UvA-DARE (Digital Academic Repository) Thromboprophylaxis ... · Summary 125 Samenvatting 129 ... Curriculum Vitae 137 PhD Portfolio 139. 1 General introduction and outline of the

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Thromboprophylaxis in orthopaedic surgery

Struijk-Mulder, M.C.

Link to publication

Citation for published version (APA):Struijk-Mulder, M. C. (2014). Thromboprophylaxis in orthopaedic surgery.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 14 Dec 2020

https://dare.uva.nl/personal/pure/en/publications/thromboprophylaxis-in-orthopaedic-surgery(87ddb5e6-eb33-4cc9-92ba-0d25b9fdf3c4).html

Marieke C. Struijk-Mulder

Thro

mboprophylaxis in

Orthopaedic Surgery

Thromboprophylaxis in O

rthopaedic Surgery

M

arieke C. Struijk-M

ulder

ISBN 978-94-6169-490-4

Thromboprophylaxis in Orthopaedic Surgery


MC Struijk-MulderThromboprophylaxis in Orthopaedic Surgery

Thesis, University of Amsterdam

ISBN: 978-94-6169-490-4

Coverdesign: MC Struijk-Mulder & Optima Grafische CommunicatieLayout: Optima Grafische CommunicatiePrinted by: Optima Grafische Communicatie

http://www.e-pubs.nl?epub=m.struijk

© Copyright 2014 MC Struijk-Mulder. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, in-cluding photography, recording or any information storage or retrieval system, without prior written permission of the copyright owner.

Financial support for the preparation of this thesis was received from:ABN AMRO N.V., Anna Fonds|NOREF, Arthrex Nederland BV, Bauerfeind Benelux B.V., Bayer B.V., Boehringer Ingelheim BV, GlaxoSmithKline, Medi Nederland BV, MRI Centrum, Nederlandse Orthopaedische Vereniging, Össur Europe, Universiteit van Amsterdam, Van der Burgh Medical Supplies B.V., Varitex NV, Wellspect HealthCare.

Thromboprophylaxis in

Orthopaedic Surgery

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het college voor promoties ingestelde

commissie, in het openbaar te verdedigen in de Agnietenkapel

op donderdag 10 april 2014, te 14:00 uur

door

Marieke Catherine Mulder

geboren te Utrecht

Promotor: Prof. dr. H.R. Büller

Co-promotoren: Dr. C.C.P.M. Verheyen Dr. H.B. Ettema

Overige leden: Prof. dr. D.P.M. Brandjes Prof. dr. S.K. Bulstra Prof. dr. R.M. Castelein Prof. dr. C.N. van Dijk Prof. dr. S. Middeldorp

Faculteit der Geneeskunde

Aan mijn moederdie twee promoties mogelijk heeft gemaakt

COnTEnTS

General introduction

Chapter 1. General Introduction and outline of the thesis 9

Thromboprophylaxis en Blood management in the netherlands

Chapter 2. Dutch orthopedic thromboprophylaxis: a 5-year follow-up survey 17

Chapter 3. Ten-year follow-up on orthopedic thromboprophylaxis in the Netherlands. DATA III survey

27

Chapter 4. Ten-year follow-up on Dutch orthopaedic blood management. DATA III survey

39

International guidelines regarding thromboprophylaxis

Chapter 5. Comparing consensus guidelines on thromboprophylaxis in orthopaedic surgery

51

Arthroscopic cruciate ligament reconstruction

Chapter 6. Deep vein thrombosis following arthroscopic cruciate ligament reconstruction: a prospective cohort study of 100 patients

65

Lower extremity amputation

Chapter 7. Death and venous thromboembolism after lower extremity amputation

79

Plaster cast immobilisation

Chapter 8. Venous thromboembolism during hip plaster cast immobilisation: Review of literature

91

Shoulder arthroplasty

Chapter 9. Incidence of deep venous thrombosis after shoulder arthroplasty. Systematic review of literature

99

Chapter 10. Incidence of deep venous thrombosis after arthroplasty of the shoulder. Study protocol and preliminary results of INDRA-P study

111

AppendicesSummary 125

Samenvatting 129

Publications 133

Dankwoord 135

Curriculum Vitae 137

PhD Portfolio 139

1

General introduction and outline of the thesis

General introduction and outline of the thesis 11

1GEnERAL InTRODuCTIOn AnD OuTLInE OF THE THESIS

Thromboprophylaxis after major orthopaedic surgery is common practice nowadays, as the risk of venous thromboembolism after total hip and knee arthroplasty is well rec-ognized.1 This thesis describes the use of thromboprophylaxis modalities by the Dutch orthopaedic departments over a period of ten years. Several uncertainties in orthopae-dic thromboprophylaxis still remain regarding smaller procedures, immobilization and upper extremity surgery.In this thesis a few of these topics are addressed: the incidence of venous thromboem-bolism after arthroscopic cruciate ligament reconstruction, lower extremity amputation, plaster cast immobilization and shoulder arthroplasty.

History of thromboprophylaxis

The relationship between surgery and venous thromboembolism (VTE) has been de-scribed as early as 1937.2 Heparin was initially used to prevent post-operative thrombo-sis in surgical patients. In the beginning of the nineteen-eighties low molecular weight heparin (LMWH) was found to be superior to unfractionated heparin.3

Vitamin K antagonists ((VKA) were used as therapeutic agents for venous thromboem-bolism from 1954 onward.3,4 Three meta-analyses have shown LMWH to be more effec-tive than Vitamin K antagonists.5,6,7 Currently, LMWH is still the preferred thrombopro-phylactic agent according to the leading ACCP (American College of Chest Physicians) guidelines.1

The synthetic pentasaccharide fondaparinux, a selective factor Xa inhibitor, was intro-duced in 2002 in Europe. A pooled analysis of the ACCP1, based on moderate-quality evidence, revealed that 12 fewer symptomatic VTE per 1,000 would be expected with the use of fondaparinux compared to placebo. However, fondaparinux comes with an increase of 12 major bleeds per 1,000 compared to placebo. Fondaparinux shows a sub-stantial reduction in asymptomatic deep venous thrombosis (DVT) compared to LMWH, but no difference was observed in the incidence of symptomatic DVT and pulmonary embolism (PE). There was a substantial increase in bleeding requiring reoperation as-sociated with the use of fondaparinux (RR 1.85; 95 % CI, 1.1-3.11), but the results failed to demonstrate a difference in nonfatal major bleeding (RR 1.35; 95 % CI, 0.89-2.05).Currently, three new oral antithrombotic agents (NOACs) are also available for the prevention of venous thrombo-embolism after hip and knee arthroplasty. Rivaroxaban and apixaban are factor Xa inhibitors, dabigatran is a direct inhibitor of thrombin. They were introduced on the Dutch market in 2008 (dabigatran and rivaroxaban) and 2011 (apixaban). To compare these agents in a indirect way, a few network meta-analyses and systematic reviews with pooled effects have been carried out.8-10 Rivaroxaban and apixa-ban were more effective than dabigatran regarding the prevention of VTE. One meta

12 Chapter 1

analysis did not show any difference in the risk of bleeding, while another meta analysis showed more bleeding events in the rivaroxaban group and less bleeding events in the apixaban group in comparison to the LMWH enoxaparin.

Thromboprophylaxis and blood management in the netherlands

To assess changing patterns in Dutch Orthopaedic thromboprophylaxis practices, three surveys were conducted. The first survey, performed in 2002, showed that evidence-based national guidelines were not properly adhered to.11,12 During the following years, more attention was given to thromboprophylaxis and new pharmacological modalities, such as oral anticoagulants, were introduced. The results of the second (2007) and third (2012) survey are described in chapter 2 and 3 respectively.When using pharmacological thromboprophylaxis after orthopaedic surgery, a major concern is the possibility of an increase in bleeding complications. Blood transfusions are frequently required after hip and knee arthroplasties. It is important to reduce the need for allogeneic blood transfusions, to minimize the adverse events associated with blood transfusions. This can be achieved by increasing the patient’s haemoglobin level preoperatively, by reducing blood loss and by auto-transfusion. In chapter 4, the use of blood saving modalities in Dutch orthopaedic departments during a 10-year follow-up period is described.


Because many VTE’s occur after discharge, orthopaedic surgeons may have a falsely low perception of the thrombosis rate in their practice. Why do surgeons have different views on the use of aspirin, heparin and Vitamin K antagonists when considering the same body of evidence? Chapter 5 aims to compare eleven (inter)national guidelines on thromboprophylaxis from different countries, and to interpret their differences.


Arthroscopically assisted cruciate ligament (ACL) reconstruction is common practice these days and is performed during day-care or short-stay surgery. After routine arthroscopy without ligament reconstruction the risk of symptomatic VTE appears to be rather low (1.5 - 2%).1,13 The risk on asymptomatic DVT ranges from 5-18% depend-ing on the screening method and population studied.13-17 Arthroscopically assisted arthroscopic anterior cruciate ligament reconstruction is considered less traumatic to an extremity than joint arthroplasty, but more traumatic than uncomplicated arthroscopic procedures such as meniscectomy, where no osseous drilling is required. There is a possibility that the incidence of thromboembolic events may actually be increased following knee ligament surgery vs. routine arthroscopy. Moreover, ACL reconstruction can be associated with haemarthrosis and postoperative leg swelling and therefore


1complicate the accurate clinical diagnosis of deep venous thrombosis. There is, however, surprisingly little data on the incidence of venous thromboembolism after arthroscopic cruciate ligament reconstruction. Therefore, we conducted a study to determine the incidence of deep venous thrombosis after ACL reconstruction, as detected by compres-sion ultrasound. The results are presented in chapter 6.


Lower extremity amputations are mostly performed in (diabetic) patients with end-stage vascular disease18, with very high mortality rates up to 53% in the first year following surgery.18-23 Uncertainty exists, however, about the incidence of DVT in the amputated leg, causing subsequent pulmonary embolism and death. Since most of these patients present with acute vascular occlusion prior to amputation, a state of hypercoagulability is very likely. Also, increased incidences of venous thrombosis prior to amputation have been reported (7.3-8.3%).24-25 In the study, described in chapter 7, we prospectively determined the presence of deep venous thrombosis and pulmonary embolism both pre- and postoperatively by means of duplex-ultrasonography and ventilation-perfusion lung scintigraphy.

Plaster cast immobilisation

Generally, immobilisation is considered a major risk factor for VTE. A meta-analysis re-garding six studies concerning leg plaster cast immobilisation, showed a highly signifi-cant and clinically relevant reduction in asymptomatic events with LMWH prophylaxis compared to placebo or untreated controls (RR 0.58, CI 0.39-0.86, p= 0,006).26 In chapter 8, a case of pulmonary embolism during trial hip plaster cast immobilisation to simulate lumbosacral fusion and a review of literature are presented.


There is no consensus regarding the need for perioperative thromboprophylaxis fol-lowing shoulder arthroplasty1. To establish whether thromboprophylaxis is warranted, first the incidence of thrombosis and pulmonary embolism after shoulder arthroplasty needs to be investigated. In chapter 9 a systematic review of literature regarding symp-tomatic thrombosis after shoulder arthroplasty is described. Currently there are two studies regarding the incidence of symptomatic DVT following shoulder arthroplasty. In both studies, thromboprophylaxis by means of aspirin and intermittent pneumatic compression was used.27-28 The aim of our study, described in chapter 10, is to establish the inci dence of asymptomatic venous thrombo-embolic complications as detected by bilateral complete compression ultrasonography of both legs and the operated arm after shoulder arthroplasty without thromboprophylaxis.

14 Chapter 1

REFEREnCES

1. Falck-Ytter Y, Francis CW, Johanson NA et al; American College of Chest Physicians. Prevention of VTE in orthopaedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S.

2. Crafoord C. Preliminary report on post-operative treatment with heparin as a prevention of thrombosis. Acta Chir Scand 1937; 79:407-26.

3. Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost. 2013 Mar;11(3):402-11. doi: 10.1111/jth.12127.

4. Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation1994; 89: 432–49.

5. Freedman KB, Brookenthal KR, Fitzgerald RH Jr, Williams S, Lonner JH. A meta-analysis of throm-boembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am. 2000 Jul;82-A(7):929-38.

6. Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism fol-lowing total hip replacement. JAMA. 1994 Jun 8;271(22):1780-5. Erratum in: JAMA 1995 Jan 25;273(4):288.

7. Mohr DN, Silverstein MD, Murtaugh PA, Harrison JM. Prophylactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment. Arch Intern Med. 1993 Oct 11;153(19):2221-8.

8. Cohen A, Drost P, Marchant N, Mitchell S, Orme M, Rublee D, Simon TA, Sutton A. The Efficacy and Safety of Pharmacological Prophylaxis of Venous Thromboembolism Following Elective Knee or Hip Replacement: Systematic Review and Network Meta-Analysis. Clin Appl Thromb Hemost. 2012 Mar 2. [Epub ahead of print].

9. Maratea D, Fadda V, Trippoli S, Messori A. Prevention of venous thromboembolism after major orthopaedic surgery: indirect comparison of three new oral anticoagulants. J thromb Haemost 2011; 9:1868-70.

10. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, riva-roxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replace-ment: systematic review, meta-analysis, and indirect treatment comparisons. BMJ. 2012 Jun 14;344:e3675. doi: 10.1136/bmj.e3675.

11. Ettema HB, Hoppener MR, Henny CP, Büller HR, Verheyen CCPM. Compliance of Dutch orthopae-dic departments with national guidelines on thromboprophylaxis. A survey of Dutch orthopaedic thromboprophylaxis. Acta Orthopaedica 2005;76 (1):99-103.

12. Schonenberg D, van Meeteren M, Nelissen RG, van der Horst-Bruinsma IE, Pöll RG, Nurmohamed MT. Thrombosis prevention in orthopaedic surgery: clinical practice in the Netherlands in 2002. Ned Tijdschr Geneeskd. 2003 Sep 20;147(38):1856-60.

13. Ramos J, Perrotta C, Badariotti G, et al. Interventions for preventing venous thromboembolism in adults undergoing knee arthroscopy. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD005259. doi: 10.1002/14651858.CD005259.pub3.

14. Hoppener M R, Ettema H B, Henny C P et al. Low incidence of deep vein thrombosis after knee ar-throscopy without thromboprophylaxis: a prospective cohort study of 335 patients. Acta Orthop 2006: 767-771.

15. Ilahi OA, Reddy J, Ahmad I. Deep venous thrombosis after knee arthroscopy: a meta-analysis. Arthroscopy 2005:727-730.


1 16. Demers C, Marcoux S, Ginsberg JS et al. Incidence of venographically proved deep vein thrombo-

sis after knee arthroscopy. Arch Intern Med 1998;158:47-50. 17. Delis KT, Hunt N, Strachan RK et al. Incidence, natural history and risk factors of deep vein throm-

bosis in elective knee arthroscopy. Thromb Haemost 2001;86:817-821. 18. Dillingham TR, Pezzin LE. Rehabilitation setting and associated mortality and medical stability

among persons with amputations. Arch Phys Med Rehabil. 2008 Jun;89(6):1038-45. 19. Remes L, Isoaho R, Vahlberg T, Hiekkanen H, Korhonen K, Viitanen M, Rautava P. Major lower

extremity amputation in elderly patients with peripheral arterial disease: incidence and survival rates. Aging Clin Exp Res. 2008 Oct;20(5):385-93.

20. Stone PA, Flaherty SK, Hayes JD, AbuRahma AF. Lower extremity amputation: a contemporary series. W V Med J. 2007 Nov-Dec;103(5):14-8.

21. Ploeg AJ, Lardenoye JW, Vrancken Peeters MP, Breslau PJ. Contemporary series of morbidity and mortality after lower limb amputation. Eur J Vasc Endovasc Surg. 2005 Jun;29(6):633-7. Epub 2005 Mar 28.

22. Aulivola B, Hile CN, Hamdan AD, Sheahan MG, Veraldi JR, Skillman JJ, Campbell DR, Scovell SD, LoGerfo FW, Pomposelli FB Jr. Major lower extremity amputation: outcome of a modern series. Arch Surg. 2004 Apr;139(4):395-9.

23. Nehler MR, Coll JR, Hiatt WR, Regensteiner JG, Schnickel GT, Klenke WA, Strecker PK, Anderson MW, Jones DN, Whitehill TA, Moskowitz S, Krupski WC. Functional outcome in a contemporary series of major lower extremity amputations. J Vasc Surg. 2003 Jul;38(1):7-14.

24. Yeager RA, Moneta GL, Edwards JM, Taylor jr LM, McConnell DB, Porter JM. Deep vein thrombosis associated with lower extremity amputation. J Vasc Surg. 1995;22:612-5.

25. Matielo MF, Presti C, Casella IB, Netto BM, Puech-Leão P. Incidence of ipsilateral postoperative deep venous thrombosis in the amputated lower extremity of patients with peripheral obstruc-tive arterial disease. J Vasc Surg. 2008 Dec;48(6):1514-9. Epub 2008 Oct 1.

26. Ettema HB, Kollen BJ, Verheyen CCPM et al (2008) Prevention of venous thromboembolism in patients with immobilisation of the lower extremity. A meta-analysis of randomised controlled trials. J Thromb Hemost 6:1093-1098.

27. Willis AA, Warren RF, Craig EV, et al. Deep vein thrombosis after reconstructive shoulder arthro-plasty: a prospective observational study. J Shoulder Elbow Surg 2009;18:100–106.

28. Widmer BJ, Bassora R, Warrender WJ, Abboud JA. Thromboembolic events are uncommon after open treatment of proximal humerus fractures using aspirin and compression devices. Clin Or-thop Relat Res. 2011;469:3332-3336.

2

Dutch orthopedic thromboprophylaxis:

a 5-year follow-up survey

HB Ettema1, MC Mulder1, MT Nurmohamed2, HR Büller3, CCPM Verheyen1

1 Department of Orthopedic Surgery and Traumatology, Isala Clinics, Zwolle, the Netherlands2 Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands

3 Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

Acta Orthopaedica. 2009; 80(1):109-112.

18 Chapter 2

ABSTRACT

Background and purpose

Previous surveys in the Netherlands have revealed that guidelines regarding orthopedic thrombopro phylaxis were not followed and that a wide variation in proto cols exists. This survey was performed to assess the current use of thromboprophylactic modalities and to compare it with the results of a previous survey.

Methods

All departments of orthopedic surgery in the Neth erlands were sent a follow-up survey on venous thromboprophy laxis, and the data obtained were compared to the results of a survey performed 5 years earlier.

Results

All departments used pharmacological thrombopro phylaxis following arthroplasties of the hip and knee. Low-molec ular-weight heparin (LMWH) was used most frequently (79%) of the departments, followed by fondaparinux (13%). 5 years earlier, coumarin treatment was the predominant prophylaxis (79%). All departments prescribed phar-macological prophylaxis after femoral and tibial fractures; 78% used LMWH. Prophylaxis was continued for 6 weeks in 85% of cases. LMWH treatment was initiated on the day be-fore surgery in 31% of cases (65% in the previous survey), perioperatively in 55%, and in the evening following surgery in 24%. In general, for daycare surgery and arthroscopies either no prophylaxis was given or a LMWH was given for 1 day. After anterior cruciate ligament reconstruction, 94% of departments prescribed some form of pharmacological prophylaxis.

Interpretation

The use of pharmacological prophylaxis after arthroplasty of the hip and knee and also after fracture surgery around the hip and knee is common practice in the Netherlands. In 5 years, the widely used coumarin derivates have been largely replaced with LMWH.

