9/24/2014

1

Clinical Pearl

Tranexamic Acid in

Orthopedic SurgeriesScott Milner PharmD, MBA

Objectives

• After this discussion the learner should be able to:

• Explain risks for bleeding in orthopedic procedures

• Identify benefits from reducing blood transfusions

• Provide dosing and preparation information for tranexamic acid

• Understand the differences between aminocaproic acid and

tranexamic acid

9/24/2014

2

Total Knee Arthroscopy (TKA) 1,2

• Close to 700,000 knee replacement procedures are done each

year in the U.S.

• Complications include:

• Blood clot: deep veins of the legs

• Infection: invasive surgery

• Stiffness: may not obtain full range of motion

• Early failure: up to 90% may last between 15-20 years

• Blood loss/transfusion: due to bone/tissue blood loss

Total Knee Arthroscopy (TKA) 3

9/24/2014

3

Total Hip Arthroscopy (THA)4

• Sir John Charnley designed first hip prosthesis in late 1960’s

• Considered to be the most successful orthopedic procedures

performed today

• Approximately 300,000 THA performed each year in the U.S.

http://www.youtube.com/watch?v=c0hgO8F1BCs

http://www.hss.edu/conditions_revision-total-hip-replacement-overview.asp

Total Hip Arthroscopy (THA)5

• Intraoperative complications:

• Fracture

• Nerve injury

• Vascular injury

• Cement related hypotension

• Postoperative complications

• Infection

• Dislocation

• Osteolysis and wear

• Aseptic loosening

• Periprosthetic fracture

• Implant failure

• Leg length discrepancy

• Thromboembolic disease

• Other (MI, UTI, etc..)

9/24/2014

4

Reduced Blood Transfusion Goals 6,7,8

• Prior to the late 1980’s “10/30 rule” to maintain:

• Hemoglobin (Hgb) above 10 g/dL

• Hematocrit above 30%

• 1988 National Institutes of Health Consensus Conference on

Perioperative Red Blood Cell Transfusions

• No set criteria, base transfusions on multiple factors

• Studies have provided evidence that transfusions increase

patient complications

• Iron overload, volume overload, allergic/immune reactions,

infections (HIV/AIDS, hepatitis, bacterial)

Reduced Blood Transfusion Goals

9/24/2014

5

Tranexamic Acid (TXA)9

• Brand Names: Cykloapron; Lysteda

• Drug Class: AntifibrinolyticAgent, antihemophilicagent, hemostatic agent, lysine analog

• Use (approved indication): • Prevent bleeding with tooth

extraction for patients with hemophilia (1986 approved)

• Treat heavy bleeding during menstruation (oral-approved 2009)

Tranexamic Acid (TXA) 10

• Use (unlabeled indication):

• Hereditary angioedema (HAE)

• Elective Caesarian section, blood loss reduction

• Hip fracture surgery, blood conservation

• Orthognathic surgery blood loss reduction

• Prevention of perioperative bleeding with cardiac surgery

• Prevention of perioperative bleeding associated with spinal

surgery

• Total hip arthroscopy, blood loss reduction

• Total knee arthroscopy, blood loss reduction

• Transurethral prostatectomy, blood loss reduction

• Trauma-associated hemorrhage

• Traumatic hyphema

9/24/2014

6

Tranexamic Acid (TXA)

https://www.jaaos.org/content/18/3/132/F1.expansion

Tranexamic Acid (TXA)

http://rebelem.com/topical-tranexamic-acid-epistaxis-oral-bleeds/

9/24/2014

7

Coagulation Cascade

TXA

http://www.frca.co.uk/article.aspx?articleid=100096

New Oral Anticoagulants

http://www.frca.co.uk/article.aspx?articleid=100096

9/24/2014

8

Who Uses TXA?

