Maniar RN, Kumar G, Singhi T, Nayak RM, Maniar PR. Most effective regimen oftranexamic acid in knee arthroplasty: a prospective randomized controlled studyin 240 patients. Clin Orthop Relat Res 2012;470:2605–12. https://doi.org/10.1007/s11999-012-2310-y.

ranexamic acid: A systematic review andmeta-analysis, TransfusMed

14 J. Montroy et al. / Transfusion Medicine Reviews xxx (2018) xxx–xxx

[86] Goyal N, Chen DB, Harris IA, Rowden NJ, Kirsh G, MacDessi SJ. Intravenous vs Intra-Articular Tranexamic Acid in Total Knee Arthroplasty: A Randomized, Double-BlindTrial. J Arthroplast 2017;32:28–32. https://doi.org/10.1016/j.arth.2016.07.004.

[87] Patel JN, Spanyer JM, Smith LS, Huang J, YakkantiMR,Malkani AL. Comparison of Intrave-nous versus Topical Tranexamic Acid in Total Knee Arthroplasty: A Prospective Random-ized Study. J Arthroplast 2014;29:1528–31. https://doi.org/10.1016/j.arth.2014.03.011.

[88] Pinsornsak P, Rojanavijitkul S, Chumchuen S. Peri-articular tranexamic acid injectionin total knee arthroplasty: a randomized controlled trial. BMC Musculoskelet Disord2016;17:313. https://doi.org/10.1186/s12891-016-1176-7.

[89] Soni A, Saini R, Gulati A, Paul R, Bhatty S, Rajoli SR. Comparison Between Intravenous andIntra-articular Regimens of Tranexamic Acid in Reducing Blood Loss During Total KneeArthroplasty. J Arthroplast 2014;29:1525–7. https://doi.org/10.1016/j.arth.2014.03.039.

Please cite this article as:Montroy J, et al, The efficacy and safety of topical tRev (2018), https://doi.org/10.1016/j.tmrv.2018.02.003

[90] North WT, Mehran N, Davis JJ, Silverton CD, Weir RM, Laker MW. Topical vs Intrave-nous Tranexamic Acid in Primary Total Hip Arthroplasty: A Double-Blind, Random-ized Controlled Trial. J Arthroplast 2016;31:1022–6. https://doi.org/10.1016/j.arth.2015.11.003.

[91] Girgin F, Maltepe F. Comparison of Local or Systemic Administration of TranexamicAcid on Blood Loss in Cardiac Surgery. Interact Cardiovasc Thorac Surg 2010.

[92] Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistentdosing of tranexamic acid prudent? Meta-analysis of randomised and large matchedobservational studies. Eur J Cardiothorac Surg 2010;37:1375–83. https://doi.org/10.1016/j.ejcts.2009.11.055.

[93] Fox MA. Tranexamic Acid: how much is enough? Anesth Analg 2010;111:580–1.https://doi.org/10.1213/ANE.0b013e3181e2914d.

ranexamic acid: A systematic review andmeta-analysis, TransfusMed