Dutch orthopedic thromboprophylaxis 19

2

InTRODuCTIOn

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common complications after orthopedic surgery, espe cially after arthroplasties and fracture surgery (Geerts et al. 2004). Dutch national guidelines (Büller et al. 2000) have not been followed (Schonen-berg et al. 2003, Ettema et al. 2005). Since more attention has been drawn to thrombo-prophylaxis and new pharmacological modalities have been introduced, we conducted this survey to assess the current situation. We also compared it with the results of a survey from 5 years ear lier (Ettema et al. 2005). As in that study, we concentrated on hip and knee arthroplasties. Additional questions were asked regarding daycare, short stay, fractures, and plaster cast immo bilization.

METHODS

A questionnaire on orthopedic departmental protocols for peri operative thrombopro-phylaxis was sent to all Dutch orthopedic departments. It was tailored to fit a similar one performed in 2002 (Ettema et al. 2005). Practice profile, and current choice, initiation, and duration of thromboprophylaxis after several orthopedic procedures were assessed.In 2007, a package with the questionnaire, a cover letter, and a stamped addressed envelope were sent to all Dutch ortho pedic departments. Non-respondents were sent a reminder after 4 months, and were contacted by telephone if necessary. Categorical data and dichotomous variables were summarized as percentages of the responding departments. For key fea tures, the results were compared with those in the 2002 data-base, which had a response rate of 87 out of 110 departments (79%).

RESuLTS

81 of 96 departments answered the questionnaire properly. All respondents stated that they had a specific departmental proto col on thromboprophylaxis.

Hip and knee arthroplasty

All departments used pharmacological thromboprophylaxis during hospital admission after hip and knee arthroplasties (Table 1). Low–molecular-weight heparin (LMWH) mono therapy had replaced vitamin K antagonist (VKA) as the pre dominant agent used by the responding departments in 2007 after elective hip and knee arthroplasty. In all departments, coumarines (when prescribed) were com bined with a LMWH during the first days of treatment until an adequate internationalized normalized ratio (INR) was

20 Chapter 2

reached. The synthetic Xa inhibitor fondaparinux was given in 13% of hip and knee arthroplasties. Since fondaparinux was not available during the survey 5 years earlier, no comparison can be made. None of the respondents used aspirin. LMWH prophylaxis was given after discharge for 3–4 weeks in 9% of patients/departments, 6 weeks in 85%, and 2–3 months in 6%. Coumarines were continued for 6 weeks in 60% of patients/depart-ments and 3 months in 40%. 5 years earlier, coumarins had been continued for 3 months in 65% of cases/departments. In the present study, fondaparinux was prescribed for 3–4 weeks in 55% of patients/departments and 5–6 weeks in 45%.

Fractures of the proximal femur and tibia

All departments used pharmacological prophylaxis after osteosynthesis or arthroplasty of hip and proximal femur frac tures, and after internal fixation of proximal tibia fractures (Table 2). In 2007, as with elective arthroplasties, LMWH had come to replace coumarins as the mainstay of thromboprophy laxis after hemiarthroplasty of the hip (compared to 5 years earlier). Prophylaxis was continued for 4–6 weeks in 88% of patients/depart-ments and for 2–3 months in 9%. In 2007 thromboprophylaxis was not continued after discharge in 3% of the departments, which was less than in 2002 (9%).

Initiation of treatment

LMWH treatment was started on the evening before surgery in 31% of patients/depart-ments, 2 h preoperatively in 23%, less than 6 h postoperatively in 22%, and in the evening following surgery (regardless of the time of surgery) in 24% of patients/departments. In 2002, 65% of all LMWH therapy was started on the evening before surgery and in 21% of cases/departments it was started 2 h preoperatively. Coumarins were started on the day of surgery in 46% of patients/departments and later in 54%. Fondaparinux was always initiated 6–12 hours postop eratively (as recommended by the manufacturer).

Table 1. Thromboprophylactic regimens used after elective arthroplasties of hip and knee in the studied orthopaedic departments (%).

In hospital only In hospital and extended thromboprophylaxis

Arthroplasty LMWH LMWH LMWH and VKA’s‡ Fondaparinux Aspirin

2002 2007 2002 2007 2002 2007 2002 2007 2002 2007

Total hip 2 None 17 79 80 7 NA 14 1 0

Revision hip 2 None 16 80 81 7 NA 13 1 0

Total knee 2 None 20 79 77 8 NA 14 1 0

Revision knee 2 None 18 80 79 7 NA 13 1 0

Hemi knee 9 3 8 78 82 7 NA 12 1 0

Average 3 1 17 79 79 7 NA 13 1 0

‡LMWH until adequate INR is reached; in 2002 12% used a coumarin only.


2

Day care, arthroscopy, and anterior cruciate ligament (ACL) reconstruction

When treating patients in daycare surgery (including arthroscopy of the knee), com-pared to 5 years earlier an increased number of departments did not use any prophylaxis in 2007 (Table 3). After ACL reconstruction 50% of departments used a LMWH for 1-3 days (or the period of admission), 5% for 1 or 2 weeks, 2% for 3-4 weeks, and 35% of departments used LMWH prophylaxis for 6 weeks. 1 hospital prescribed fondaparinux for 2 weeks. Another hospital used a coumarin for 6 weeks. No form of prophylaxis was given in 6% of cases/departments.

Plaster cast immobilization (Table 4)

During lower leg immobilization, some form of pharmaco logical prophylaxis was given in 70% of cases/departments. During immobilization of both knee and ankle, thrombopro-phylaxis was used in 94% of the departments. In 2002, most departments prescribed a coumarin derivate but by 2007 this had generally been replaced with a LMWH.

Table 2. Thromboprophylactic regimens used after fracture surgery around the hip and knee in the studied orthopaedic departments (%).

In hospital only In hospital and extended out of hospital thromboprophylaxis

Trauma procedure LMWH LMWH and VKA’s‡ Fondaparinux

2002 2007 2002 2007 2002 2007 2002 2007

Fractures around the hip

Hemi hip arthroplasty 9 3 15 78 75 9 10

Hip internal fixation 1 81 9 9

Proximal femur internal fixation 4 78 8 10

Fractures around the knee

Proximal tibia internal fixation 12 79 8 5

‡LMWH until adequate INR is reached.

Table 3. Thromboprophylactic regimens used after day-care surgery and arthroscopy of the knee in the studied orthopaedic departments (%).

Procedure no prophylaxis LMWH once or during admission Other

2002 2007 2002 2007 2002 2007

Day-care 40 64 59 34* 0 2ξ

Arthroscopy 40 4 59 49¥ 1 3§

*54% initiation preoperatively, ¥ 52% initiation preoperatively, ξ One department uses fondaparinux for two weeks and one LMWH for 5 days, § one department uses 5 days of LMWH, one department recommends 6 weeks of vitamin K antagonist prophylaxis and one department 14 days of fondaparinux.

22 Chapter 2

nSAIDs, aspirin and coumarins

83% of the departments discontinued aspirin for 3–10 days before surgery. Continued use of aspirin until the day of sur gery was a reason for delayed surgery in 26% of these depart ments. NSAIDs were discontinued for 2–10 days before sur gery in only 40% of the hospitals; non-compliance with this protocol was a reason for cancellation of surgery in only 10% of the departments. Coumarin therapy was interrupted in all departments for 2–10 days. Patients were managed with vita min K or clotting factor infusions in 58% of departments, or surgery was delayed when it was not discontinued (42% of depart-ments).

Mechanical prophylaxis

In addition to pharmacological prophylaxis, some hospi tals used mechanical prophy-lactic devices. Elastic stockings were used after total hip arthroplasty in 8% of depart-ments as compared to 20% in 2002, and after knee arthroplasty in 5% of departments as compared to 11% previously. Intermit tent pneumatic compression was not employed in any of the departments that responded to the questionnaire.Of all the departments, 93% did not prescribe any standard prophylaxis for patients be-low 16 years of age, 5% treated these patients as adults, and 2% had a more complicated pro tocol.The most frequently prescribed LMWH was nadroparin (76%), followed by dalteparin (19%) and enoxaparin (5%) in their standard prophylactic doses (98%). This has not changed appreciably in 5 years.

DISCuSSIOn

Our follow-up survey reveals that within 5 years, vitamin K antagonists have been largely replaced with LMWH and fondaparinux for the prevention of venous thromboembolic events (VTEs) in orthopedic surgery in the Netherlands. There is still considerable varia-tion in protocols among diff erent departments. The Dutch consensus document “Deep venous thrombosis and pulmonary embolism” recommends thromboprophylaxis with a

Table 4. Thromboprophylactic regimens used with immobilisation of the lower extremity in the studied orthopaedic departments (%).

Type of immobilisation no prophylaxis LMWH LMWH when non-weight baring

fondaparinux coumarin

2002 2007 2002 2007 2002 2007 2002 2007 2002 2007

Below the knee only 50 30 10 52 3 13 NA 4 37 1

Above the knee and ankle 11 6 16 84 5 5 NA 3 68 2


2

LMWH for a period of 6 weeks after major orthopedic surgery of the hip and knee, and VKA is considered an alternative only (Büller et al. 2000). Gener ally, a LMWH is prescribed after arthroplasty of the hip and knee; this shows that compliance with the consensus is better than in the previous two surveys (Schonenberg et al. 2003, Ettema et al. 2005). Since the consensus originated in 2000, it does not include new anticoagulants such as fondaparinux. Newer guidelines (Geerts et al. 2004) do favor fondaparinux after arthroplasty and hip fracture surgery. Clearly, a consid erable number of orthopedic departments have looked ahead and introduced these synthetic agents before any new national guidelines appear. We believe these results are representative because of the high response rate.We found that LMWH is generally started perioperatively (between 2 h before and 6 h after surgery) in the Netherlands. The remaining departments start either on the day be-fore or the evening after surgery. It appears that a preoperative start is no more effective than a postoperative start (Strebel et al. 2002). A perioperative start is apparently more effective, but this is counterbalanced by a marked increase in the risk of major bleed-ing in comparison with a preoperative or postop erative regimen (Strebel et al. 2002). Although international guidelines advise against the use of spinal and epidural blocks in patients on LMWH perioperatively (Horlocker et al. 2003), the Dutch practice does not contradict the Dutch guidelines for single-shot spinal anesthesia (De Lange et al. 2004).Extended pharmacological thromboprophylaxis is stan dard after hip and knee arthro-plasty and hip fracture surgery. A meta-analysis showed a favorable effect of LMWH with a reduction in total thrombosis after hip arthroplasties (asymp tomatic as well as symp-tomatic) when compared to placebo or no prophylaxis after 30–42 days of treatment. The data regarding knee arthroplasty are less obvious (Eikelboom et al. 2001).Although favorable results have been reported in a number of studies with mechanical methods of prophylaxis (Kaempffe et al. 1991, Francis et al. 1992), pneumatic compres-sion devices were no longer used by the responders in our study. Elastic stockings are used, but only as an adjuvant to a pharmacologi cal regimen.The use of prophylaxis after smaller procedures such as arthroscopy of the knee or ACL reconstruction remains con troversial (Nurmohamed 2007, Verheyen 2007); the risk after arthroscopy of the knee appears to be low (Ettema et al. 2006, Hoppener et al. 2006) whereas the risk of thrombosis after ACL reconstruction is unknown. This uncertainty is reflected in the wide variation in regimens following these procedures in the respond-ing departments. Much of the same applies to plaster cast immobilization: the national guidelines recom mend the use of prophylaxis after above–the-knee casts, but not with below-knee casting. Furthermore, the ACPP consen sus statement does not recommend routine prophylaxis with below-knee fractures (Geerts et al. 2004). Even so, a recent meta-analysis of randomized controlled trials investigating thromboprophylaxis with

24 Chapter 2

plaster cast immobilization has shown a favorable effect of LMWH on asymptomatic end points (Ettema et al. 2008).In summary, the use of pharmacological prophylaxis after arthroplasty of the hip and knee and also after fracture sur gery around the hip and knee is common practice in the Neth erlands. Generally speaking, it is continued after discharge. LMWH or fondaparinux is mainly used, whereas 5 years ago coumarin derivates were the preferred treatment. There still remains a wide variability in regimens after smaller proce dures such as ar-throscopy and ACL reconstruction and after immobilization of the leg.


2

REFEREnCES

Büller H R, van der Meer J, Oudkerk M. CBO guideline ‘Deep venous throm bosis and pulmonary embo-lism; revision of the earlier guidelines. Dutch Organization for Quality Assurance in Hospitals. Ned Tijdschr Geneeskd 2000; 144: 1531-7.

De Lange J J, Van Kleef J W, Van Everdingen J J. The practice guideline ‘Neuraxis blockade and anticoagu-lation’. Ned Tijdschr Geneeskd. 2004; 148: 1528-31.

Eikelboom J W, Quinlan D J, Douketis J D. Extended-duration prophylaxis against venous thromboem-bolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet JID - 2985213R 2001; 358: 9-15.

Ettema H B, Hoppener M R, Henny C P, Büller H R, Verheyen C C. Compli ance of Dutch orthopedic depart-ments with national guidelines on throm boprophylaxis. A survey of Dutch orthopedic thrombopro-hylaxis. Acta Orthop 2005; 76: 99-103.

Ettema H B, Hoppener M R, Veeger N J, Büller H R, van der M J. Low inci dence of venographically detected deep vein thrombosis after knee arthros copy without thromboprophylaxis: a prospective cohort study. J Thromb Haemost 2006; 4: 1411-3.

Ettema H B, Kollen B J, Verheyen C C, Büller H R. Prevention of venous thromboembolism in patients with immobilisation of the lower extremity: a meta-analysis of randomised controlled trials. J Thromb Haemost 2008; 6 (7): 1093-8.

Francis C W, Pellegrini V D, Jr., Marder V J, Totterman S, Harris C M, Gabriel K R, Azodo M V, Leibert K M. Comparison of warfarin and exter nal pneumatic compression in prevention of venous thrombosis after total hip replacement. JAMA 1992; 267: 2911-5.

Geerts W H, Pineo G F, Heit J A, Bergqvist D, Lassen M R, Colwell C W, Ray J G. Prevention of venous thromboembolism: the Seventh ACCP Con ference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338S-400S.

Hoppener M R, Ettema H B, Henny C P, Verheyen C C, Buller H R. Low incidence of deep vein thrombosis after knee arthroscopy without thrombo prophylaxis: a prospective cohort study of 335 patients. Acta Orthop 2006; 77: 767-71.

Horlocker T, Wedel J, Benzon H, et al. Regional anesthesia in the antico agulated patient: defining the risks (the second ASRA Consensus Confer ence on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 281: 72–97.

Kaempffe F A, Lifeso R M, Meinking C. Intermittent pneumatic compression versus coumadin. Prevention of deep vein thrombosis in lower-extremity total joint arthroplasty. Clin Orthop 1991; (269): 89-97.

Nurmohamed M T. Thromboprophylaxis is indicated for knee arthroscopy and cast immobilisation. Ned Tijdschr Geneeskd 2007; 151: 1730.

Schonenberg D, van Meeteren M, Nelissen R G, van der Horst-Bruinsma I E, Poll R G, Nurmohamed M T. Thrombosis prevention in orthopaedic sur gery: clinical practice in the Netherlands in 2002. Ned Tijdschr Geneeskd 2003; 147: 1856-60.

Strebel N, Prins M, Agnelli G, Buller H R. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002; 162: 1451-6.

Verheyen C C. Thromboprophylaxis is not indicated for knee arthroscopy and cast immobilisation. Ned Tijdschr Geneeskd 2007; 151: 1731.

3

Ten-year follow-up on orthopedic thromboprophylaxis

in the NetherlandsDATA III survey

MC Struijk-Mulder, M.D.1, HB Ettema, M.D. PhD1, HR Büller, Prof. M.D.2, CCPM Verheyen M.D. PhD1

1 Department of Orthopedic Surgery and Traumatology, Isala Klinieken, Zwolle, the Netherlands2 Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands

Submitted

28 Chapter 3

ABSTRACT

Introduction

Our previous surveys in the Netherlands have revealed that a wide variation exists in protocols on orthopedic thromboprophylaxis. The DATA III survey (Dutch Antithrom-botic Treatment for Arthroplasties) was performed to assess the current use of thrombo-prophylactic modalities.

Materials and methods

All departments of orthopedic surgery in the Netherlands were sent a follow-up survey; data obtained were compared to the results of two surveys performed 5 and 10 years earlier and current national guidelines.

Results

The response rate was 92 out of 108 departments (85%). All used extended pharmaco-logical thromboprophylaxis following total hip arthroplasty (4-6 weeks) and total knee arthroplasty (2-6 weeks). Low molecular weight heparin (LMWH) was used most fre-quently (79% of all departments). Ten years earlier, VKA treatment was the predominant prophylaxis (79%). For daycare surgery and arthroscopies either no prophylaxis was given (68% and 56% respectively), or a single shot of LMWH (23% and 39% respectively). After anterior cruciate ligament reconstruction, 89% of the departments used prophy-laxis. Patients treated with a below knee plaster cast, received thromboprophylaxis in 88% of the departments (compared to 50% ten years ago).

Conclusions

The use of (extended) pharmacological prophylaxis after arthroplasty of the hip and knee is common practice in the Netherlands. Although currently low molecular weight heparin remains the most commonly used thromboprophylactic agent, the new oral anticoagulants are now used in 25% of departments. There is a significant increase in the use of thromboprophylaxis during plaster cast immobilization and in the use of extended thromboprophylaxis after ACL surgery.

Ten-year follow-up on orthopedic thromboprophylaxis in the Netherlands 29

3

InTRODuCTIOn

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common complications after orthopedic surgery, especially after arthroplasties joint replacement and fracture surgery.[1] Dutch national guidelines [2] have not been adhered to in the past.[3] Since then more attention has been drawn to thromboprophylaxis and new pharmacological modalities have been introduced. We conducted a survey to assess the present situation. The results were also compared to two prior surveys, performed 5 and 10 years earlier [3,4] and with current national guidelines.[5] In the first study, we focused on hip and knee arthroplasties. In the second and current third study, additional questions were asked regarding daycare, short stay, fractures, and plaster cast immobilization.

MATERIALS AnD METHODS

A questionnaire focussing on orthopedic departmental protocols for peri-operative thromboprophylaxis was sent to all 110 Dutch orthopedic departments in Dutch hospi-tals. It was tailored to fit similar ones conducted in 2002 and 2007 [3,4]. Practice profile, and current choice, initiation, and duration of thromboprophylaxis after several ortho-pedic procedures were assessed. Response rates in 2002 and 2007 were 79% (87 out of 110 departments) and 84% (81 out of 96 departments). The power analysis showed that, with a confidence interval of 95%, the response of at least 86 departments was required for our analysis.In 2012, a package with the questionnaire, a cover letter, and a stamped addressed envelope was sent to all Dutch orthopedic departments. Non-respondents were sent a reminder after 4 months, and were contacted by telephone if necessary. Categorical data and dichotomous variables were summarized as percentages of the responding departments by means of SPSS 21 (New York, United States).

RESuLTS

94 out of 110 departments ultimately answered the questionnaire properly. Two clinics were excluded, because they reported to perform spine surgery exclusively. The ad-justed response rate therefore was 85%. All respondents stated that they had a specific departmental protocol on thromboprophylaxis.

30 Chapter 3

Tabl

e 1.