http://stockfresh.com/image/1669997/many-people-shouting-me-to-stand-out-in-a-crowd

https://www.google.com/search?q=people+in+the+ crowd&espv=2 &biw=115 3&bi h=747 &source =lnms&tbm=isch&sa= X&e i=hnkgVMDuG pDioAS4loCgCg&ved= 0CAY Q_AUoAQ#fa cr c=_ &i mgdii= _&i mgr c= O3rFpHE lt4I5eM%253A%3 BrSFQPuWPGB8Bj M%3Bhttp%253A%252F%252Fwww.mindsways.com%25 2Fabout%252Flearnmindmagi c%252Flear nmi ndmagi ci mages%252Fstand-out-of-crowd.jpg%3 Bhttp%253A%252F%252Fgalleryhip.com%25 2Fstand-out -fr om-the-crowd-people.html%3B16 13%3B1190

TXA Studies 12-32

Author/Year Cases (TA/C) Usage DVT

Prophylaxis

Control

Hiippala 1995 28 (15/13) Weight based LMWH Saline

Benoni 1996 86 (43/43) Weight based LMWH Saline

Hiippala 1997 77 (39/38) Weight based LMWH Saline

Jansen 1999 42 (21/21) Weight based LMWH Saline

Ido 2000 43 (21/22) 1000 mg (2) N/A None

Elis 2001 20 (10/10) Weight based LMWH Saline

Engel 2001 24 (12/12) Weight Based LMWH None

Tanaka 2001 99 (73/26) Weight based N/A Saline

Veien 2002 30 (15/15) Weight based LMWH None

Good 2003 51 (27/24) Weight based LMWH Saline

Zohar 2004 40 (20/20) Weight based LMWH None

9/24/2014

9

TXA Studies 12-32

Author/Year Cases (TA/C) Usage DVT

Prophylaxis

Control

Camaras 2006 95 (35/60) Weight based LMWH Saline

Orpen 2006 29 (15/14) Weight based LMWH Saline

Molloy 2007 95 (46/49) 500 mg (2) LMWH None

Zhang 2007 102 (51/51) 1000 mg (2) LMWH Saline

Alvarez 2008 95 (46/49) Weight based LMWH Saline

Kakar 2009 24 (12/12) Weight based LMWH Saline

Charoencholva

nich 2011

100 (50/50) Weight based Ankle pump Saline

Gautum 2011 40 (20/20) Weight based N/A Saline

McConnell

2012

44 (22/22) Weight based Asa None

Lee 2012 72(36/36) Weight based LMWH None

Study #1 12

• “The effect of tranexamic acid on blood loss and transfusion

rate in primary total knee arthroplasty”

• Retrospective January 2009-May 2012

• 2269 TKA in 2069 patients

• 1838 no TXA (control)

• 330 TXA via IV infusion

• 130 TXA topically

9/24/2014

10

Study #1 Cont... 12

• TXA infusion (330)

• 1000 mg prior to

incision

• 1000 mg upon closure

• Control group (1838)

• No TXA given to the

patients

• TXA Topically

• Previous embolism

• MI within 6 months

• Stent placed previous

year

• Applied directly into

joint at closure

Analysis12

• Chi square to analyze

variable

• t-tests for statistical

differences between

TXA groups

• Significance P<0.05

9/24/2014

11

Results12

TXA Infusion TXA Topical Control

Transfusion Rate 0.3%, 1/330

(p=0.001)

0%, 0/130

(p=0.15)

6.5%, 120/1839

PE 0.03%, 1/330 0.077%, 1/130 0.33%, 6/1839

DVT 1.82%, 6/330 1.54%, 2/130 1.69%, 31/1839

http://en.wikipedia.org/wiki/Surgical_tourniquet

Results12

Post-Op Hct Days of discharge Hct

IV TXA vs all others 36.32 (+/- 3.89 g/dL)

P=0.003

31.21 (+/- 4.05 g/dL)

P=0.001

Topical TXA vs all others 35.57 (+/- 4.2 g/dL)

p=0.81

29.57 (+/- 3.37 g.dL)

p=0.60

9/24/2014

12

Conclusions

• Strengths

• Higher number of

patients than most

studies

• Review of adverse

events

• Retro review may not

have clouded

coumadin dosing for

DVT prophylaxis

• Weaknesses

• Retro-review

• Not randomized

• New oral

anticoagulants may

affect DVT/PE rates?

