A systematic review of the effect of Tranexamic acid in knee and hip arthroplasty Christine Schutz Research Coordinator Wakefield Orthopaedic Clinic.

Overview

Background to how TX works

The studies of TX acid in Orthopaedics

Results of retrospective study at WOC

Blood management in elective THR and TKR surgery.

Conclusions re dose of tranexamic acid.

Where to from here?

Disclosures No conflict of interest

Thank you to ANZONA

Thank you to Surgeons at WOC

National Joint Registry Australia. Annual report 2012.

Hip Arthroplasty Increasing 4% per year in Australia 37,849 in 2012.

Knee Arthroplasty 2012 48,385

Indications for Joint replacement Pain : severity at rest, distance walking commonly due to

Osteoarthritis.

Function : Need for a cane, Climbing stairs, Daily living

Examination: ROM, Joint stability, other.

Radiographic. Joint space limited.

Tranexamic Acid Inhibits fibrinolysis by

blocking lysine-binding site of plasminogen to fibrin

Reduces blood loss and need for Blood transfusions

TX ACID Mechanism of Action. Tranexamic acid also know as CYKLOKAPRON in Aust. Given as IV , intra articular, oral, spray., Topical

Found to reduce blood loss in trauma and elective surgery reducing transfusion rates by a third.

Is a synthetic lysine derivative that stops the breakdown of fibrin by inhibiting activation of plasminogen.

Has a 2 hour half life. Excreted mainly via kidneys.

.

Contraindications for TX use Previous History of DVT Sensitivity to Tranexamic acid Visual problems colour disturbances Poor renal function. ____________________________________ COMMON SIDE EFFECTS: Nausea Vomiting and Diarrhoea Dizziness Hypotension Rash (allergic reaction) Over dosage rare.

CRASH 2 trial (Trauma) Largest trial published

Cause of death TXA Placebo Risk of death P value 10,060 10,067 Bleeding 489 574 0.85 (0.76–0.96) 0.0077 Thrombosis 33 48 0.69 (0.44–1.07) 0.096 Organ failure 209 233 0.90 (0.75–1.08) 0.25 Head injury 603 621 0.97 (0.87–1.08) 0.60 Other 129 137 0.94 (0.74–1.20) 0.63 Any death 1463 1613 0.91 (0.85–0·97) 0·0035

RESULTS CRASH 2

Risk ratio (95% CI)

TXA worse TXA better

TXA

allocated

(10,060)

Placebo

allocated

(10,067)

Any 168 (1.63%) 201 (1.95%)

.6 .7 .8 .9 1 1.1 1.2

Stroke 57 (0.56%) 66 (0.65%)

DVT 40 (0.40%) 41 (0.41%)

PE 72 (0.69%) 71 (0.70%)

MI 35 (0.35%) 55 (0.52%)

There was no increase in thrombosis

Tranexamic acid dose Same for hips and knees.

15mg/kg initial dose IV

Follow 6 – 8 hrs post surgery

CYKLOKAPRON Solution for Injection IV

500mg ampoules in 5ml Water

1000mg ampoules in 10ml Water

Tablets available in 500mg (bottle of 100 tabs)

Use in Total Knee Arthroplasty meta analysis 16 randomised placebo controlled studies

11 = efficacy (reduced blood loss)

Mean age = 65-77 years

N= 365 tranx patients

N= 390 controls

Cemented and non cemented prosthesis used.

Post LMWH

Overall dose 10- 30mg/kg efficacy shown

Knee arthroplasty

Topical v Intra articular for TKA

• Antapur et al Bone and joint (2012)

• Study Number= 99 pts

• Randomized to 3 sub groups

• Doses 1.5, placebo and 3gm.

• Results:

• No difference in rate of transfusion between the 1.5g group and placebo

• The TX group of 3 g = 0 transfusion.

• 2 out of 99 pts had PE in the 1.5 g group.

Meta analysis of TKA trials Cochrane Bone, joint and Trauma J Bone Joint Surg Br 2011 Dec 93 (12 )

1577 - 85

Reduction in allogenic blood transfusion 16% (95% CI : )9-0.26

Total blood loss 460 mls

19 Randomized controlled trials.

Concluded that TX was effective and safe for use in TKA and reduced blood loss.

Tx does not increase prevalence of DVT or PE.

Timing of Administration of TXA 10 - 15 minutes before tourniquet released, repeat q 6 - 8

hrs for first day

Nielsen, Ugeskr Laeger 2002

One injection pre-op, one on release of tourniquet

Tanaka, JBJS (Br) 2001

Just prior to tourniquet release and 3 hrs later

Good, BJA 2003

Oral TX study Repat (50TKA) 25 acid/25 placebo in progress

Dose studies Andreau study (71 TKA )

Looked at 2 dose schedules. IV

Dose 1. Given IV in theatre 15mg/kg.