In h

ospi

tal a

nd e

xten

ded

thro

mbo

prop

hyla

ctic

regi

men

s us

ed a

fter

art

hrop

last

ies

of h

ip a

nd k

nee

in th

e st

udie

d or

thop

edic

dep

artm

ents

, N(%

)

In h

ospi

tal o

nly

In h

ospi

tal a

nd e

xten

ded

thro

mbo

prop

hyla

xis

Art

hrop

last

yLM

WH

LMW

HLM

WH

+ VK

Aa

Fond

apar

inux

Riva

roxa

ban

Dab

igat

ran

2002

2007

2012

2002

2007

2012

Pb20

0220

0720

12Pb

2007

2012

Pb20

1220

12

Tota

l hip

2 (2

)-

-14

(17)

69 (7

9)63

(69)

0.11

65 (8

0)6

(7)

00.

01 *

12 (1

4)6

(6)

0.07

18 (2

0)5

(5)

Revi

sion

hip

2 (2

)-

-13

(16)

70 (8

0)75

(81)

0.05

66 (8

1)6

(7)

1 (1

)0.

02 *

11 (1

3)6

(5)

0.07

10 (1

1)2

(2)

Hem

i hip

7 (9

)3

(3)

1 (1

)12

(15)

68 (7

8)83

(90)

0.05

61 (7

5)8

(9)

00.

02 *

9 (1

0)6

(6)

0.31

2 (2

)1

(1)

Tota

l kne

e2

(2)

--

16 (2

0)69

(79)

63 (6

9)0.

1762

(77)

6 (7

)1

(1)

0.00

2 *

12 (1

4)6

(5)

0.06

18 (2

0)5

(5)

Revi

sion

kne

e2

(2)

--

15 (1

8)70

(80)

75 (8

2)0.

5164

(79)

6 (7

)1

(1)

0.00

2 *

11 (1

3)6

(5)

0.07

10 (1

1)1

(1)

Hem

i kne

e7

(9)

3 (3

)-

6 (8

)68

(78)

75 (8

1)0.

5166

(82)

6 (7

)1

(1)

0.00

2 *

10 (1

2)3

(3)

0.05

13 (1

4)1

(1)

a LM

WH

unt

il ad

equa

te IN

R is

reac

hed.

b Si

gnifi

canc

e of

diff

eren

ce b

etw

een

2007

and

201

2 da

ta a

re c

alcu

late

d*

P <

0,05

: sig

nific

ant d

iffer

ence

1% o

f dep

artm

ents

use

d as

pirin

aft

er e

very

art

hrop

last

y in

200

2LM

WH

= lo

w m

olec

ular

wei

ght h

epar

inVK

A=

Vita

min

K A

ntag

onis

t


3

Hip and knee arthroplasty

All departments used extended pharmacological thromboprophylaxis for total hip and total knee arthroplasties (Table 1). In 2007, low molecular weight heparin (LMWH) mono therapy had replaced vitamin K antagonist (VKA) as the predominant prophylactic method. Although in 2012, subcutaneous LMWH remains the most used thrombopro-phylactic agent, there seems to be a shift towards the newly introduced oral factor Xa and IIa inhibitors rivaroxaban and dabigatran, which are now prescribed by a quarter of the departments. If a LMWH is prescribed, nadroparin is most frequently used (Table 2). The majority of departments still give extended thromboprophylaxis for 6 weeks, although a trend towards a shorter period is observed (Table 3). Ten years ago, VKA were continued for 3 months in 65% of departments.

Fractures of the proximal femur and tibia

All departments used pharmacological prophylaxis after osteosynthesis or arthroplasty of the hip for proximal femur fractures, and after internal fixation of proximal tibia frac-tures during admission. Most departments gave extended prophylaxis after surgical treatment of these fractures, except for four departments. Nowadays 94% use LMWH for proximal femur fractures and 98% for proximal tibia fractures. LMWH is used slightly more frequently than fondaparinux and VKA compared to 2007. Although rivaroxaban and dabigatran are not registered for fracture surgery, respectively 2 and 1 percent of departments did administer these agents for hip hemi-arthroplasty. In fracture surgery

Table 2. Type of LMWH, N(%)

LMWH 2002 2007 2012

Nadroparin 57 (70) 66 (76) 64 (69)

Dalteparin 16 (20) 17 (19) 21 (23)

Enoxaparin 5 (6) 4 (5) 7 (8)

Tinzaparin 3 (4) - -

Table 3. Duration of extended thromboprophylaxis after arthroplasties of hip and knee in the studied orthopedic departments, N(%)

Weeks THA TKA Hemi HA

2007 2012 2007 2012 2007 2012

0-3 1 (1) - 1 (1) 4 (4) 3 (4) 1 (1)

4-5 10 (11) 22 (25) 10 (11) 18 (20) 8 (9) 18 (20)

6 70 (80) 60 (65) 69 (79) 70 (76) 67 (77) 73 (79)

>6 7 (8) - 7 (9) - 9 (10) -

THA = Total Hip ArthroplastyTKA = Total Knee ArthroplastyHemi HA = Hemi Hip Arthroplasty

32 Chapter 3

the same trend towards a shorter duration of thromboprophylaxis was observed, as with arthroplasty. Prophylaxis was continued for 4-6 weeks in 96%, whereas in 2007, 88% of departments gave 4–6 weeks and 9% gave 2–3 months of thromboprophylaxis.

Initiation of treatment

Thromboprophylaxis after hip and knee arthroplasty is preferably started post-opera-tively nowadays (70%); even more so than five years ago (Table 4). A significant differ-ence is observed between 2007 and 2012 (P = 0.002). In total 48% of the departments start thromboprophylaxis during a well-defined time span postoperatively and 22% give it in the evening following surgery (regardless of the time of surgery).

Day care, arthroscopy, and anterior cruciate ligament (ACL) reconstruction

In daycare surgery (including arthroscopy of the knee), compared to ten and five years earlier, an increased number of departments did not use any prophylaxis in 2012 (Table 5). After ACL reconstruction, most departments prescribed LMWH. A trend towards a longer period of extended prophylaxis for ACL surgery is observed. In 2012 71% applies extended prophylaxis: 29% for 10-14 days, 21% for 3-4 weeks and 21% for 5-6 weeks. In 2007, 92% of the departments gave prophylaxis, but only 46% gave extended prophy-laxis.

Plaster cast immobilization (Table 6)

During plaster cast immobilization, more departments use thromboprophylaxis pres-ently. Patients treated with a below knee plaster cast, received thromboprophylaxis in 88 % of the departments (compared to 50% ten years ago). patients with a plaster cast above the knee were given thromboprophylaxis in 96% of cases. Prophylaxis was most frequently given by means of LMWH, which have replaced the VKA’s that were used in 68% of departments in 2002.

Table 4. Initiation of thromboprophylactic treatment after arthroplasties in the studied orthopedic departments, N(%).

2002 2007 2012

Preoperative 74 (91) 47 (54) 28 (30)

day before surgery 50 (62) 27 (31) 20 (21)

day of surgery 24 (29) 20 (23) 8 (9)

Postoperative 7 (9) 40 (46) 64 (70)

day of surgery 7 (9) 19 (22) 44 (48)

evening of surgery - 21 (24) 20 (22)


3

Mechanical prophylaxis

Intermittent pneumatic compression was seldom applied and never routinely used. The previous surveys showed identical results. Graduated compression stockings (GCS) are not used by the majority of departments. In 2012 GCS were used by 8% after total hip ar-throplasty during admission and 6% prolonged the use after discharge. After total knee arthroplasty, 9 % used GCS during admission, and 8 % continued them after discharge. These percentages are comparable to 2007. In 2002 more patients were given GCS: 20% after total hip arthroplasty and 11% after total knee arthroplasty.

COnCLuSIOnS

We believe the results of these surveys are valid because of the repeated high response rate in all of the surveys. The present follow-up survey reveals that in ten years time the oral vitamin K antagonists have at first been largely replaced by the subcutaneous

Table 5. Thromboprophylactic regimens used after day-care surgery and arthroscopy of the knee in the studied orthopedic departments, N(%).

Procedure no prophylaxis LMWH once or during admission

LWMH extended Other

2002 2007 2012 2002 2007 2012 2002 2007 2012 2002 2007 2012

Day care 32 (40) 56 (64) 63 (68) 48 (59) 30 (34) 21 (23) - 1 (1) 2 (2) - 1 (1)a 7 (7) b

Arthroscopy 32 (40) 42 (48) 52 (56) 48 (59) 43 (49) 36 (39) - 1 (1) 3 (3) 1 (1) 2 (2)c 2 (2) d

ACL surgery NA 5 (6) 10 (11) NA 44 (50) 23 (25) NA 37 (42) 58 (63) NA 2 (2) c 1 (1 )e

a 1 department: 2wk fondaparinuxb 1 department: LMWH when lower extremity operation and DVT in historyc 1 department: 2wk fondaparinux, 1 department: 6 wk. vitamin K antagonist1 department: 6 weeks LMWH in all foot operations4 departments: LMWH when risk factors are present1 department: >30 min OK duration: 10 days LMWHd 2 departments: LMWH when risk factors are presente 1 department: fondaparinuxACL = anterior cruciate ligament

Table 6. Thromboprophylactic regimens used with immobilisation of the lower extremity in the studied orthopedic departments, N(%).

Plaster cast no prophylaxis LMWHnWB and WB

LMWHnWB only

Fondaparinux VKA

2002 2007 2012 2002 2007 2012 2002 2007 2012 2002 2007 2012 2002 2007 2012

Below knee 41 (50) 26 (30) 11 (12) 8 (10) 45 (52) 54 (59) 2 (3) 11 (13) 25 (27) NA 3 (4) 2 (2) 30 (37) 1 (1) -

Above knee 9 (11) 5 (6) 4 (4) 13 (16) 73 (84) 86 (93) 4 (5) 4 (5) 1 (1) NA 3 (3) 2 (2) 55 (68) 2 (2) -

LMWH = low molecular weight heparinNWB and WB = non-weight bearing and weight bearing patients

34 Chapter 3

LMWH and its synthetic analogue fondaparinux, while lately the oral direct Xa and thrombin inhibitors rivaroxaban and dabigatran have gained popularity for the preven-tion of venous thromboembolic events (VTEs) in orthopedic surgery in the Netherlands. There is still some variation in protocols among different departments. The Dutch con-sensus document “ Diagnosis, Prevention and Treatment of Venous Thrombo Embolism and secondary prevention of Arterial Thrombosis” [5] recommends thromboprophylaxis with fondaparinux, LMWH or VKA after major orthopedic surgery of the hip and knee. Generally to, a LMWH is prescribed after arthroplasty of the hip and knee; this shows that adherence the consensus is better than before.[3] Since the latest consensus origi-nated in 2008, it does not include advices regarding the new oral anticoagulants such as rivaroxaban, dabigatran and apixaban. The newest ACCP guidelines (2012) do favour LMWH after arthroplasty and hip fracture surgery, whereas in 2004 fondaparinux was preferred. [6] Clearly, a considerable number of orthopedic departments have looked ahead and introduced the new oral anticoagulants before new national guidelines were published.

We found that LMWH is generally started post-operatively (after surgery or the evening after surgery) in the Netherlands. The Dutch guideline advises to start either pre- or post operatively while a peri-operative start is not mentioned. The ACCP guidelines advise to start either 12 h or more preoperatively or 12 h or more postoperatively rather than within 4 h or less preoperatively or 4 h or less postoperatively. This advice is mainly based on a systematic review, which concluded that a peri-operative start (2 h before to 4 h or less after surgery) is apparently more effective, but this is counterbalanced by a marked increase in risk of major bleeding in comparison with a preoperative or postoperative regimen.[7] It also appears that a preoperative start is no more effective than a postop-erative start.[7] Data on blood loss are confirmed by another study that concluded that pre- and post operative start of prophylaxis result in the same total amount of blood loss, but there was a trend toward fewer blood transfusions with a postoperative start.[8]

Extended pharmacological thromboprophylaxis is standard after hip and knee arthro-plasty and hip and knee fracture surgery. The Dutch guidelines recommend a period of 4-5 weeks postoperatively after hip arthroplasty and at least 10 days after knee arthro-plasty. Most departments give similar extended thromboprophylaxis for both THA and TKA of 4-6 weeks. In the past 10 years a trend towards shorter-term prophylaxis can be observed in the Netherlands. While in 2002 most departments used prophylaxis with VKA for three months, in 2012 prophylaxis with mostly LMWH is continued for 2-6 weeks. There is a continuing discussion about the optimal duration a prophylaxis. Studies with short term prophylaxis combined with rapid mobilization protocols following joint replacement surgery show favourable results compared to more extended prophylaxis


3

[9,10] while recent ACCP guidelines advise towards a longer extended prophylaxis regi-men of five weeks for all major orthopedic surgery patients. [1]

Although the Dutch guidelines state that intermittent pneumatic compression (IPC) can be used as an alternative to pharmacological prophylaxis after total knee surgery, the responders in our study did not use pneumatic compression devices. ACCP guidelines advice to use IPC as an addition to pharmacological prophylaxis during hospital stay, because adding a compression device to pharmacological prophylaxis reduced the incidence of asymptomatic DVT by more than 70%. Elastic stockings are used, but only as an adjuvant to a pharmacological regimen in the minority of departments.

The use of prophylaxis after smaller procedures such as arthroscopy of the knee or ACL reconstruction remains controversial. The risk after arthroscopy of the knee appears to be low. [11-13] ACCP guidelines do not recommend routine thromboprophylaxis in patients without risk factors, due to the low rate of VTE (1,5-2%, with 14 fewer symp-tomatic VTE per 1,000 expected with LMWH), combined with the potential risk for major bleeding (an additional three per 1,000). The studies cited are of moderate quality and multiple concomitant procedures were performed in the knee. Dutch guidelines recom-mend that in case of prolonged arthroscopic reconstructive surgery or complicated surgery and in patients with a high risk of VTE, thromboprophylaxis with LMWH can be considered. This uncertainty is reflected in the wide variation in regimens following these procedures in the responding departments.

The same applies to plaster cast immobilization. The national guidelines leave the choice to the clinician whether thromboprophylaxis is given and duration of thrombo-prophylaxis, because of lack of evidence. Furthermore, the ACPP consensus statement does not recommend routine prophylaxis with below-knee plaster cast immobilization.[1] Their analysis of literature, based on low and moderate level of evidence, did not show a benefit from LMWH. Patients with a high risk of VTE were excluded from these studies though. The incidence of VTE in the general population is expected to be higher than the mentioned risk of PE of 3:1000 and risk of DVT of 24:1000 without thrombo-prophylaxis. Even so, a meta-analysis of randomized controlled trials investigating thromboprophylaxis with plaster cast immobilization has shown a favourable effect of LMWH on asymptomatic endpoints.[14]

In summary, the use of pharmacological prophylaxis after arthroplasty of the hip and knee and also after fracture surgery around the hip and knee is common practice in the Netherlands. In general, national guidelines are properly adhered to. There is a significant increase in the use of thromboprophylaxis during below knee plaster cast

36 Chapter 3

immobilization and in the use of extended thromboprophylaxis after ACL surgery nowadays. Five years ago, the widely used VKA had been largely replaced with LMWH and fondaparinux . Although currently low molecular weight heparin remains the most commonly used thromboprophylactic agent, the new oral anticoagulants are now used in 25% of departments after hip and knee arthroplasty.


3

REFEREnCES

1. Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, Ortel TL, Pauker SG, Colwell CW Jr; American College of Chest Physicians (2012) Prevention of VTE in orthopedic surgery pa-tients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141(2 Suppl):e278S-325S.

2. Büller HR, van der Meer J, Oudkerk M. CBO guideline ‘Deep venous thrombosis and pulmonary embolism; revision of the earlier guidelines. Dutch Organization for Quality Assurance in Hospi-tals (2000) Ned Tijdschr Geneeskd 144:1531-1537.

3. Ettema HB, Hoppener MR, Henny CP, Büller HR, Verheyen CC (2005) Compliance of Dutch orthope-dic departments with national guidelines on thromboprophylaxis. A survey of Dutch orthopedic thromboprohylaxis. Acta Orthop 76: 99-103.

4. Ettema HB, Mulder MC, Nurmohamed MT, Büller HR, Verheyen CC (2009) Dutch orthopedic thromboprophylaxis: a 5-year follow-up survey. Acta Orthop 80:109-112.

5. CBO (2008) Richtlijn Diagnostiek, Preventie en Behandeling van Veneuze Trombo-embolie en Secundaire Preventie Arteriële Trombose.

6. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG (2004) Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:338S-400S.

7. Strebel N, Prins M, Agnelli G, Büller HR (2002) Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 162:1451-1456.

8. Borgen PO, Dahl OE, Reikerås O (2012) Blood loss in cemented THA is not reduced with postop-erative versus preoperative start of thromboprophylaxis. Clin Orthop Relat Res 470:2591-8.

9. Pearse EO, Caldwell BF, Lockwood RJ, Hollard J (2007) Early mobilisation after conventional knee replacement may reduce the risk of postoperative venous thromboembolism. J Bone Joint Surg Br 89:316-322.

10. Husted H, Otte KS, Kristensen BB, Ørsnes T, Wong C, Kehlet H (2010) Low risk of thromboembolic complications after fast-track hip and knee arthroplasty. Acta Orthop 81:599-605.

11. Ettema HB, Hoppener MR, Veeger NJ, Büller HR, van der MJ (2006) Low incidence of venographi-cally detected deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study. J Thromb Haemost 4:1411-1413.

12. Hoppener MR, Ettema HB, Henny CP, Verheyen CC, Büller HR (2006) Low incidence of deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study of 335 patients. Acta Orthop 77:767-71.

13. Maletis GB, Inacio MC, Reynolds S, Funahashi TT (2012) Incidence of symptomatic venous throm-boembolism after elective knee arthroscopy. J Bone Joint Surg Am 94:714-720.

14. Ettema HB, Kollen BJ, Verheyen CC, Büller HR (2008) Prevention of venous thromboembolism in patients with immobilisation of the lower extremity: a meta-analysis of randomised controlled trials. J Thromb Haemost 6:1093-1098.

4

Ten-year follow-up on Dutch orthopaedic blood management

DATA III survey

MC Struijk-Mulder1, WG Horstmann2, CCPM Verheyen1, HB Ettema1

1 Department of Orthopaedic Surgery and Traumatology, Isala Clinics, Zwolle, the Netherlands2 Department of Orthopaedic Surgery, Kennemer Gasthuis Haarlem, the Netherlands

Archives of Orth and Trauma Surg. 2014 Jan;134(1):15-20.

40 Chapter 4

ABSTRACT

Introduction

Hip and knee arthroplasties are frequently complicated by the need for allogeneic blood transfusions. This survey was conducted to assess the current use of perioperative blood-saving measures and to compare it with prior results.


All departments of orthopaedic surgery at Dutch hospitals were sent a follow-up survey on perioperative blood-saving measures, and data were compared to the results of two surveys conducted 5 and 10 years earlier.

Results

The response rate was 94 out of 108 departments (87%). Most departments used eryth-ropoietin prior to hip and knee replacements at the expense of preoperative autologous blood donation. The use of intraoperative autologous retransfusion in revision hip (56 vs. 54%) as well as revision knee arthroplasty (26 vs. 24%), was virtually unchanged. Postoperative autologous retransfusion is still used by the majority of departments after both primary arthroplasty and revision of hip (58/53%) and knee (65/61%).