Aminocaproic Acid 11

• Brand Names: Amicar

• Drug Class: Antifibrinolytic Agent, antihemophilic agent, hemostatic agent, lysine analog

• Use (approved indication): • Acute bleeding

• Control of bleeding with severe thrombocytopenia

• Use (unaproved)• Control of oral bleeding in congenital and acquired coagulation disorder

• Prevention of dental procedure bleeding in patients on oral anticoagulant therapy

• Prevention of perioperative bleeding associated with cardiac surgery

• Traumatic hyphema

• Pediatric Uses:• Prevent bleeding with cardiac surgery

• Prevent bleeding with extracorporeal membrane oxygenation (ECMO)

• Prevent bleeding with spinal surgery

• Traumatic hyphema

9/24/2014

13

Aminocaproic Acid MOA

• Competitively binds

to plasminogen,

blocking the binding

of plasminogen to

fibrin effectively

blocking fibrin

degradation

Kringle Site?

http://whatscookingamerica.net/Bread/Kringle.htmhttp://guardianlv.com/2013/12/kris-kringle-to-receive-eviction-notice-in-near-future/

9/24/2014

14

Tranexamic Acid Summary

• Strengths

• Robust journal history

• Use trends towards

non-weight based

dosing

• Anecdotal evidence

abounds

• Lower blood

transfusions in

patients interest

• Weaknesses

• Exclusion criteria

could be more clear

• DVT rates approach

control rates

• Topical vs intravenous

• Anecdotal evidence

abounds

Question 1

• If a doctor asked you for a recommended dose of tranexamic

acid for a TKA surgery what would you recommend for a

patient?

A: 30 mg/kg before surgery, and repeat day of discharge

B: 1000 mg infusion prior to incision, 1000mg infusion prior to

tourniquet release

C:go to Canada, drugs cost less money

9/24/2014

15

Question 2

• Tranexamic acid is without adverse events and should be used

on all patients

• True/False

Question 3

• What is an effective method to decrease patients need for a

transfusion in orthopedic procedures when blood loss is likely

to occur?

A: Saline

B:Tranexamic Acid

C:Gauze

D: Aspirin prior to surgery

9/24/2014

16

References

1. Kurts S, Ong K, et al, “Projections of Primary and revision hip and knee arthroplasty in the United States from 2005-2030”. Bone Joint Surg Am. 2007 Apr;89(4):780-5.

2. Mahomed NN, Barrett J, Katz JN, et al,“Epidemiology of total knee replacement in the United States Medicare population“. J Bone Joint Surg AM 2005 Jun; 87(6): 1222-8

3. Kepley, R. “ Total Knee Replacement“ youtube.com Published June 26, 2013

4. HCPUnet, Healthcare Cost and Utilization Project. Agency for Healthcare research and Quality. http://hcupnet.ahrq.gov (Accessed on December 20, 2012)

5. Beswick AD, Wylde V, et al, “What is the proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2012;12(1):e000435.

6. Wang JK, Klein HG, “Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger” Vox Sang 2010;98(1):2

7. Consensus conference. Perioperative red blood cell transfusion. JAMA 1988;260(18):2700.

8. Carson JL, Grossman BJ, et al. “Red blood cell transfusion: a clinical practice guideline from the AABB”. Ann Intern Med 2012;157(1):49

9. DailyMed “CYKLOKAPRON-tranexamic acid injection, solution” Pharmacia and Upjon Co Updated 2/14, accessed 8/2014

10. UpToDate “Tranexamic Acid”, accessed 8/2014

11. DailyMed “AMICAR-aminocaproic acid solution” Clover Pharmaceuticals package insert Updated 12/12, accessed 8/2014

12. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on blood loss and transfusion rate in primary total knee arthroplasty. J Arthroplasty. 2013;28(7):1080-3.Study 3

13. Hiippala S Strid L et al, Tranexamic acid (cycllapron) reduces perioperative blood loss associated with total knee arthroplasty. Br J Anaesth 1995; 74 (5):534-7

14. Janse AJ, Andreica S et al, Use of tranexamic acid radically deacreases blood loss and transfusions associated with total knee arthroplasty. Anesth Analg 1997; 84(4):839-44

References

14. Jansen AJ, Andreica S, Claeys M, et al. Use of tranexamic acid for an effective blood conservation strategy after total knee arthroplasty. Br J Anaesth 1999;83(4):596-601.

15. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. ArchOrthop Trauma Surg 2000;120(9):518-20.

16. Ellis MH, Fredman B, Zohar E, et al The effect of tourniquet application, tranexamic acid, and desmopressin on the procoagulant and fibrinolytic systems during total kneereplacement. J Clin Anesth 2001;13(7):509-13.

17. Engel JM, Hohaus T, Ruwoldt R, et al. Regional hemostatic status and blood requirements after total knee arthroplasty with and without tranexamic acid or aprotinin.Anesth Analg2001;92(3):775-80.

18. Tanaka N, Sakahashi H, Sato E, et al. Timing of the administration of tranexamic acid for maximum reduction in blood loss in arthroplasty of the knee. J Bone Joint Surg Br 2001;83(5):702-5.

19. Veien M, Sorensen JV, Madsen F, et al. Tranexamic acid given intraoperatively reduces blood loss after total knee replacement: a randomized, controlled study. Acta Anaesthesiol Scand2002;46(10):1206-11.

20. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth 2003;90(5):596-9.

21. Zohar E, Ellis M, Ifrach N, et al. The postoperative bloodsparing efficacy of oral versus intravenous tranexamic acid after total knee replacement. Anesth Analg 2004;99(6):1679-83.

22. Camarasa MA, Olle G, Serra-Prat M, et al. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth2006:96(5):576-82.

23. Orpen NM, Little C, Walker G, et al. Tranexamic acid reduces early post-operative blood loss after total knee arthroplasty: a prospective randomised controlled trial of 29 patients. Knee 2006;13(2):106-10.

9/24/2014

17

References Cont…

24. Molloy DO, Archbold HA, Ogonda L, et al. Comparison of topical fibrin spray and tranexamic acid on blood loss after total knee replacement: a prospective, randomisedcontrolled trial. J Bone Joint Surg Br 2007;89(3):306-9

25. Zhang F, Gao Z, Yu J. Clinical comparative studies effect of tranexamic acid on blood loss associated with total knee on arthroplasty. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi2007;21(12):1302-4.

26. Alvarez JC, Santiveri FX, Ramos I, et al. Tranexamic acid reduces blood transfusion in total knee arthroplasty even when a blood conservation program is applied. Transfusion 2008;48(3):519-25.

27. Kakar PN, Gupta N, Govil P, et al. Efficacy and safety of tranexamic acid in control of bleeding following TKR: a randomized clinical trial. Indian J Anaesth 2009;53(6):667-71.

28. Charoencholvanich K, Siriwattanasakul P. Tranexamic acid reduces blood loss and blood transfusion after TKA: a prospective randomized controlled trial. Clin Orthop Relat Res 2011;469(10):2874-80.

29. Gautam PL, Katyal S, Yamin M, et al. Effect of tranexamic acid on blood loss and transfusion requirement in total knee replacement in the Indian population: a case series. Indian J Anaesth2011;55(6):590-93.

30. McConnell JS, Shewale S, Munro NA, et al. Reducing blood loss in primary knee arthroplasty: a prospective randomised controlled trial of tranexamic acid and fibrin spray. Knee 2012;19 (4):295-8.

31. Chareancholvanich K, Siriwattanasakul P, NarkbunnamR, et al. Temporary clamping of drain combined with tranexamic acid reduce blood loss after total knee arthroplasty: a prospective randomized controlled trial. BMC Musculoskelet Disord 2012;13:124.

32. De-jie FU, Cheng C, et al. Use of intravenous tranexamic acid in total knee arthroplasty: a meta-analysis of randomized controlled trials. Chinese Journal of Traumatology 2013; 16(2): 67-76