Dose 2 Given 3 hours post surgery 15mg/kg.

Group 1

Showed no Transfusion required in TX group.

Group 2 (control)

37 % requiring Transfusion in non TX group.(autologous blood)

Tourniquet times 86-92 mins

• Arthroplasty Hip and Knee with DVT prophylaxis.

• Review presented by Blake et al July 2012

• Low risk of Thromboembolic Complications

• N = 2246 primary THA and TKA

• Dose TX = 1 g IV beginning and at closure.

• Results: rate of DVT similar across groups

• p = 0.61

• Aspirin alone

• Warfarin

• LMWH

Dose studies some concerns Lack of information

regarding DVT prophylaxis and use of TX acid.

Variable dose regimes

Multiple confounding variables

1st Dose of commencement of injectable LMWH post operatively unclear.

• Imai et al J of Arthroplasty V 27 2012

• BLOOD LOSS FOCUS.

• HIP________________________________

• N= 107 patients.

• Randomized to 5 groups (Dose and Timing)

• Found most effective dose for reduction of blood loss for hip arthroplasty

• 1g TXA given prior to surgery and 6 hrs post.

• Limited data on risks of DVT

TX in hip arthroplasty Limited dose selected studies

6 studies included in meta analysis

No studies that used the dose of 60mg/kg.

Same dosing is used as for knees.

Should be given as slow intravenous infusion

Loading dose 50mg/min

1g in 100ml can give at 5ml/min

TXA and DVT General consensus.

No increased DVTs with TXA

Nielsen, Ugeskr Laeger 2002

Tanaka, JBJS (Br) 2001

Good, BJA 2003

Yang J Bone and Joint 2012

TGA report: For every 100 pts knee arthroplasty 6 patients at risk of DVT in TX group.

Meta analysis re blood loss Hiipala et al

No increase in Thromboembolic events.

Transfusion risk reduced by 64%

Dutch 10 yr Study (Slappendal)

80% less transfusion

40% less infection

Decreased morbidity

Reduced hospital duration

Trend Of DVT In TX reports. Recent FDA reports. May 2013 1505 people reported side effects of TX acid.

(Gastro type effects)

31 ie (2.06% ) with DVT

Most DVT occurred in < 1 month (88.24%)

1- 6 months DVT occurred in 11.76 %

Retrospective study at WOC Review of 354 records

Hip (151)

61 m

90 f

Knee (203)

86m

117 f

RESULTS OF REVIEW WOC

88 24

27

12

HIPs

TX

Blood and TX

Transfusion

No TX no Tf

RESULTS OF REVIEW WOC Knees

105

5

39

54

Knees 203

TX

Blood andTX

Transfusion

No TX noTF

Adverse events for hip and knees

Hypotension (29 H) (17 K)

Pulmonary embolism (3 H)

Rash (6)

Confusion (5)

Clinical Perspective Blood management protocol

• Preoperative:

• Get sound history of bleeding v clotting

• Cease supplements eg fish oils etc.

• Cease NSAIDs antiplatelet meds and aspirin 7- 10 days before surgery.

• Discontinue warfarin 5 days prior check INR

• Check for preoperative anaemia.

• Consider iron therapy if <100 ug/l

Clinical Perspective Blood management protocol

• Perioperative management

• Revising the transfusion trigger to 8Hbg or below has been shown to be safe.

• Maintain normothermia

• Surgeon preference re tourniquet and drain.

• TX given by anaesthetist 15mg/kg before tourniquet release and 2nd dose surgeon pref.

Clinical Perspective Blood management protocol.

• Post operative

• Maintain normothermia

• Limb elevation

• Withhold thromboprophylaxis until surgical haemostasis (ie 6-8 hrs)

• Check Hg status transfusion trigger post 8 hr surgery.(<8Hgb)

Conclusions TX Acid reduces mortality in bleeding trauma

patients. Reduces bleeding generally by 25- 30% and leads to decreased transfusion rates.

TX acid Preoperatively in Total Knee Replacement does not increase incidence of DVT and PE Best dose : how, timing, and dose ????

Preoperative anaemia , intraoperative blood loss and post operative care can be influenced by blood management protocols.

Audit regularly TX administration. Dose studies needed

References Blake et al Clinical orthopaedic Research July 2012

Alvarez J et al Transfusion 2008 48: 519 -525

Benoni C Acta othopaedics Scand 2001 72: 442-448

Naudi Douglas Ralley Clinical Orthopaedics and related research July 2010 V 468 pg 1905

Product Information Cyklokapron p 1- 27.

Imai et al Arthroplasty 2012

Thankyou