Conclusions

Currently, just as in 2007, the majority of Dutch orthopaedic departments uses erythro-poietin, normothermia and postoperative autologous retransfusion with hip and knee arthroplasty. Intraoperative retransfusion is used mainly with hip revision arthroplasty. Other effective blood management modalities such as tranexamic acid have not been widely implemented.

Ten-year follow-up on Dutch orthopaedic blood management 41

4

InTRODuCTIOn

Blood transfusions are frequently required after hip and knee arthroplasties. Adverse events can occur after allogeneic red blood cell transfusions. These include infections due to contaminated blood, (incompatibility) transfusion reactions [1-3], increased risk of postoperative infection due to effects on the immune system [3-6], delay of wound healing and prolonged hospital stay [3,5]. It is therefore important to reduce the need for allogeneic blood transfusions. This can be achieved by increasing the patient’s hae-moglobin level preoperatively, by reducing blood loss and by auto-transfusion. There is an increasing focus on perioperative blood management [7]. This survey was conducted to assess the current use of perioperative blood-saving measures and to compare it with the results of prior surveys and national guidelines.

MATERIALS AnD METHODS

A questionnaire on orthopaedic departmental protocols for perioperative blood man-agement measures was sent to all 110 orthopaedic departments in Dutch hospitals. It was tailored to fit similar ones conducted in 2002 and 2007 [7]. Response rates in 2002 and 2007 were 79% (87 out of 110 departments) and 84% (81 out of 96 departments). The power analysis showed that, with a confidence interval of 95%, the response of at least 86 of 110 departments was required for our analysis. The questionnaire was expanded to include newly-introduced blood-saving measures. The current choice of perioperative blood management measures with total hip, hemi hip and revision hip arthroplasty as well as total knee, hemi knee and revision knee arthroplasty were as-sessed. In 2012 a package with the questionnaire, a cover letter, and a stamped return envelope were sent to all these orthopaedic departments. Non-respondents were sent a reminder after four months, and were contacted by telephone if necessary. Categorical data and dichotomous variables were summarised as percentages of the responding departments by means of SPSS 21 (New York).

RESuLTS

The questionnaire was ultimately answered properly by 94 out of 110 departments. Two clinics were excluded because they reported performing spine surgery exclusively. The adjusted response rate was therefore 87%. Eleven (12%) departments stated that they had no specific departmental protocol on blood-saving measures in 2012.

42 Chapter 4

Preoperative blood-saving measures

The use of preoperative autologous blood donation has been steadily decreasing over the years and is currently used in only 4% of departments (Table 1). Compared to 2002, in 2007 there was a considerable increase in the use of erythropoietin for hip as well as for knee arthroplasty. Currently, the majority (50-60 %) of orthopaedic departments continues to use erythropoietin after primary and revision hip and knee arthroplasty, although a slight decrease can be observed. Iron suppletion is being used by 27% of departments.Table 2 shows the discontinuation of different anticoagulants and the associated time before operation. Most departments discontinue the various anticoagulants, except for non-steroid anti-inflammatory drugs (NSAIDS) and Cox-2 selective NSAIDS, which are stopped preoperatively by a minority (40%). Also noteworthy is the significant decrease in the number of departments that discontinues aspirin before the operation (P < 0.001).

Table 1. Preoperative blood-saving measurements used prior to arthroplasties of hip and knee in the studied orthopaedic departments N,(%)

Arthroplasty Preop. autologous blood donation Erythropoietin Iron

2002 2007 2012 Pa 2002 2007 2012 Pa 2012

Total hip 11 (14) 10 (11) 4 (4) 0.10 26 (32) 57 (65) 55 (60) 0.50 27 (29)

Revision hip 6 (8) 9 (10) 4 (4) 0.17 25 (31) 58 (67) 52 (57) 0.21 27 (29)

Total knee 7 (9) 8 (9) 4 (4) 0.23 26 (32) 56 (64) 51 (55) 0.23 26 (28)

Revision knee 4 (5) 8 (9) 4 (4) 0.10 20 (25) 54 (62) 52 (57) 0.39 27 (29)

Hemi knee 2 (3) 6 (7) 2 (2) 0.26 11 (13) 36 (41) 43 (47) 0.50 23 (25)

a Significance of difference between 2007 and 2012 data is calculated

Table 2. Cessation of anticoagulants preoperatively, prior to arthroplasties of hip and knee in the studied orthopaedic departments N,(%)

Anticoagulant Discontinuation of medication Days prior to operationa

2007 2012 Pb 2007 2012 Pb

NSAIDs 36(41) 33(36) 0.54 5.9 (2-10) 4.5 (1-10) 0.03 *

Cox-2 selective NSAIDs NA 37(40) - NA 4.8 (1-14) -

Acetylsalicylic acid 72(83) 50(54) < 0.001 * 7.6 (3-42) 6.8 (5-10) 0.34

Clopidogrel NA 77(84) - NA 6.9 (1-10) -

Dipyridamol NA 64(70) - NA 6.3 (1-10) -

Acenocoumarol 87(100) 90(98) 0.18 5.0 (2-10) 4.6 (2-10) 0.27

Fenprocoumon 87(100) 90(98) 0.18 5.0 (2-10) 6.3 (2-10) 0.27

a Significance of difference between 2007 and 2012 data is calculatedb Mean and range* Significant difference


4

Intraoperative blood-saving measures

Intraoperative retransfusion is predominantly used during revision hip arthroplasty (56% of departments) (Table 3). A further decrease in use of cell saving is observed in primary hip and knee arthroplasty, compared to 2007 and 2002. Normothermia and tourniquets are used by most departments. Tranexaminic acid is used by 8-15%. The use of other techniques, such as epinephrine injections, acute normovolemic hemodilution and controlled hypotension, are listed in Table 3.

Postoperative blood-saving measures

The marked increase in the use of postoperative autologous retransfusion observed in 2007 was maintained, and the majority of departments still uses retransfusion drains in 2012 (Table 4). A slight increase is observed with hemi hip and hemi knee arthroplasty. Blood transfusion was done according to the 4-5-6-transfusion trigger rule [8] in all

Table 3. Intraoperative blood-saving measurements during arthroplasties of hip and knee in the studied orthopaedic departments N,(%)

Arthroplasty Intraoperative retransfusion

TA nT T FG PG Epi AnH CH

‘02 ‘07 ‘12 Pa ‘12 ‘12 ‘12 ‘12 ‘12 ‘12 ‘12 ‘12

Total hip 12(15) 17(19) 13(14) 0.06 13(14) 68(74) NA 0 0 3(3) 11(12) 10(11)

Revision hip 32(40) 47(54) 52(56) 0.73 14(15) 67(73) NA 0 0 2(2) 14(15) 13(14)

Hemi hip 5(6) 10(12) 6(7) 0.07 7(8) 67(73) NA 0 0 2(2) 10(11) 11(12)

Total knee 8(10) 12(14) 8(9) 0.06 11(12) 66(72) 83(90) 1(1) 1(1) 5(5) 11(12) 11(12)

Revision knee 13(16) 21(24) 24(26) 0.85 12(13) 65(71) 80(87) 1(1) 1(1) 2(2) 12(13) 12(13)

Hemi knee 5(6) 10(11) 7(8) 0.17 8(9) 67(73) 78(85) 1(1) 1(1) 3(3) 10(11) 10(11)

a Significance of difference between 2007 and 2012 data is calculatedTA = tranexaminic acid, NT = normothermia, T = tourniquet, FG = fibrin gel, PG= platelet gel, Epi= epinephrine injections or lavage, ANH= normovolemic hemodilution, CH = controlled hypotension

Table 4. Postoperative blood-saving measurements after arthroplasties of hip and knee in the studied orthopaedic departments N,(%)

Arthroplasty Postop. autologous retransfusion

no drain Compressionbandage

Cryo-therapy Legelevation

Fixed flexion knee

2002 2007 2012 Pa 2012 2012 2012 2012 2012

Total hip 11(14) 50(58) 53(58) 0.97 26(28) 28(30) 4(4) NA NA

Revision hip 10(13) 47(54) 49(53) 0.91 19(21) 28(30) 5(5) NA NA

Hemi hip 6(8) 36(41) 43(47) 0.41 26(28) 24(26) 3(3) NA NA

Total knee 19(23) 61(70) 60(65) 0.41 23(25) 58(63) 15(16) 16(17) 1(1)

Revision knee 12(15) 51(59) 56(61) 0.85 17(19) 57(62) 11(12) 13(14) 1(1)

Hemi knee 6(8) 42(48) 49(53) 0.54 27(29) 55(60) 14(15) 16(17) 1(1)

a Significance of difference between 2007 and 2012 data is calculated

44 Chapter 4

departments, except for three. Thirty-three percent of departments used Cox-2 selective NSAIDS postoperatively, instead of non-selective NSAIDS.

COnCLuSIOnS

Principle findings

The use of perioperative blood-saving measures is varied but standard in the Nether-lands. The most-used modalities are erythropoietin, normothermia, tourniquets in knee surgery, retransfusion drains, and the 4-5-6-transfusion trigger. NSAIDS and aspirin are less frequently discontinued preoperatively than before, and effective blood-saving measures such as tranexamic acid are not implemented by the majority of departments.

Strengths and weaknesses

We believe the results of our survey are valid, because the high survey response (84, 79 and 84%) limits non-responder bias. Furthermore, we included a very complete list of possible blood-saving measures. Potential weaknesses are those common to postal sur-veys: lack of control over who completes the questionnaire and potential inaccuracy in the information provided. This represents an audit of practice, without additional infor-mation on the reasons for the responses given. Also, we did not quantify the frequency with which different blood-saving measures were used in individual departments in this and previous surveys.

Meaning of findings

Only two comparable surveys could be identified. A 2006 Scottish questionnaire on hip revision arthroplasty showed that 10 out of 62 (16%) orthopaedic surgeons routinely used intraoperative cell salvage, 11% used postoperative cell savage, 3% routinely used tranexamic acid and 73% used a transfusion protocol [9]. By contrast, our survey shows that 56% of departments uses intraoperative cell salvage and 53% postoperative cell sal-vage. Thirty-two percent of Scottish surgeons stated that cell salvage was not available.The other survey was conducted amongst 81 Dutch orthopaedic departments in January 2012 [10]. Post-operative drainage and retransfusion and erythropoietin were used most frequently, in concordance with our analysis. The frequency of the use of blood saving measures after total hip or total knee arthroplasty was described as frequent (regularly, almost always or always) or non-frequent (never and almost never). No distinction was made between hip and knee surgery, nor between primary or revision surgery. The use of blood saving measures after hemi hip arthroplasty and hemi knee arthroplasty were not investigated.


4

Because blood loss varies between different types of surgery, e.g. hemi knee arthro-plasty or revision hip arthroplasty, blood saving measures also vary: they are tailored to the type of surgery. Therefore in our study more details regarding type of surgery and a wider range of blood saving measures were described. Moreover, we were able to compare data from October 2012 to data from our two previous surveys with exactly the same design.

Preoperative blood-saving measures

Our study shows that only 4% of Dutch orthopaedic departments still uses preoperative blood donation, compared to 10% in 2007. Preoperative blood donation reduces the relative risk of receiving allogeneic blood transfusion. The risk on any transfusion (allo-geneic of autologous), however, is augmented [11]. The infrequent use is in concordance with the Dutch guideline on blood transfusion [12], which advises using this technique with reticence due to complex logistics and relatively high costs.The efficacy of erythropoietin in orthopaedic surgery has been demonstrated in several randomized controlled trials [13-15]. For patients with preoperative Hb>10 to ≤13 g/dl, epoetin alfa therapy dramatically increases perioperative Hb levels and reduces patient exposure to allogeneic blood transfusion [13,15]. Its costs, although reduced, remain an issue. Most departments currently use erythropoietin.According to one report, 23% of patients with preoperative anaemia has an iron defi-ciency [16]. Iron, orally or intravenously supplied, decreases preoperative anaemia and is less expensive than erythropoietin. However, iron is not widely used in the Netherlands, even though the Dutch guidelines [12] advise correcting preoperative iron deficiency at least four weeks prior to major elective surgery.

Intraoperative blood-saving measures

Intraoperative retransfusion is predominantly used during revision hip arthroplasty (56% of departments), when substantial blood loss is to be expected. Intraoperative retransfusion is an effective method to significantly decrease the use of donor blood [12,17-19].Hypothermia reduces the function of thrombocytes and coagulation factors, resulting in increased risk of bleeding [20,21]. Maintaining normothermia therefore aids in the reduction of blood loss. Currently, more than 70% of departments aims to maintain normothermia. When the expected blood loss is at least 40% of circulating blood volume, Acute Nor-movolemic Hemodilution (ANH) is a safe and cheap technique to reduce the amount of allogeneic blood transfusions [22,23]. A reduction of 30% transfusions is observed, but results vary [24,25]. ANH is reportedly the most cost-effective method to reduce the

46 Chapter 4

amount of allogeneic blood transfusions [12,26], but is not used often because of its extensive procedure.Use of fibrin sealant can reduce the number of allogeneic blood transfusions. A Cochrane review and meta-analysis reported that fibrin sealant treatment reduced the rate of allo-geneic red cell transfusions by 54 % on average [27,28]. Other reviews emphasise its very promising use, especially in TKA [29,30], but more high-quality evidence is necessary. Not enough evidence is available to recommend the use of platelet-leucocyte-enriched gel as a local method for haemostasis [12]. Low rates of use in our survey may reflect clinical uncertainty.Another very potent and cost-effective agent to reduce intraoperative blood loss is tranexaminic acid. Even though the Dutch guideline advises using tranexaminic acid, it is not widely used. Tranexaminic acid significantly reduces blood loss, number of blood transfusions and the number of patients that needs a blood transfusion [31] without increasing the risk on thromboembolic events.

Postoperative blood-saving measures

Compared to 2002, in 2007 a dramatic increase in the use of postoperative autologous retransfusion was observed. In 2012, the majority of departments used postoperative autologous retransfusion, as in 2007. This is in accordance with the Dutch guideline, which advises using perioperative auto transfusion in all cases of major surgery in which a great amount of blood loss is to be expected. A slight increase is observed with hemi hip and hemi knee arthroplasty. Reductions in the number of allogeneic blood transfu-sions of 55% are observed in orthopaedic surgery [19].No drainage compared with closed-suction drainage without auto transfusion reduces the transfusion rates from 40% to 31% in THA, and from 50% to 31% in TKA [32]; 19-29% of the departments in our survey did not use a drain. The trigger for postoperative al-logeneic blood transfusion was according to the 4-5-6 rule [8] in all departments, except for three. Restrictive transfusion strategies reduced the risk of receiving a RBC transfu-sion by 39%.The combined use of multiple blood-saving methods is much more effective than a single technique [4,33,34]. With a blood management algorithm, allogeneic red blood cell transfusions can be reduced up to 80% [4,33,34].

In summary, our survey reveals that there is a positive attitude among orthopaedic sur-geons towards blood saving measures. The use of perioperative blood-saving measures is varied but standard in the Netherlands in 2012, just as in 2007. The most-used modali-ties are erythropoietin, normothermia, tourniquets in knee surgery, retransfusion drains, and the 4-5-6-transfusion trigger. NSAIDS and aspirin are discontinued preoperatively


4

less frequently than before, and effective blood-saving measures such as tranexamic acid are not widely implemented.

48 Chapter 4

REFEREnCES

1. Goodnough LT (2003) Risks of blood transfusion. Crit Care Med 31:S678–S686. 2. Shander A, Javidroozi M, Ozawa S, Hare GM (2011) What is really dangerous: anaemia or transfu-

sion? Br J Anaesth Dec;107 Suppl 1:i41-59. 3. Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB (1999) An analysis of

blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 81:2–10.

4. Slappendel R, Dirksen R, Weber EW, van der Schaaf DB (2003) An algorithm to reduce allogeneic red blood cell transfusions for major orthopaedic surgery. Acta Orthop Scand 74:569–575.

5. Blumberg N (1997) Allogeneic transfusion and infection: economic and clinical implications. Semin Hematol 34:34–40.

6. Innerhofer P, Klingler A, Klimmer C, Fries D, Nussbaumer W (2005) Risk for postoperative infec-tion after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopaedic patients undergoing primary arthroplasty. Transfusion 45:103–110.

7. Horstmann WG, Ettema HB, Verheyen CCPM (2010) Dutch orthopaedic blood-management sur-veys 2002 and 2007. An increasing use of blood saving measures. Arch Orth and Trauma Surgery 130(1):55-59.

8. Carson JL, Carless PA, Hebert PC (2012) Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. Apr 18;4:CD002042.

9. Harkness M, Palmer JB, Watson D, Walsh TS (2008) A questionnaire-based survey of perioperative blood conservation practice for revision hip arthroplasty in Scotland. Transfus Med. Oct;18(5):296-301.

10. Voorn VMA, Marang-van de Mheen PJ, Wentink MM, So-Osman C, Vliet Vlieland TPM, Koopman-Van Gemert AWMM, Nelissen RGHH, Van Bodegom-Vos L, the LISBOA study group (2013) Frequent use of blood-saving measures in elective orthopaedic surgery: a 2012 Dutch blood management survey. BMC Musculoskeletal Disorders. Aug 5;14:230.

11. Henry DA, Carless PA, Moxey AJ, O’Connell D, Forgie MA, Wells PS, Fergusson D (2002) Pre-oper-ative autologous donation for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. (2):CD003602. Review.

12. Centraal Begeleidings Orgaan (2011) Guideline Blood Transfusion. 13. Earnshaw P (2001) Blood conservation in orthopaedic surgery: the role of epoetin alfa Interna-

tional Orthopaedics 25:273–278. 14. Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P (2008) Pre-operative

injections of epoetin-alpha versus post-operative retransfusion of autologous shed blood in total hip and knee replacement: a prospective randomised clinical trial. J Bone Joint Surg Br. Aug;90(8):1079-83.

15. Weber EW, Hémon Y, Mähler S, Dalén T, Rouwet E, van Os J, Vosmaer A, van der Ark P (2005) Effects of epoetin alfa on blood transfusions and postoperative recovery in orthopaedic surgery: the European Epoetin Alfa Surgery Trial (EEST). Eur J Anaesthesiol. Apr;22(4):249-57.

16. Saleh E, McClelland DB, Hay A, Semple D, Walsh TS (2007) Prevalence of anaemia before major joint arthroplasty and the potential impact of preoperative investigation and correction on perioperative blood transfusions. Br J Anaesth 99:801-8.

17. Horstmann WG, Swierstra MJ, Ohanis D, Castelein RM, Kollen BJ, Verheyen CC (2013) Reduction of blood loss with the use of a new combined intra-operative and post-operative autologous blood


4

transfusion system compared with no drainage in primary total hip replacement. Bone Joint J. May;95-B(5):616-22.

18. Huët C, Salmi LR, Fergusson D, Koopman-van Gemert AW, Rubens F, Laupacis A (1999) A meta-analysis of the effectiveness of cell salvage to minimize perioperative allogeneic blood transfu-sion in cardiac and orthopaedic surgery. International Study of Perioperative Transfusion (ISPOT) Investigators. Anesth Analg. Oct;89(4):861-9.

19. Carless PA, Henry DA, Moxey AJ, O’Connell D, Brown T, Fergusson DA (2010) Cell salvage for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. Mar 17;(3):CD001888.

20. Corazza ML, Hranchook AM (2000) Massive blood transfusion therapy. AANA J. Aug;68(4):311-4. 21. Eastridge BJ, Malone D, Holcomb JB (2006) Early predictors of transfusion and mortality after

injury: a review of the data-based literature. J Trauma. Jun;60(6 Suppl):S20-5. 22. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, FerrarisVA, Ferraris SP,

Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S (2007) Peri-operative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. May;83(5 Suppl):S27-86.

23. Bryson GL, Laupacis A, Wells GA (1998) Does acute normovolemic hemodilution reduce periop-erative allogeneic transfusion? A meta-analysis. The International Study of Perioperative Transfu-sion. Anesth Analg. Jan;86(1):9-15.

24. Höhn L, Schweizer A, Licker M, Morel DR (2002) Absence of beneficial effect of acute normo-volemic hemodilution combined with aprotinin on allogeneic blood transfusion requirements in cardiac surgery. Anesthesiology. Feb;96(2):276-82.

25. Ramnath AN, Naber HR, de Boer A, Leusink JA (2003) No benefit of intraoperative whole blood sequestration and auto transfusion during coronary artery bypass grafting: results of a random-ized clinical trial. J Thorac Cardiovasc Surg. Jun;125(6):1432-7.

26. Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C (2006) Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model. Health Technol Assess. Nov;10(44):iii-iv, ix-x, 1-210.

27. Carless PA, Henry DA, Anthony DM (2003) Fibrin sealant use for minimising peri-operative al-logeneic blood transfusion. Cochrane Database Syst Rev. (2):CD004171.

28. Carless PA, Anthony DM, Henry DA (2002) Systematic review of the use of fibrin sealant to mini-mize perioperative allogenic blood transfusion, Br J Surg 89:695-703.

29. Patel S, Rodriquez-Merchan EC, Haddad FS (2010) The use of fibrin glue in surgery of the knee, J Bone Joint Surg Br 92:1325-31.

30. Thoms RJ, Marwin SE (2009) The role of fibrin sealants in orthopaedic surgery. J Am Acad Orthop Surg. 17:727-36.

31. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, Ker K (2011) Anti-fibrino-lytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. Mar 16;(3):CD001886.

32. Parker MJ, Livingstone V, Clifton R, McKee A (2007) Closed suction surgical wound drainage after orthopaedic surgery. Cochrane Database Syst Rev. Jul 18;(3):CD001825

50 Chapter 4

33. Wong CJ, Vandervoort MK, Vandervoort SL, Donner A, Zou G, MacDonald JK, Freedman J, Karkouti K, MacDonald SJ, Feagan BG (2007) A cluster-randomized controlled trial of a blood conservation algorithm in patients undergoing total hip joint arthroplasty. Transfusion 47(5):832–841.

34. Pierson JL, Hannon TJ, Earles DR (2004) A blood-conservation algorithm to reduce blood transfu-sions after total hip and knee arthroplasty. J Bone Joint Surg Am 86-A(7):1512–1518

5

Comparing consensus guidelines on thromboprophylaxis in

orthopedic surgery

MC Struijk-Mulder,1 HB Ettema,1 CC Verheyen1 and HR Büller2

1 Department of Orthopedic Surgery, Isala Clinics, Zwolle, the Netherlands2 Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands

Journal of Thrombosis and Heamostasis. 2010; 8: 678–83.

52 Chapter 5

ABSTRACT

Background

Different guidelines exist regarding the prevention of venous thrombo embolism (VTE) in orthopedic surgery.

Objectives

We aim to compare (in ter)national guidelines and analyse their differences.

Methods

MEDLINE, the Cochrane Library and the internet were searched for guidelines on the prevention of VTE in orthopedic surgery. From these, we constructed a table comparing the different antithrombotic regimens during different orthopedic surgical and plaster cast treatments.

Results

Eleven guidelines from nine different countries and one international guideline were included. Few guidelines advise on thromboprophylaxis after plaster cast immobiliza-tion, (prolonged) arthroscopic surgery and isolated lower extremity trauma. Different opinions exist on the sole use of aspirin and mechanical prophylaxis and on the use of vitamin K antagonists after major hip and knee surgery.

Conclusion

Based on the same available literature, different guidelines recommend different throm-boprophylactic regimens. Ideally, the grade of recommendation should be based on the same level of evidence world-wide. Whilst there is no agreement on the relevance of different endpoints (e.g. asymptomatic DVT), it is very difficult to reach consensus. Thromboprophylaxis guidelines should be reviewed and updated on a regular basis, because the evidence is evolving rapidly.

Comparing consensus guidelines on thromboprophylaxis in orthopedic surgery 53

5

InTRODuCTIOn

Venous thromboembolism (VTE) is a serious complication of orthopedic surgery. a-symptomatic VTE is detected by means of venography in 10–40% of hospitalized patients and occurs in up to 40–60% of patients that undergo orthopedic surgery when no prophylaxis is used [1]. When thromboprophylaxis is administered, 1–10% of patients develop symptomatic VTE within the 3 months after surgery [1]. As many VTEs occur after discharge, orthopedic surgeons may have a falsely low perception of the rate of thrombosis in their practise. Understandably, orthopedic surgeons are concerned about complications such as major bleeding and wound infection associated with the use of pharmacological thromboprophylaxis. Why do surgeons have different views on the use of aspirin, heparin and vitaminK antagonists (VKA) when considering the same body of evidence? This article aims to compare both national and international guidelines on thromboprophylaxis, and to interpret their differences.

METHODS

PubMed, the Cochrane Library and the internet (using the Google search engine) were searched in February 2009 for various national and international guidelines on the prevention of VTE in orthopedic surgery. The following search terms were used: thrombosis, prophylaxis and guideline. Only guidelines considering orthopedic surgery were included. Different national medical associations’ websites were also searched. Only open access guidelines in English or German were included. It was not intended to search all countries in the world: we selected major European countries and a selec-tion of countries from each continent, as well as the most well-known and most cited guidelines.

RESuLTS

Eleven guidelines from the following associations were included: The American College of Chest Physicians (ACCP)[1], the American Academy of Orthopaedic Surgeons (AAOS) [2], the Cardiovascular Disease Educational and Research Trust (ICS) [3], the National Institute for Clinical health and Excellence (NICE, United Kingdom) [4], the Scottish In-tercollegiate Guidelines Network (SIGN) [5], Die Arbeitsgemeinschaft der Wissenschaftli-chen Medizinischen Fachgesellschaften (AWMF, Germany) [6], Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV) [7], the South African Society of Thrombosis and Haemostasis [8], Medical Front International Limited (Japan) [9], the French Society

54 Chapter 5

Tabl

e 1.

Ove

rvie

w o

f gui

delin

es o

n pr

even

tion

of th

rom

bo e

mbo

lism

Inte

rven

tion

Prop

hyla

xis

ACC

PA

AO

SA

us/n

Zn

ice

ICS

Fran

ceBr

azil

S.A

fric

aJa

pan

Ger

man

ySI

Gn

Tota

l Hip

Art

hrop

last

yH

epar

inx

xx

xx

xx

xx

xx

Fond

apar

inux

xx

xx

xx

x

VKA

xx

xx

xx

x

Asp

irin

xx

x

Tota

l Kne

eA

rthr

opla

sty

Hep

arin

xx

xx

xx

xx

xx

x

Fond

apar

inux

xx

xx

xx

x

VKA

xx

xx

xx

x

Asp

irin

xx

Hip

frac

ture

surg

ery

Hep

arin

xx

xx

xx

x

Fond

apar

inux

xx

xx

xx

VKA

xx

x

Asp

irin

x

Knee

arth

rosc

opy

Non

ex

xx

xx

Hep

arin

RFRF

RF

Imm

obil.

low

er e

xtr.

Non

ex

xx

Hep

arin

RFx

Fond

apar

inux

x

VKA

x

VKA

= v

itam

in K

ant

agon

ist

RF=

if ri

sk fa

ctor

s ar

e pr

esen

t


5

Tabe

l 2. C

ompa

rison

of g

rade

s of

reco

mm

enda

tion

betw

een

guid

elin

es

Gra

deM

etho

dolo

gica

l str

engt

h of

sup

port

ing

evid

ence

ACC

PA

AO

SIC

SFr

ance

Braz

ilSI

Gn

ARC

Ts: c

onsi

sten

t res

ults

RCTs

: con

sist

ent r

esul

tsRC

Ts: c

onsi

sten

t res

ults

RCTs

Expe

rimen

tal s

tudi

es,

best

qua

lity

1 hi

gh q

ualit

y RC

T

Met

a-an

alys

is R

CTs

Obs

erva

tiona

l stu

dies

, be

st q

ualit

yM

eta-

anal

ysis

RC

Ts

Revi

ew o

f RC

Ts

BRC

Ts: i

ncon

sist

ent r

esul

tsCo

hort

: con

sist

ent r

esul

tsRC

Ts: l

ess

cons

iste

nt

resu

ltsRC

Ts: l

ow p

ower

Expe

rimen

tal s

tudi

es,

low

qua

lity

RCTs

, ext

rapo

late

d

RCTs

: maj

or m

etho

dolo

gica

l w

eakn

esse

sCa

se c

ontr

ol: c

onsi

sten

t res

ults

RCTs

: met

hodo

logi

cal

wea

knes

ses

Non

-ran

dom

ized

con

trol

led

tria

lsO

bser

vatio

nal s

tudi

es,

low

qua

lity

Revi

ew

Coho

rt s

tudi

esCa

se s

erie

sCa

se c

ontr

ol, l

ow ri

sk o

f bia

s

CO

berv

atio

nal s

tudi

esCa

se s

erie

sO

bser

vatio

nal s

tudi

esCa

se c

ontr

olCo

hort

, low

risk

of b

ias

Expe

rt o

pini

onCo

ntro

lled

stud

ies

with

bia

s

Retr

ospe

ctiv

e st

udie

s an

d ca

se s

erie

s

Obs

erva

tiona

l ep

idem

iolo

gica

l stu

dies

DEx

pert

agr

eem

ent

Expe

rt o

pini

onEx

pert

opi

nion

Case

ser

ies

Aust

ralia

/New

Zea

land

, NIC

E, S

outh

Afr

ica,

Japa

n an

d G

erm

any

did

not g

ive

grad

es o

f rec

omm

enda

tion.

56 Chapter 5

for Anaesthesiology and Intensive Care (SFAR) [10] and the Australia and New Zealand working party on the management and prevention of venous thromboembolism [11]. Table 1 summarizes the different regimens recommended by these guidelines.The grades of recommendation for the thromboprophylaxis regimens proposed are defined differently in the guidelines. The level of evidence for each grade also varies between the guidelines. An overview is provided in Table 2. Those guidelines not men-tioned in Table 2 did not specify the level of evidence for their recommendations.

Total hip arthroplasty (THA)

Most guidelines agree on the use of mechanical prophylaxis as a possible additional antithrombotic measure to pharmacological thromboprophylaxis with either heparin, fondaparinux or VKA. The recommended duration of thomboprophylaxis varies from 7 to 42 days for heparin, and from 10 to 35 days for fondaparinux. Despite this, most guidelines do not advise about the optimal duration of thromboprophylaxis. The ACCP, ICS, SIGN, the French and the Brazilian guidelines, however, also support the use of mechanical devices without pharmacological prophylaxis in patients at a high risk of bleeding. The ICS states that Foot Impulse Technology (FIT) or Intermittent Pneumatic Compression (IPC) combined with Graduated Elastic Compression Stockings (GECS) represent an alternative to low-molecular-weight heparin (LMWH) (Grade A recommen-dation, Table 2). They can be used as long as tolerated and, thereafter, replaced by phar-macological prophylaxis for the proceeding post-operative 5 weeks. The ICS guidelines do not cite any data that compare IPC with pharmacological prophylaxis. FIT combined with GECS is probably superior to unfractionated heparin [12] and equivalent to LMWH [13,14] (Grade A). The SIGN guidelines state that foot pumps are more effective, while IPC is less effective in the prevention of proximal deep vein thrombosis (DVT) (Grade A). For this, they recommend the use of IPC in combination with GECS or foot pumps. The Japanese guidelines advise use of IPC in patients undergoing orthopedic surgery of the lower extremities without pharmacological prophylaxis. They report a lower incidence of VTE in the Japanese population due to a lower incidence of genetic abnormalities in clotting factors when compared with Western countries. Alternatively in Japan, low-dose unfractionated heparin can be used.

Total knee arthroplasty (TKA)

Most guidelines advise some form of pharmacological thromboprophylaxis after TKA, much like the recommendations for THA. Interestingly, the ACCP, ICS, SIGN, and the Bra-zilian and Japanese guidelines all recommend the sole use of mechanical prophylaxis as an alternative to pharmacological prophylaxis, whereas the other guidelines do not. This recommendation is based on five studies based on small sample sizes that show that IPC, started intra-operatively or immediately after surgery and continued until full


5

ambulation, is an effective means of thromboprophylaxis [1]. To date, the use of IPC alone has not been compared with combined thromboprophylaxis with IPC and either LMWH or adjusted-dose VKA in a randomized clinical trial (RCT). As the estimates of VTE protection by IPC are based on RCTs with small sample size, inconsistent results or major methodological weaknesses, mechanical prophylaxis received a lower grade of recommendation (Grade B). Furthermore, due to poor compliance, patient intolerance and the inability for treatment to be continued after hospital discharge, IPC is recom-mended as an alternative only to pharmacological thromboprophylaxis in patients at high risk of bleeding when pharmacological prophylaxis is not advisable. Due to the inferior efficacy, ACCP advises against the sole use of venous foot pumps (Grade A). The SIGN guidelines recommend GECS with or without IPC and foot pumps (Grade A). The ICS advises the use of IPC or FIT plus GECS as an alternative for pharmacological prophylaxis in TKA, but they state that more studies are needed (Grade B). Hip fracture surgery (HFS) HFS was not addressed in every guideline. Most of the guidelines advise the same regime as is recommended for THA.The French guideline and SIGN state that VKA should not be used as a first line pro-phylaxis in HFS for logistic reasons (such as monitoring), and because of a higher risk of bleeding associated with the use of VKA (Grade A). ACCP and the French guidelines prefer fondaparinux (Grade A) rather than LMWH(Grade B and C, respectively). The ACCP and the ICS advice the use of mechanical prophylaxis without pharmacological agents in the case of a high risk of bleeding (Grade A). The Australian/New Zealand guidelines, NICE and SIGN advise use of mechanical prophylaxis in addition to pharmacological prophylaxis.

Knee arthroscopy

Only five of the 11 guidelines examined actually addressed this type of surgery. Gen-erally, thromboprophylaxis is only advised when concomitant risk factors are present [Grade A (Brazil), B (ACCP and ICS)]. Few data exist on prolonged arthroscopic proce-dures, such as anterior cruciate ligament reconstruction and arthroscopically assisted repair of tibia plateau fractures. Due to the longer operation time and more extensive surgery, the ACCP (Grade B) and the ICS guidelines advise use of LMWH prophylaxis, but do not provide recommendation on the duration of prophylaxis.

Plaster cast immobilization and isolated lower extremity injuries

Plaster cast immobilization is regarded as representing a moderate risk for thrombosis [1]. Thromboprophylaxis during plaster cast immobilization is only recommended by the German and the French guidelines. The German guidelines advise the use of pharmacological thromboprophylaxis in joint-immobilizing plaster casts, whereas the French guidelines advise starting prophylaxis in lower limb fractures (Grade B) and knee

58 Chapter 5

injuries without fracture, irrespective of any risk factors present (grade D). With regard to isolated lower extremity injuries treated with or without operation and/or plaster cast immobilization, the ACCP guidelines advise not to give routine prophylaxis (Grade 1A). They state that it is uncertain whether thromboprophylaxis reduces clinically significant DVT or whether it is cost effective. The ICS guidelines advise LMWH if risk factors are present.

Aspirin

The AAOS, the SIGN and the Brazilian guidelines are the only ones to recommend aspirin as the sole measure of thromboprophylaxis (Grade B, A and A, respectively). The AAOS states that the presumed direct pathophysiologic link between DVT and pulmonary em-bolism (PE) has not been proven by clinical observation in joint replacement. Therefore, all studies investigating DVT rates using venography and compression ultrasonography (CUS) to assess asymptomatic thromboembolism as an endpoint are not regarded as relevant and are therefore not taken into account. To date, no RCT investigates the rate of (fatal) PE using LMWH, fondaparinux, VKA, mechanical devices or aspirin alone, because of the large number of patients needed. The 90-day non-fatal PE rate after total hip and knee surgery without prophylaxis is 0.93% and 0.41%, respectively, according to two register-based studies [15,16]. According to the AAOS, only the incidence of major bleeding under different prophylactic regimens can be retrieved from the literature, whereas the rate of PE cannot be assessed adequately. Based on two studies, aspirin is recommended because it causes less bleeding, although it does not reduce the risk of DVT [17,18]. When an elevated risk for PE is present, aspirin is not recommended. The ACCP and the French guidelines on the other hand advise clearly against the use of aspirin as the sole method of thromboprophylaxis (Grade A and B, respectively). The ACCP guideline states that aspirin is less effective than other thromboprophylactic regimens [19,20]. The efficacy of aspirin in preventing asymptomatic DVT (as detected by venography) has never been evaluated in an RCT.

DISCuSSIOn

Agreements between guidelines

THA, TKA and HFS All guidelines agree that heparin can be used for thromboprophylaxis in THA and TKA (Grade A). LMWH is the most intensively studied thromboprophylactic agent [1]. Pooled data from five large clinical trials [1] comparing adjusted dose warfarin thromboprophylaxis with LMWH among 2979 total hip replacement patients show that the respective rates of all DVT were 20.7% and 13.7% (P = 0.0002). Major bleedings oc-curred in 3.3% of the VKA recipients and 5.3% of the LMWH recipients (P = 0.002).


5

The pentasaccharide, fondaparinux, was approved by the American Food and Drug As-sociation in 2001. Fondaparinux is regarded as an equal alternative to LMWH by all six guidelines developed from 2006 onward, except for the 2006 ICS guideline that gives a grade B recommendation for TKA because only one study was available at that time. The German guidelines are another exception, as they were developed in 2003. These appear to have been updated in 2008, but it is not clear whether new drugs were included. In HFS, heparin and fondaparinux are the most commonly recommended pharmacological antithrombotic agents. Major drawbacks of VKAs are logistic difficulties and the higher risk of bleeding, according to the French and SIGN guidelines (Grade A).

Knee arthroscopy

Thromboprophylaxis is only advised when risk factors are present [Grade A (Brazil), B (ACCP and ICS)]. Simple knee arthroscopy is associated with a low risk of thrombosis. Pooled data from prospective studies of knee arthroscopy reveal rates of 9% of asymp-tomatic DVT and 3% of asymptomatic proximal DVT using venography and 5% and 0.7%, respectively, when detected by CUS [1]. Two out of three RCTs on thromboprophylaxis following knee arthroscopy showed no significant difference in the incidence of VTE in patients treated with LMWH or placebo/GECS [1].

Disagreements between guidelines

THA and TKA VKAs are recommended in THA and TKA in seven out of 11 guidelines. The ICS prefers LMWH and fondaparinux above VKA in THA, because two large stud-ies showed less efficacy and higher rates of major bleeding with VKA compared with LMWH[21,22]. Moreover, warfarin was identified as a major risk factor for readmission and fatal bleeding in national registries [23,24]. When a high bleeding risk is present in THA, the sole use of mechanical devices for thromboprophylaxis is recommended by five guidelines. In TKA, mechanical devices without pharmacological prophylaxis are recommended in five guidelines, irrespective of the bleeding risk. However, the level of evidence for the sole use of mechanical devices is lower than that for pharmacological prophylaxis. Due to a lower incidence of genetic abnormalities of clotting factors com-pared with Western countries, Japan reports having a lower incidence of VTE, justifying their use of mechanical devices alone.

Plaster cast immobilization and isolated lower extremity injuries

Only four guidelines give advice on thromboprophylaxis for patients with plaster cast immobilization and isolated lower extremity injuries. Most guidelines recommend against the use of thromboprophylaxis, although some guidelines make exceptions for patients with risk factors, fractures or joint immobilizing casts. Recent evidence suggests that thromboprophylaxis is effective in reducing the rate of VTE during immobilization

60 Chapter 5

of the lower extremities [25,26]. In a recent meta-analysis [25], 1456 patients from six randomized trials were included. In four studies venography was used to detect asymptomatic DVT and two studies used ultrasonography, while positive results were confirmed by venography. The mean rate of VTE reduced from 17.1% to 9.6% with the use of LMWH. The frequency of bleeding did not seem to increase with LMWH. A 2009 Cochrane review [26] reported an incidence of VTE ranging from 4.3% to 40% in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least 1 week and who received no prophylaxis or placebo. This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization (event rates ranging from 0% to 37%; odds ratio 0.49).

Aspirin

The main issue leading to conflicting recommendations on the use of aspirin is whether there is a relationship between asymptomatic DVT detected by venography or CUS and clinically important VTE (symptomatic DVT and PE). The ACCP, for instance, states that there is a strong relationship between asymptomatic DVT and symptomatic DVT and PE [27]. In contrast, the AAOS concludes that there is no convincing evidence linking asymptomatic DVT to clinically relevant symptomatic DVT and PE. The ACCP seems to put a greater emphasis on the effective reduction of VTE, and the AAOS seems more concerned with bleeding complications. Both VTE and bleeding risk are, of course, very important considerations when selecting thromboprophylaxis. The mix of hematolo-gists and orthopedic surgeons on the specific committees seems a possible explanation for the different views. Another consideration is that a high grade of recommendation can be given against the use of aspirin as a thromboprophylactic agent when the results of high quality RCTs based on asymptomatic VTE are taken into account [20,28–31]. When the evidence from these trials is discarded, only a grade B recommendation in favour of aspirin remains.

The future

In order to avoid major disagreements between guidelines, several aspects need to be addressed. First, it is necessary to agree on one universal definition for grades of rec-ommendation for different regimens. The grade of recommendation should ideally be based on the same level of evidence. Second, it will be very difficult to reach a consensus whilst there is no agreement on the relevance of different endpoints (e.g. asymptomatic DVT). Finally, guidelines should be updated continuously as new evidence becomes available. Still, local differences will exist due to differences in healthcare systems, avail-ability of drugs or devices, and regional variations in risk factors for the development of VTE. Newer oral antithrombotic drugs such as direct thrombin and factor Xa inhibitors are not yet included in the abovementioned guidelines, although numerous studies


5

have been conducted since 2002. Recently, both dabigatran (an oral thrombin inhibitor) and rivaroxaban (an oral Xa inhibitor) have registered in Europe for thromboprohylaxis in orthopedic surgery patients.

In summary, based on the same available evidence, different guidelines advise different regimens of thromboprophylaxis following orthopedic procedures. Thromboprophy-laxis guidelines should be reviewed and updated on a regular basis, so that all available evidence is assessed and to make sure that patients receive the highest quality and safest care possible.

62 Chapter 5

REFEREnCES

1 Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of ve-nous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl.): 381S–453S.

2 American Academy of Orthopedic Surgeons (US). American Academy of Orthopedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty [Internet]. 2007. p 63. http://www.aaos.org/Research/guidelines/PE_guideline.pdf.

3 Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educa-tional and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlebologie. Prevention and treat-ment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol. 2006; 25: 101–61.

4 National Institute for Health and Clinical Excellence. NICE Clinical guideline 46. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery [Internet]. London, 2007. p. 163. http://www.nice.org.uk/Guidance/CG46/Guidance/pdf/English.

5 Scottish Intercollegiate Guidelines Network. Prophylaxis of venous thromboembolism. SIGN guideline No. 62 [Internet]. Edinburgh, 2002. p. 51. http://www.sign.ac.uk/pdf/sign62.pdf ISBN 189989932.

6 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (Germany). Stationäire und ambulante Thromboembolie-Prophylaxe in der Chirurgie und der perioperativen Medizin [Internet]. 2003. p. 12. http://leitlinien.net/.

7 Grupo de Elaboração de Normas de Orientação Clínica em Trombose Venosa Profunda da SBACV. Normas de orientação clínica para prevenção, diagnóstico e tratamento da trombose venosa profunda (revisão)[Internet]. Maffei FHA, Caiafa JS, Ramacciotti E, Castro AAl. Salvador (Brazil). 2001 [revised 2005 April 2]; [cited 2009 Feb]. 16 p. Available from: http://www.sbacv-nav.org.br.

8 Southern African Society of Thrombosis and Haemostasis. Guideline for prophylactic anticoagu-lation. S AfrMed J. 2004; 94: 691–5.

9 Kobayashi T,Nakamura M, Sakuma M, Yamada N, SakonM, Fujita S, Seo N. Incidence of pulmonary thromboembolism (PTE) and new guidelines for PTE prophylaxis in Japan. Clin Hemorheol Micro-circ 2006; 35: 257–9.

10 Samama CM, Albaladejo P, Benhamou D, Bertin-Maghit M, Bruder N, Doublet JD, Laversin S, Leclerc S, Marret E, Mismetti P, Samain E, Steib A. Committee for Good Practice Standards of the French Society for Anaesthesiology and Intensive Care (SFAR). Venous thromboembolism prevention in surgery and obstetrics: clinical practice guidelines. Eur J Anaesthesiol 2006; 23: 95–116.

11 The Australia and New Zealand working party on the Management and Prevention of Venous Tromboembolism. Prevention of Venous Thromboembolism [Internet]. Australia: Health Educa-tion and Management Innovations: 2007. p. 20. http://www.safetyandquality.health.wa.gov.au/docs/squire/14.%20ANZ%20Prevention%20of%20VTE%20Ed3%202005.pdf. ISBN 0957890915.

12 Santori FS, Vitullo A, Stopponi M, Santori N, Ghera S. Prophylaxis against deep vein thrombosis in total hip replacement. Comparison of heparin and foot impulse pump. J Bone Joint Surg Br 1994; 76: 579–83.


5

13 Pitto RP, Hamer H, Heiss-Dunlop W, Kuehle J. Mechanical prophylaxis of deep-vein thrombosis after total hip replacement a randomised clinical trial. J Bone Joint Surg Br 2004; 86: 639–42.

14 Warwick D. Intermittent pneumatic compression prophylaxis for proximal deep venous thrombo-sis after total hip replacement. J Bone Joint Surg Am 1998; 80: 141–2.

15 Katz JN, Losina E, Barrett J, Phillips CB, Mahomed NN, Lew RA, Guadagnoli E, Harris WH, Poss R, Baron JA. Association between hospital and surgeon procedure volume and outcomes of total hip replacement in the United States medicare population. J Bone Joint Surg Am 2001; 83: 1622–9.

16 SooHoo NF, Lieberman JR, Ko CY, Zingmond DS. Factors predicting complication rates following total knee replacement. J Bone Joint Surg Am 2006; 88: 480–5.

17 Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21: 139–43.

18 Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452: 175–80.

19 Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophy-laxis among surgical and medical patients. BMJ 1994; 308: 235–46.

20 Powers PJ, Gent M, Jay RM, Julian DH, Turpie AG, Levine M,Hirsh J.A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med 1989; 149: 771–4.

21 Mismetti P, Laporte S, Zufferey P, Epinat M, Decousus H, Cucherat M. Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis. J Thromb Haemost 2004; 2: 1058–70.

22 Samama CM, Vray M, BarreL J, Fiessinger JN, Rosencher N, Lecompte T, Potron G, Basile J, Hull R, Desmichels D; SACRE Study Investigators. Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecularweight heparin with oral anticoagulant. Arch Intern Med 2002; 162: 2191–6.

23 Budnitz DS, Pollock DA, Mendelsohn AB, Weidenbach KN, McDonald AK, Annest JL. Emergency department visits for outpatient adverse drug events: demonstration for a national surveillance system. Ann Emerg Med 2005; 45: 197–206.

24 Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004; 329: 15–9.

25 Ettema HB, Kollen BJ, Verheyen CC, Büller HR. Prevention of venous thromboembolism in patients with immobilization of the lower extremities: a meta-analysis of randomized controlled trials. J Thromb Haemost 2008; 6: 1093–8.

26 Testroote M, Stigter W, De Visser DC, Janzing H. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database of Syst Rev 2008;CD006681.

27 Quinlan DJ, EikelboomJW, Dahl OE, Eriksson BI, Sidhu PS, Hirsh J.Association between asymptom-atic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. J Thromb Haemost 2007; 5:1438–43.

28 Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embo-lism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) Trial. Lancet 2000; 355: 1295–302.

64 Chapter 5

29 Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total knee arthroplasty: pneumatic planter compression and aspirin compared with aspirin alone. J Bone Joint Surg Am 1996; 78:826–34.

30 Graor RA, Stewart JH, Lotke PA. RD heparin (ardeparin sodium) vs aspirin to prevent deep venous thrombosis after hip or knee replacement surgery [abstract]. Chest 1992; 102: 118S.

31 Gent M, Hirsh J, Ginsberg JS, Powers PJ, Levine MN, Geerts WH, Jay RM, Leclerc J, Neemeh JA, Turpie AG. Low-molecular-weight heparinoid orgaran is more effective than aspirin in the pre-vention of venous thromboembolism after surgery for hip fracture. Circulation 1996; 93: 80–4.

6

Deep Vein Thrombosis After Arthroscopic Anterior Cruciate

Ligament Reconstruction: A Prospective Cohort Study of 100 Patients

MC Struijk-Mulder1, M.D., HB. Ettema1, M.D., Ph.D., CCPM Verheyen1, M.D., Ph.D., and HR Büller2, M.D., Ph.D.

1 Department of orthopaedic surgery and traumatology, Isala Klinieken, Zwolle, the Netherlands2 Department of vascular medicine, Academic Medical Centre, Amsterdam, the Netherlands

Arthroscopy. 2013; 29(7):1211-1216.

66 Chapter 6

ABSTRACT

Purpose

To establish the incidence of venous thromboembolic complications as detected by bilateral complete compression ultrasonography (CCUS) after arthroscopic anterior cruciate ligament (ACL) reconstruction without thromboprophylaxis.

Methods

We performed a prospective cohort study to establish the incidence of venous throm-boembolic complications after arthroscopic ACL reconstruction, as detected by bilateral CCUS at 14 days (range 11 to 17 days) postoperatively. One hundred consecutive pa-tients underwent bilateral extended ultrasonography.

Results

One hundred predominantly European patients with a mean age of 30 ± 10 years and mean body mass index of 25 ± 4 underwent ACL reconstruction with a mean opera-tive duration of 68 ± 23 minutes and a tourniquet time of 76 ± 23 minutes. In 84% of patients an autologous hamstring graft was used, in 14% a bone-patellar tendon-bone graft was used, and 2 patients received an allograft. Of 100 patients, 9 (incidence 9%; 95% confidence interval 4.2-16.4) showed asymptomatic proximal or distal deep vein thrombosis on CCUS, of whom 4 (incidence 4%; 95% confidence interval 1.1-9.9) were symptomatic. A nonfatal pulmonary embolus developed in 1 patient during the 8-week follow-up period.

Conclusions

This study shows that the incidence of venous thromboembolism after arthroscopic ACL reconstruction is relatively high: a 9% incidence of asymptomatic proximal or distal deep vein thrombosis was found, whereas 4% of patients were symptomatic. Further research is recommended to assess the need for thromboprophylaxis in patients undergoing ACL reconstruction, especially when risk factors are present.

Deep vein thrombosis after arthroscopic anterior cruciate ligament reconstruction 67

6

InTRODuCTIOn

Without prophylaxis, the risk of venographically detected deep vein thrombosis (DVT) ranges from 40% to 70% after major orthopaedic procedures, such as total hip and knee arthroplasty. Therefore, after joint replacement, it is standard practice to use pharmaco-logic thromboprophylaxis.1-3 After routine arthroscopy without ligament reconstruction, the risk of symptomatic venous thromboembolism (VTE) appears to be rather low (1.5% to 2%).1,4 The risk of asymptomatic DVT ranges from 5% to 18% depending on the screen-ing method and population studied.4-8 Generally, thromboprophylaxis is not advised for routine arthroscopy in the absence of additional risk factors,1,4 such as tourniquet time greater than 1 hour, history of VTE, age greater than 65 years, obesity, smoking, female hormone intake, and venous insufficiency.7,8

Arthroscopically assisted arthroscopic anterior cruciate ligament (ACL) reconstruction is considered less traumatic to an extremity than joint arthroplasty but more traumatic than uncomplicated arthroscopic procedures such as meniscectomy, in which no os-seous drilling is required. There is a possibility that the incidence of thromboembolic events may actually be increased after knee ligament surgery versus routine arthroscopy. Moreover, ACL reconstruction can be associated with hemarthrosis and postoperative leg swelling and, therefore, may complicate the accurate clinical diagnosis of DVT. Cur-rently, there are few studies regarding the incidence of asymptomatic DVT after ACL reconstruction without thromboprophylaxis.8-11 The incidence ranges from 0% to 33% depending on the screening method. The symptomatic 90-day pulmonary embolus (PE) rate in population-based studies ranges from 0.028% to 0.18%.12-14

There is no consensus regarding the need for perioperative thromboprophylaxis after ACL reconstruction.1,4 The aim of our study was to establish the incidence of venous thromboembolic complications as detected by bilateral complete compression ultraso-nography (CCUS) after arthroscopic ACL reconstruction without thromboprophylaxis. We hypothesized that the incidence of VTE after ACL reconstruction would be higher than the previously reported incidence of VTE after routine knee arthroscopy for men-iscectomy.

METHODS

A consecutive cohort of patients aged 16 years or older who met our inclusion criteria and underwent arthroscopically assisted ACL reconstruction received bilateral CCUS approximately 14 days after the procedure (range, 11 to 17 days). Clinical data including date of birth, sex, race, weight, and height were recorded at entry. Patients meeting one of the following criteria were excluded from the study: inability or unwillingness

68 Chapter 6

to give written informed consent, inability to be followed up, ongoing treatment with anticoagulant therapy (excluding aspirin), any other cause of immobility, and a history of DVT. Exclusion criteria were limited, to keep selection bias to a minimum.We used a single-incision, arthroscopically assisted surgical technique, using autolo-gous hamstring tendon, bone-patellar tendon-bone, or allograft and a tourniquet. Con-comitant treatments (such as meniscectomy), operative time, and tourniquet time were recorded. An intra-articular drain was inserted and was removed on the first postopera-tive day. No brace or knee immobilizer was used postoperatively. Patients started full weight bearing and physiotherapy including active motion exercises and thigh muscle strengthening on the first postoperative day. Patients were encouraged to move as much as tolerated. No limitations were placed on motion or ambulatory status, regard-less of concomitant procedures. A pain protocol with acetaminophen was followed, and patients were allowed to use nonsteroidal anti-inflammatory drugs according to their need. Physiotherapy was continued for 6 months. Patients were admitted to the hospital for 1 or 2 days. No thromboprophylaxis was given, either during the hospital stay or after discharge. Compression stockings were not used.Two follow-up contacts were scheduled, when CCUS was performed and after 8 weeks in the outpatient clinic. Patients were asked whether they had had any clinical signs or symptoms of VTE after the operation. The clinical signs documented were pain, tender-ness, swelling or redness of the legs, dyspnea, chest pain, and hemoptysis. In addition, patients were instructed to contact the hospital if one of these signs or symptoms oc-curred before a follow-up contact. Three ultrasonography technicians performed CCUS of the leg veins. All of them received a supervised period of training before participating as sonographers in this study. The ultrasonography device used was a 3- to 9-MHz sonographic scanner (Philips IU22, L9-3 linear array probe; Philips Medical Systems, Best, the Netherlands). A standardized protocol for CCUS was applied,15 requiring an examination time of approximately 40 minutes for both legs.The criterion for the diagnosis of DVT was the inability to compress the veins with the ultrasonography transducer. Ultrasonography findings were recorded as normal (nega-tive), abnormal (positive), or inadequate for interpretation if a complete vein or segment of a vein could not be visualized. A venous thrombus was classified as proximal throm-bosis (with or without concomitant calf vein thrombosis), isolated calf vein thrombosis, or muscle vein thrombosis. The proximal venous system was defined as the deep veins in the pelvis, the thigh, and the popliteal region cephalad to the trifurcation of the calf veins.The primary outcome measure of the study was the combined incidence of symp-tomatic and asymptomatic venous thromboembolic complications and death after arthroscopically assisted ACL reconstruction of the knee during the 2-week follow-up


6

period (as diagnosed by a single postoperative compression ultrasonography scan [CCUS]). The secondary outcome measure was the incidence of symptomatic venous thromboembolic complications and death after arthroscopy of the knee during the 8 weeks of follow-up. The primary safety outcome measure was the cumulative incidence of major bleeding events and clinically relevant non-major bleeding events. A major bleeding event was defined as a clinically overt hemorrhage associated with a decrease in hemoglobin level requiring transfusion, a bleeding event requiring reintervention, or a hemarthrosis with joint drainage of more than 250 mL. A clinically relevant non-major bleeding event was defined as a hemarthrosis with joint drainage of 100 to 250 mL that did not require reintervention. This is an observational cohort study, but because ultrasonography was performed, informed consent was requested and the study was approved by the local ethics com-mittee.

Statistical Analysis

Because the expected incidence of DVT after ACL reconstruction was unknown, we calculated the sample size, presuming an incidence of 10%. With a sample size of 100 patients, a sufficiently narrow confidence interval (CI) was reached. The analysis was an intention-to-treat analysis. Incidences are presented as a proportion of the studied population. We calculated 95% CIs using CIA software (BMJ Books, London, England) using the exact method. Continuous variables were compared by use of the Student t test or, in the case of an abnormal distribution, the Mann-Whitney U test. Categorical data were compared with cross tabulation (χ2 and Fisher exact test).

RESuLTS

During the study period, 120 consecutive patients were scheduled for arthroscopic ACL reconstruction. A total of 18 patients met one or more of the exclusion criteria: age under 16 years (1 patient), use of anticoagulant therapy (1 patient), another cause of immobili-zation (2 patients), inability to provide informed consent (8 patients), and inability to be followed up (6 patients). Thus, 102 patients were included and gave their consent. The mean duration of hospital stay was 1.1 days (range, 1 to 5 days). One additional patient was excluded because of a conversion perioperatively to another procedure. The other patient did not present for the ultrasonography investigation. Ultimately, 100 patients were included for the analysis of the primary outcome. Three patients inadvertently received 1 dose of low molecular weight heparin (LMWH) the evening after surgery, but they were included in the present intention-to-treat analysis. The baseline characteris-tics of the 100 patients who completed the ultrasonography studies are listed in Table 1.

70 Chapter 6

Table 1. Baseline demographic and operation characteristics

All Patients (n=100)

Patients without VTE (n=91)

Patients with VTE (n=9)

Age in yrs, mean ± SD 30 ± 10 30 ± 10 38 ± 12*

BMI, mean ± SD 25 ± 4 25 ± 4 26 ± 4

Gender, n (%) Male 77 72 (79) 5 (56)

Female 23 19 (21) 4 (44)

Ethnicity, n (%) European 96 87 (96) 9 (100)

African 2 2 (2) -

Mixed 2 2 (2) -

Side, n (%) Left 46 41 (45) 5 (56)

Right 54 50 (55) 4 (44)

Medication, n (%) Aspirin 1 - 1 (11)

Dipyridamol 1 1 (1) -

NSAID 7 7 (8) -

Other # 5 5 (6) -

Malignancy - - -

Contraceptives, n (%) Current use 10 8 (9) 2 (22)

Previous use 12 11 (12) 1 (11)

HRT, n (%) Current use - - -

Previous use 1 1 (1) -

Family history of VTE, n (%) 14 14 (15) -

Varicosis, n (%) 3 3 (3) -

Thrombophilic factors - - -

Anesthesia, n (%) Loco regional 62 56 (62) 6 (67)

General 38 35 (38) 3 (33)

Type of graft, n (%) AHG 84 77 (85) 7 (78)

ABPTB 14 12 (13) 2 (22)

Allograft 2 2 (2) -

Concomitant procedures, n (%) None 47 42 (46) 5 (56)

Meniscectomy (partial)

32 30 (33) 2 (22)

Debridement 11 11 (12) -

Other ## 10 8 (9) 2 (22)

Duration in min, Mean ± SD Arthroscopy 68 ± 22 68 ± 22 64 ± 20

Tourniquet 76 ± 23 76 ± 23 71 ± 20

ABPTB, autologous bone patellar tendon-bone graft; AHG, autologous hamstring graft; BMI, body mass index; HRT, hormone replacement therapy; NSAIDs, nonsteroidal anti-inflammatory drugs.*P = 0.02.# Other medication included a b-blocking agent (1), methylphenidate (1), inhalation therapy (1), psychopharmaceutical agent (1), and antihistamine (1) in patients without VTE.## Other concomitant procedures included microfracture (2) and unspecified procedures (6) in patients without VTE and microfracture (1) and meniscal repair (1) in patients with VTE.


6

All ultrasonography scans were evaluated as adequate. In 9 patients (incidence, 9%; 95% CI, 4.2 to 16.4), the CCUS was positive for VTE. Four of these patients were symptomatic (incidence, 4%; 95% CI, 1.1 to 9.9). Symptoms consisted of a painful, swollen lower leg in all 4 patients. The detailed results are shown in Table 2.All 5 asymptomatic patients, who had a positive CCUS examination at the 2-week follow-up visit, had a repeat follow-up CCUS after 1 week. According to our hospital protocol (and American guidelines), asymptomatic patients were not treated with anti-coagulants, but a repeat CCUS was performed after 1 week. Because all clots were stable after 1 week, no treatment was given. A symptomatic nonfatal pulmonary embolism developed in 1 of these asymptomatic patients 3 weeks postoperatively. Diagnosis was confirmed with a spiral computed tomography scan, and the patient was subsequently treated. The 4 symptomatic patients were treated with anticoagulants. Nadroparin, 5700 IU, was administered subcutaneously twice daily for at least 5 days, until an adequate international normalized ratio of 2.5 to 3.5 was reached with vitamin K antagonists. The patient characteristics and operation details are listed in Table 1. The patient characteris-tics were similar for the patients in whom VTE developed and the patients in whom VTE did not develop, except for the significantly higher age of the VTE patient group.Regarding the primary safety outcome, no major bleeding events occurred. The patients did not require transfusions, and no bleeding events requiring reintervention were observed. Four clinically relevant non-major bleeding events with a hemarthrosis of 100 to 250 mL were found. None of these patients were in the group of 3 patients who inadvertently received 1 dose of LMWH or in the VTE group. There were no bleeding episodes associated with therapy for symptomatic DVT during the study period. Post-thrombotic syndrome was not observed in our patient group.

Table 2. Results of extended duplex ultrasonography 2 weeks after arthroscopy, and cumulative results after 8 weeks of follow-up.

2 weeks 8 weeks

Total number of thrombo-embolic events 9 9

Death - -

Symptomatic PE (nonfatal) - 1

Symptomatic proximal DVT 2 2

Symptomatic distal DVT 2 2

Asymptomatic distal DVT 5 5

Safety end point Major bleeding event - -

Clinically relevant non major bleeding event 4 4

PE = pulmonary embolusDVT = deep venous thrombosis

72 Chapter 6

DISCuSSIOn

Incidence of VTE

This study shows a slightly higher incidence of symptomatic and asymptomatic DVT (9%) detected by CCUS after arthroscopic ACL reconstruction without thromboprophy-laxis as compared with routine arthroscopy with or without meniscectomy, where this has been reported to be approximately 7.5% to 7.7%.4,6

Four other studies reported on the incidence of thrombosis after ACL reconstruction without the use of pharmacologic prophylaxis. One previous study in young men with no history of thrombosis was conducted. The authors reported a low incidence (1 of 67 patients) of proximal vein thrombosis on screening ultrasonography 3 and 10 days after reconstruction.9 Patients were only screened for proximal DVT, however. Another study reported an incidence of asymptomatic DVT of 1.78% (2 of 112 patients) as detected by ultrasonography up to 4 weeks postoperatively.10 A mainly Asian study population might account for the much lower rate of VTE in this study.16 A third study showed that DVT did not develop after ACL reconstruction in any of the 23 patients.11 The authors did not report whether thromboprophylaxis was used. The final study included only 12 patients with ACL reconstructions, a subgroup of 184 knee arthroscopy patients. Asymptomatic DVT developed in 4 patients (33%).7 The study included a high-risk, relatively old population, used venography as a screening method and included only a very small number of patients.The symptomatic 90-day PE rate in population-based studies ranges from 0.028% to 0.18%.12-14 A recent English readmission study after 13,941 ACL reconstructions showed a 90-day symptomatic DVT rate of 0.3% and PE rate of 0.18%.13 The same research group also reported on 16,552 patients who underwent arthroscopically assisted ligament re-construction.17 The 90-day DVT and PE incidence rates were comparable: 0.2% and 0.1%, respectively. The low rate can in part be explained by the fact that only symptomatic, readmitted patients were included (excluding outpatients and deaths). In addition, no data were collected on type and duration of thromboprophylaxis. We saw 1 symptomatic episode of pulmonary embolism in a patient with an asymptomatic calf vein thrombosis at 2 weeks’ follow-up.

Risk Factors

In our study only older age could be identified as a risk factor for the development of DVT after ACL reconstruction. The reported risk factors for the incidence of VTE after ar-throscopic procedures of the knee are variable and not consistent. Nevertheless, several risk factor have been reported, including tourniquet time greater than 1 hour, history of VTE, age greater than 65 years, obesity, smoking, female hormone intake, and venous insufficiency.2,8 Although data on the effects of tourniquet use in the development of


6

DVT are conflicting, injury to the venous endothelium in combination with tourniquet-induced stasis may result in clot formation.18,19

Thromboprophylaxis After ACL Surgery

Only 1 study, specifically designed for ACL surgery, randomized patients who under-went ACL reconstruction to extended prophylaxis (20 days) with LMWH or in-hospital prophylaxis (3 to 7 days) with LMWH followed by placebo.20 The authors found a signifi-cant reduction in the incidence of total DVT from 28 of 68 patients to 2 of 72 patients and femoral DVT from 6 of 68 patients to 1 of 72 patients. This study had a number of methodologic shortcomings. It also had an unusually long operating time (median, > 2 hours) and duration of hospital admission (3 to 7 days). The investigators chose mag-netic resonance imaging to detect VTE, which is less reliable in detecting asymptomatic calf vein thrombosis.21

One review including 4 trials (527 patients), comparing any type of LMWH with placebo after knee arthroscopy,4 found the relative risk of VTE to be 0.16 (95% CI, 0.05 to 0.52) when LMWH was used. All DVTs were distal. Adverse events (mostly minor bleeding) were more common in the intervention group (relative risk, 2.04; 95% CI, 1.21 to 3.44). The number needed to treat was 17; the number needed to harm was 20. The authors stated that only 2 studies were of adequate methodologic quality, although they had small sample sizes and were poorly defined or stratified regarding their arthroscopic intervention. No strong evidence was found to conclude that thromboprophylaxis is effective to prevent thrombotic events and is safe.Another large randomized controlled trial (1761 patients) compared graduated com-pression stockings with either 1 or 2 weeks of LMWH after knee arthroscopy (duration < 60 minutes).22 A large number of ACL reconstructions (598) were performed. The study found a significant reduction in symptomatic PE and symptomatic and asymptomatic (mostly distal) DVT with the use of 1 week of LMWH after knee arthroscopy, detected by ultrasonography (4.7% vs 1.8%). This risk was somewhat counterbalanced by the increased frequency of mostly minor bleeding events. Whereas meniscectomy was an independent risk factor for the development of DVT, ACL reconstruction was not. Because meniscectomy and ACL reconstruction both represented roughly half of the study population, this suggests that the rate of DVT in the ACL group was even lower, although the exact rate of DVT in the ACL reconstruction group was not reported. This is surprising because ACL reconstruction is considered a much more extensive procedure than simple arthroscopic meniscectomy, involving at least 1 extra incision for the prepa-ration of autologous tendon graft and both tibial and femoral bone drilling for tendon graft fixation. Furthermore, ACL reconstruction generally has a longer operative time and is, at least in our study, often accompanied by meniscectomy. Besides LMWH and

74 Chapter 6

graduated compression stockings, there are no studies on thromboprophylaxis either with other agents or with mechanical prophylaxis.

Post-Thrombotic Syndrome

Preventing PE is the main reason for which preventing DVT after ACL reconstruction is needed because PE can be fatal in 20% to 50% of cases, depending on the population. The post-thrombotic syndrome is another potentially disabling sequela of thrombosis worth mentioning because it is often underreported. The post-thrombotic syndrome comprises a spectrum of morbidities, ranging from fatigued legs and painful swelling to ulcers. Asymptomatic postoperative DVT may be associated with an increased risk of late development of the post-thrombotic syndrome.23 Haas24 reported the post-thrombotic syndrome in 24% of lower extremities with asymptomatic DVT after major orthopaedic surgery within 2 to 4 years. This syndrome was not observed in our patient group.

Limitations

One potential limitation of our study is the relatively small number of patients studied. This is presumably the reason that we could not identify a specific high-risk group other than older age for the development of VTE in our population. In addition, our risk fac-tor analysis is limited. Second, we chose ultrasonography over contrast venography to assess the incidence of DVT, potentially underestimating the actual incidence. Contrast venography is a more sensitive method for detecting DVT and is considered the golden standard.1,25,26 Venography is invasive, however. Up to 20% of venograms are considered inadequate for evaluation,27 a considerable degree of intraobserver and interobserver variation is present,27 and the clinical relevance of small thrombi is uncertain.28 Therefore the use of venography as a screening test in unselected patients is undesirable. Ultraso-nography is noninvasive and repeatable. The accuracy of ultrasonography is somewhat reduced for the calf veins, however, and it is operator dependent.27 Sensitivity and specificity for the detection of symptomatic DVT with ultrasonography are equivalent to venography.21 However, combined data from 11 Level I studies investigating the utility of various ultrasonography techniques for the diagnosis of asymptomatic DVT in orthopaedic patients showed a sensitivity of 62% for proximal DVTs and 48% for below-knee DVTs. Reduced sensitivity can be explained by the fact that asymptomatic thrombi are more likely to be fresh, smaller, and nonocclusive than their symptomatic counterparts.29-31

The presence of preoperative asymptomatic thrombi was not determined in this study. However, a very low risk in this young, mobile, and otherwise healthy patient group without a history of VTE must be assumed.Furthermore, we excluded patients with a history of VTE, potentially causing a further underestimation of the risk of VTE.


6

Finally, results from prospective cohort studies have shown that most asymptomatic thrombi in patients undergoing hip or knee replacement remain clinically silent. These results raise questions about the clinical relevance of asymptomatic DVT detected by ultrasonography. There is, however, a relation between asymptomatic DVT and symp-tomatic VTE.32,33 It remains unclear what percentage of asymptomatic lower leg thrombi propagate proximally, from where they might become a cause of pulmonary embolism. In symptomatic calf vein clots, 20% propagate proximally28 and asymptomatic proximal DVTs have shown a risk of symptomatic PE in 40% of cases.34 Both phenomena (VTE/DVT) are symptoms of the same disease process of hypercoagulability, a condition that we believe should be prevented.

COnCLuSIOnS

This study shows that the incidence of VTE after arthroscopic ACL reconstruction is rela-tively high; a 9% incidence of asymptomatic proximal or distal DVT was found, whereas 4% of patients were symptomatic. Further research is recommended to assess the need for thromboprophylaxis in patients undergoing ACL reconstruction, especially when risk factors are present.

Acknowledgment

The authors are grateful for the excellent technical support of M. van Kippenberg, S. Muis, and J. Roord.

76 Chapter 6

REFEREnCES

1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physi-cians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(suppl):e278S-e325S.

2. Mont MA, Jacobs JJ, Boggio LN, et al. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg 2011;19:768-776.

3. Struijk-Mulder MC, Ettema HB, Verheyen CCPM, et al. Comparing consensus guidelines on throm-boprophylaxis in orthopedic surgery. J Thromb Haemost 2010;8:678-683.

4. Ramos J, Perrotta C, Badariotti G, et al. Interventions for preventing venous thromboembolism in adults undergoing knee arthroscopy. Cochrane Database Syst Rev 2008;(4):CD005259.

5. Hoppener MR, Ettema HB, Henny CP, et al. Low incidence of deep vein thrombosis after knee ar-throscopy without thromboprophylaxis: A prospective cohort study of 335 patients. Acta Orthop 2006;77:767-771.

6. Ilahi OA, Reddy J, Ahmad I. Deep venous thrombosis after knee arthroscopy: A meta-analysis. Arthroscopy 2005;21:727-730.

7. Demers C, Marcoux S, Ginsberg JS, et al. Incidence of venographically proved deep vein thrombo-sis after knee arthroscopy. Arch Intern Med 1998;158:47-50.

8. Delis KT, Hunt N, Strachan RK, et al. Incidence, natural history and risk factors of deep vein throm-bosis in elective knee arthroscopy. Thromb Haemost 2001;86:817-821.

9. Cullison TR, Muldoon MP, Gorman JD, et al. The incidence of deep venous thrombosis in anterior cruciate ligament reconstruction. Arthroscopy 1996;12:657-659.

10. Adala R, Anand A, Kodikal G. Deep vein thrombosis and thromboprophylaxis in arthroscopic anterior cruciate ligament reconstruction. Indian J Orthop 2011;45:450-453.

11. Williams JS Jr, Hulstyn MJ, Fadale PD, et al. Incidence of deep vein thrombosis after arthroscopic knee surgery: A prospective study. Arthroscopy 1995;11:701-705.

12. Maletis GB, Inacio MC, Reynolds S, et al. Incidence of symptomatic venous thromboembolism after elective knee arthroscopy. J Bone Joint Surg Am 2012;94:714-720.

13. Jameson SS, Dowen D, James P, et al. Complications following anterior cruciate ligament recon-struction in the English NHS. Knee 2012;19:14-19.

14. Hetsroni I, Lyman S, Do H, et al. Symptomatic pulmonary embolism after outpatient arthroscopic procedures of the knee: The incidence and risk factors in 418,323 arthroscopies. J Bone Joint Surg Br 2011;93:47-51.

15. Schellong SM, Schwarz T, Halbritter K, et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003;89:228-234.

16. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res 2009;123(suppl 4):S11-S17.

17. Jameson SS, Dowen D, James P. The burden of arthroscopy of the knee. A contemporary analysis of data from the English NHS. J Bone Joint Surg Br 2011;93:1327-1333.

18. Hirota K, Hashimoto H, Tsubo T, et al. Quantification and comparison of pulmonary emboli formation after pneumatic tourniquet release in patients undergoing reconstruction of anterior cruciate ligament and total knee arthroplasty. Anesth Analg 2002;94:1633-1638.

19. Jarrett PM, Ritchie IK, Albadran L, et al. Do thigh tourniquets contribute to the formation of intra-operative venous emboli? Acta Orthop Belg 2004;70:253-259.


6

20. Marlovits S, Striessnig G, Schuster R, et al. Extended duration thromboprophylaxis with enoxa-parin after arthroscopic surgery of the anterior cruciate ligament: A prospective, randomized, placebo-controlled study. Arthroscopy 2007;23:696-702.

21. Polak JF, Cutter S, Oleary D. Deep veins of the calf: Assessment with color Doppler flow imaging. Radiology1989;171:481-485.

22. Camporese G, Bernardi E, Prandoni P, et al. Low molecular-weight heparin versus compression stockings for thromboprophylaxis after knee arthroscopy: A randomized trial. Ann Intern Med 2008;149:73-82.

23. Wille-Jorgensen P, Jorgensen LN, Crawford M. Asymptomatic postoperative deep vein thrombo-sis and the development of postthrombotic syndrome: A systematic review and meta-analysis. Thromb Haemost 2005;93:236-241.

24. Haas S. Deep vein thrombosis: Beyond the operating table. Orthopedics 2000;23(suppl):S629-S632.

25. Lausen I, Jensen R, Wille-Jørgensen P, et al. Colour Doppler flow imaging ultrasonography versus venography as screening method for asymptomatic postoperative deep venous thrombosis. Eur J Radiol 1995;20:200-204.

26. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(suppl):e351s-e418s.

27. Barnes RW, Nix ML, Barnes CL, et al. Perioperative asymptomatic venous thrombosis: Role of duplex scanning versus venography. J Vasc Surg 1989;9:251-260.

28. Philbrick J, Becker D. Calf vein thrombosis: A wolf in sheep’s clothing? Arch Intern Med 1988;148:2131-2138.

29. Lensing AW, Doris CI, McGrath FP, et al. A comparison of compression ultrasound with color Doppler ultrasound for the diagnosis of symptomless postoperative deep vein thrombosis. Arch Intern Med 1997;157:765-768.

30. Wells PS, Lensing WA, Davidson BL, et al. Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopaedic surgery. A metaanalysis. Ann Intern Med 1995;122:47-53.

31. Nicolaides A, Kalkodi E. Duplex scanning in post-operative surgical patients. Haemostasis 1993;23(suppl 1):72-79.

32. Turpie AG, Bauer KA, Eriksson BI, et al. Superiority of fondaparinux over enoxaparin in prevent-ing venous thromboembolism in major orthopaedic surgery using different efficacy end points. Chest 2004;126:501-508.

33. Segers AE, Prins MH, Lensing AW, et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies? J Thromb Haemost 2005; 3:1099-1102.

34. Kelly J, Rudd A, Lewis RR, et al. Screening for subclinical deep-vein thrombosis. Q J Med 2001;94:511-519.

7

Death and venous thromboembolism after lower extremity amputation

MC Struijk-Mulder1, W Van Wijhe2, YK Sze2, S Knollema2, CC Verheyen1, HR Büller3, WM Fritschy2, HB Ettema1

1 Department of Orthopaedic Surgery, Isala Clinics, Zwolle, the Netherlands2 Department of Vascular Surgery, Isala Clinics, Zwolle, the Netherlands

3 Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands

J Thromb Haemost. 2010; 8:2680-2684.

80 Chapter 7

ABSTRACT

Background

Lower extremity amputation is often performed in patients with end-stage vascular disease and is considered a high-risk procedure. Uncertainty exists about the rate of venous thromboembolism (VTE) in these patients.

Objectives

To establish the incidence of death and venous thromboembolism after lower extremity amputation.

Methods

A prospective cohort study was performed to establish the incidences of death and VTE after lower extremity amputation, as detected by bilateral complete compression ultrasonography and ventilation-perfusion scintigraphy performed preoperatively and around day 14 postoperatively. Standard low-molecular-weight heparin thrombopro-phylaxis was given during the study period. A secondary outcome was the incidences of mortality and symptomatic venous thromboembolic complications during 8 weeks of postoperative follow-up.

Results

Forty-nine patients (53 amputations) were ultimately included in the intention-to-treat analysis. Five patients died within the 2-week follow-up period and an additional seven patients died during the 8-weeks clinical follow-up period. The total mortality rate there-fore was 12 out of 53 amputations [22.6%; 95% confidence interval (CI) 12.3–36.2%]. Six patients developed pulmonary embolism (of which two were fatal) and one patient developed an asymptomatic contralateral distal deep venous thrombosis, resulting in a total VTE rate of 7 out of 53 amputations (13.2%; 95% CI 5.47–25.3%).

Conclusion

Lower extremity amputation is accompanied by a high mortality rate from sepsis, and respiratory and vascular causes. This study shows that VTE substantially contributes to the morbidity and mortality after lower extremity amputation despite adequate phar-macological thromboprophylaxis in this vulnerable population of patients.

Death and venous thromboembolism after lower extremity amputation 81

7

InTRODuCTIOn

The aim of this study was to investigate the incidence of all cause mortality, symptom-atic and asymptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing lower extremity amputation. These major amputations are mostly performed in (diabetic) patients with endstage vascular disease [1], with very high mortality rates, up to 53% in the first year following surgery [1–6]. Uncertainty exists, however, about the incidence of DVT in the amputated leg, causing subsequent pulmo-nary embolism and death. Because most of these patients present with acute vascular occlusion prior to amputation, a state of hypercoaguability is very likely. Also, increased incidences of venous thrombosis prior to amputation have been reported (7.3–8.3%) [7,8]. In this study we prospectively determined deep venous thrombosis and pulmonary embolism both pre- and postoperatively by means of duplex-ultrasonography and ventilation-perfusion lung scintigraphy. All-cause mortality and VTE rates after major amputation were documented and thrombosis risk factors and the importance of phar-macological thromboprophylaxis were assessed. This is the first study that identifies both pulmonary embolism (PE) and deep venous thrombosis (DVT) pre- and postopera-tively in patients after low extremity amputation receiving adequate pharmacological thromboprophylaxis.

METHODS

The study was conducted between April 2007 and February 2009 in the Isala Clinics, Zwolle, the Netherlands. All consecutive patients older than 18 years of age, scheduled for lower extremity amputation, were considered eligible. The included patients were scheduled for bilateral complete compression ultrasonography (CCUS) and ventilation-perfusion lung scintigraphy 1–3 days preoperatively and 11–17 days postoperatively. Patients meeting one of the following criteria were excluded from the study: VTE at entry, inability or unwillingness to give written informed consent, inability to be followed-up and ongoing treatment with anticoagulant therapy. When bilateral amputations were performed, a minimum of 3 months between amputations was required to be included in the study as a separate case. Two follow-up contacts were scheduled, at 2 weeks in the clinic and by telephone or visit at 8 weeks. Patients were asked if they had any clinical signs or symptoms of VTE following the operation. The clinical signs documented were pain, tenderness, swelling or redness of the leg or stump, dyspnoea, chest pain and hemoptysis. In addition, patients were instructed to contact the hospital if one of these signs or symptoms occurred prior to the follow-up contact. Demographic data were

82 Chapter 7

recorded as well as patient history, risk factors for thromboembolism, concomitant medication, indication for amputation, the ASA classification and details concerning the operation. CCUS of the leg veins was performed by experienced ultrasonographists. All of them had received a supervised CCUS-specific training. The ultrasound devices used were a 5- or 7.5-MHz linear-array sonographic scanner (Acuson 128XP; Acuson, Siemens, Mountain View, CA, USA). A standardized protocol for complete compression ultrasonography was applied [9]. The criterion for the diagnosis of DVT was the inability to compress the veins with the ultrasound transducer. Ultrasonographic findings were recorded as normal (negative), abnormal (positive), or inadequate for interpretation if a complete vein or segment of a vein could not be identified. The proximal venous system was defined as the deep veins in the thigh, and the popliteal region cephalad to the trifurcation of the calf veins.Lung perfusion scanning was performed by intravenous injection of Tc99m labelled macroaggregates followed by gamma ray camera imaging of the lungs. When perfu-sion scintigraphy was considered abnormal, a ventilation scan using krypton inhalation was performed. The scans were classified as: no pulmonary embolism, low probability, intermediate probability or high probability. In patients who showed symptoms of PE before the scheduled ventilation-perfusion scan, either a computed tomography (CT) scan or a ventilation-perfusion scan was performed.The primary outcome parameters were all cause mortality and the incidence of (a)symptomatic VTE after lower extremity amputation during the first 2 weeks of follow-up. The secondary outcome measures were the incidence of mortality and symptomatic venous thromboembolic complications after amputation during the first 8 postopera-tive weeks. When the preoperative investigations showed venous thromboembolism, the patient was treated according to the local treatment protocol and excluded from the analysis. During the 8 weeks of the study period, all patients received thromboprophy-laxis according to the departmental guidelines, with subcutaneous injections of either nadroparin 2850 IU once daily (od), 3800 IU od, 5700 IU od or 2 times 5700 IU. Approval of the Institutional Review Board was obtained.

RESuLTS

A total of 113 lower extremity amputations in 109 consecutive patients were scheduled during the study period. Seven patients did not meet the inclusion criteria because they refused informed consent (5) or received treatment with vitamin K antagonists (2).Due to the urgent indication for amputation we could not perform the preoperative tests in 49 patients (53 amputations). Two patients showed VTE at the preoperative


7

tests and were excluded from the final analysis: one patient had a high probability of PE according to the ventilation-perfusion lung scan and was treated with anticoagulants before amputation, but subsequently died within 3 days after the amputation. The other patient showed DVT on the preoperative ipsilateral leg and refused further study participation. This patient died 5 months after amputation of cardiovascular complica-tions. In five cases the CCUS was not available; in two cases the perfusion scan was not available. Therefore 53 amputations (49 patients) were included in the final intention to treat analysis for the primary outcome of death and venous thromboembolism after the amputation. Figure 1 shows the trial profile. Table 1 lists the baseline characteristics of the study group, Table 2 the operative characteristics and Table 3 the risk factors and comorbidity.All ultrasounds and ventilation-perfusion lung scans were evaluated as adequate. The rate of mortality and VTE is listed in Table 4. Four patients developed symptoms of pul-monary embolism and were diagnosed with PE on a spiral CT scan; in two patients the

Figure 1. Trial profile

Excluded 53 not scheduled for pre-op tests 2 ongoing vitamin K treatment 3 ineligible 1 pre-op high probability V/P scan: treated for PE 1 refused participation after positive pre-operative CCUS

53 amputations (49 patients) Pre- and postoperative CCUS and V/P scan

5 CCUS not available 2 V/P scans not available

53 amputations (49 patients) analysed

113 Lower Extremity Amputations (109 patients)

Figure 1. Trial profile

84 Chapter 7

PE was fatal. In two patients the ventilation-perfusion scan showed a high probability for postoperative PE. The total rate of PE was therefore 6/53 (11.3%; 95% CI, 4.3– 23%), of which 2/53 (3.8%; 95% CI, 0.46–13.0%) were fatal. One proximal asymptomatic DVT was diagnosed in the 2-week follow-up period; the total rate of DVT was therefore 1/53 (1.9%) in the postoperative group. All VTEs occurred in the first two postoperative weeks; in the 8-week follow-up period no additional VTEs were recorded. Three more patients died within the first 2 weeks, diagnosed as sepsis (2) or cardiorespi-ratory failure (1). Another seven patients died within the 8- week follow-up period, also due to sepsis (3) and cardiorespiratory complications (4). We did not acquire permission for autopsy; hence the definitive cause of death remained uncertain. Two out of 53 amputations were performed because of trauma; one amputation was carried out because of a pain syndrome. Vascular insufficiency was the main reason for amputation. No VTE was encountered in patients who were operated on because of trauma or pain syndrome. All patients received standard thromboprophylaxis with either nadroparin 2850 IU (n = 6) od, 3800 IU (n = 2), 5700 IU od (n = 38) or 2 times 5700 IU (n = 7). The two patients with fatal PE received 5700 IU; the non-fatal PEs were detected in patients using either 5700IU od (3) or 2 times 5700 IU od (1). The DVT was encountered in a patient receiving 5700 IU od. There were no major bleeding events.

Table 1. Baseline demographic characteristics (N=49 patients, 53 amputations)

Age in yrs, mean ± SD 72 ± 12.0

BMI, mean ± SD 26 ± 4.2

Gender, n (%) Male 27 (55)

Female 22 (45)

Ethnicity, n (%) Caucasian 49 (100)

Side, n (%) Left 26 (49)

Right 27 (51)

Indication, n (%) Dysvascular 50 (94)

Pain Syndrome 1 (2)

Traumatic 2 (4)

ASA classification ASA I 1 (2)

ASA II 8 (15)

ASA III 42 (79)

ASA IV 2 (4)

SD = Standard deviation, BMI = Body mass index


7

Table 2. Risk factors in 49 patients (N,%)

Previous DVT 2 (4.1)

Previous PE 2 (4.1)

Contraceptives 1 (2.0)

HRT 3 (6.1)

Family history of VTE -

Co-morbidity, n (%) Cardiovascular 25 (51.0)

Hypertension 44 (89.8)

Diabetes 23 (46.9)

Pulmonary 11 (22.4)

Sepsis 7 (14.3)

Malignancy 9 (18.4)

Medication, n (%) Cardiovascular 44 (89.8)

Pulmonary 12 (24.5)

Diabetes 23 (46.9)

Aspirin 31 (63.3)

NSAID 6 (12.2)

HRT = Hormone replacement therapy

Table 3. Operation characteristics (N=53 amputations)

Anesthesia, n (%) Regional 25 (47)

General 25 (47)

Both 3 (6)

Amputation type, n (%) Transfemoral 9 (17)

Exarticulation knee 2 (4)

Transtibial 42 (79)

SD = Standard deviation

Table 4. Mortality, deep vein thrombosis and pulmonary embolism after lower extremity amputation (N=53 amputations)

2 weeks 8 weeks

Total end point (death and VTE) n, (%) 12 (22.6) 19 (35.8)

Total VTE n, (%) 7 (13.2) 7 (13.2)

Fatal PE 2 (3.8) 2 (3.8)

Pulmonary embolism (nonfatal) 4 (7.5) 4 (7.5)

Distal DVT (asymptomatic) 1 (1.9) 1 (1.9)

All cause mortality n, (%) 5 (9.4) 12 (22.6)

86 Chapter 7

DISCuSSIOn

Uncertainty exists about the incidence of VTE after lower extremity amputation. Arterial thrombosis is the primary indication for amputation and is characterized by a cold, pale and atrophic leg. In venous thrombosis, however, there is precisely the opposite clinical image of a red, swollen and warm extremity. These symptoms are often absent in an amputation stump, which may lead to an underestimation of the problem. The absence of the muscles in the calf increases venous blood pooling and a decreased mobility may cause venous stasis and subsequent thrombosis. The risk profile is further influenced by patient factors such as history of venous disease [7], thrombophilic abnormalities, obesity, (operation) trauma and a history of malignancy [10].The risk of VTE has been reported as ranging from 4.2% in the early postoperative period [7] to 28–50% 1 month after surgery [8,11] in lower extremity amputees not receiving thromboprophylaxis, although the number of patients studied was small. Other studies showed a lower incidence of 0–14% with different follow-up periods [12–15]. In these studies not all patients received thromboprophylaxis. There are two other studies that used ultrasonography to screen for pre- and postopera-tive DVT. Yeager et al. [7] showed that of the nine patients diagnosed with postoperative DVT, six of them already had a DVT before surgery. This report corresponds with our finding that two patients were diagnosed with preoperative asymptomatic VTE, reflect-ing the state of hyper-coagulability and end-stage vascular disease in these patients. Matielo et al. [8] found six preoperative DVTs in 82 eligible patients and excluded them from further analysis.Lastoria et al. [16] compared the use of enoxaparin with unfractionated heparin in 75 lower extremity amputations and showed a non-significant difference of 9.8% vs. 11.8% DVTs 8 days postoperatively.Despite the fact that all patients in our study received pharmacological prophylaxis we found a high rate of pulmonary embolism. This could be explained by this study being the only one that screened for asymptomatic pulmonary embolism by means of ventilation-perfusion scanning.We believe that our findings are valid because we screened for both PE and DVT and we performed these examinations preoperatively as well as postoperatively. A limitation of our study is the moderate number of patients studied and the relatively low inclu-sion rate (45%). Patients often postpone the decision for amputation to the point of an advanced dysvascular state or until infection and sepsis requires acute surgery. This complicates the scheduling for preoperative investigations. For this reason, some of the most acutely ill patients were excluded, which may cause a selection bias. This study therefore probably underestimates the true incidence of postoperative death and pos-sibly also the incidence of VTE. The small number of patients also does not allow analysis


7

of outcome in relation to indication for operation. Another weakness is our inability to provide the definite cause of death because autopsy was invariably refused. Most of the patients died of sepsis and subsequent cardiovascular and respiratory failure. Two patients died before their postoperative CCUS and perfusion scan was performed. In these patients the diagnosis of pulmonary embolism could neither be confirmed nor rejected. The present study confirms that in patients with end-stage vascular disease with associated morbidity requiring a lower extremity amputation there is a high risk of postoperative death (22.6%).Our study further shows that the contribution of VTE to the morbidity and mortality after lower extremity amputation in patients receiving adequate thromboprophylaxis appears to be high. We found seven VTEs: one patient had asymptomatic contralateral postoperative distal DVT; and pulmonary embolism occurred in six patients and was fatal in two patients. Some patients received more (n = 7) or less (n = 8) nadroparin than the standard 5700 IU od. Remarkably, the primary outcome parameter of VTE was not encountered in patients receiving <5700 IU od. On the contrary: one of the patients with non-fatal PE received 2 times 5700 IU of nadroparin. Considering the high rate of VTE in this group despite the use of adequate prophylaxis, a more aggressive thromboprophylactic regimen seems warranted. Some additional methods currently available come to mind. Inferior vena cava (IVC) filters are reserved for patients with proven proximal DVT and either an absolute contraindication to full-dose anticoagulation or planned major surgery in the near future [17,18]. The use of IVC filters as thromboprophylaxis has expanded recently, because of the introduction of retrievable filters. Those filters are placed in the interventional radiology suite under fluoroscopy. IVC filters are associated with a low rate of short-term complications, such as thrombosis during filter placement, migration, infection and perforation. No difference in the rates of PE among patients with or without prophylactic IVC filters were found in a meta-analysis of prospective studies [19]. Moreover, there are no RCTs concerning the prophylactic use of IVC filters in any patient population [17,18]. Because of lack of evidence of efficacy and high costs, we can not recommend the use of IVC filters as thromboprophylaxis in patients who will have an amputation.Mechanical prophylaxis with intermittent pneumatic compression (IPC) or graduated compression stockings (GCS) applied to the contralateral leg could be a useful addition to LMWH. Some guidelines on thromboprophylaxis after total knee arthroplasty even suggest the sole use of mechanical prophylaxis as an alternative to pharmacological prophylaxis [20]. As these recommendations are based on studies with small sample sizes and RCTs with inconsistent results or major methodological weaknesses, more studies are needed. Mechanical prophylaxis in patients with lower extremity amputa-tion has not been studied to date.

88 Chapter 7

In conclusion, despite thromboprophylaxis with LMWH the incidence of VTE after lower extremity amputation remains high in this study. Currently it is unclear which additional measures could be applied to reduce this high rate of VTE in these patients.


7

REFEREnCES

1 Dillingham TR, Pezzin LE. Rehabilitation setting and associated mortality and medical stability among persons with amputations. Arch Phys Med Rehabil 2008; 89: 1038–45.

2 Remes L, Isoaho R, Vahlberg T, Hiekkanen H, Korhonen K, Viitanen M, Rautava P. Major lower extremity amputation in elderly patients with peripheral arterial disease: incidence and survival rates. Aging Clin Exp Res 2008; 20: 385–93.

3 Stone PA, Flaherty SK, Hayes JD, AbuRahma AF. Lower extremity amputation: a contemporary series. WVMed J 2007; 103: 14–8.

4 Ploeg AJ, Lardenoye JW, Vrancken Peeters MP, Breslau PJ. Contemporary series of morbidity and mortality after lower limb amputation. Eur J Vasc Endovasc Surg 2005; 29: 633–7. Epub 2005 March 28.

5 Aulivola B, Hile CN, Hamdan AD, Sheahan MG, Veraldi JR, Skillman JJ, Campbell DR, Scovell SD, Logerfo FW, Pomposelli FB Jr. Major lower extremity amputation: outcome of a modern series. Arch Surg 2004; 139: 395–9

6 Nehler MR, Coll JR, Hiatt WR, Regensteiner JG, Schnickel GT, Klenke WA, Strecker PK, Anderson MW, Jones DN, Whitehill TA, Moskowitz S, Krupski WC. Functional outcome in a contemporary series of major lower extremity amputations. J Vasc Surg 2003; 38: 7–14.

7 Yeager RA, Moneta GL, Edwards JM, Taylor LM Jr, McConnell DB, Porter JM. Deep vein thrombosis associated with lower extremity amputation. J Vasc Surg 1995; 22: 612–5.

8 Matielo MF, Presti C, Casella IB, Netto BM, Puech-Leo P. Incidence of ipsilateral postoperative deep venous thrombosis in the amputated lower extremity of patients with peripheral obstructive arterial disease. J Vasc Surg 2008; 48: 1514–9. Epub 2008 October 1.

9 Schellong SM, Schwarz T, Halbritter K, Beyer J, Siegert G, Oettler W, Schmidt B, Schroeder HE. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003; 89: 228–34.

10 Baars EC, Ettema HB, Fritschy WM. Deep venous thrombosis in an amputation stump. Ned Tijdschr Geneeskd 2007; 151: 2061–3.

11 Burke B, Kumar R, Vickers V, Grant E, Scremin E. Deep vein thrombosis after lower limb amputa-tion. Am J Phys Med Rehabil 2000; 79: 145–9.

12 Barnes RW, Slaymaker EE. Postoperative deep vein thrombosis in the lower extremity amputee: a prospective study with Doppler ultrasound.Ann Surg 1976; 183: 429–32.

13 Huang ME, Johns JS, White J, Sanford K. Venous thromboembolism in a rehabilitation setting after major lower-extremity amputation. Arch Phys Med Rehabil 2005; 86: 73–8.

14 Zickler RW, Gahtan V, Matsumoto T, Kerstein MD. Deep venous thrombosis and pulmonary embo-lism in bilateral lower-extremity amputee patients. Arch Phys Med Rehabil 1999; 80: 509–11.

15 Chong DK, Panju A. Deep venous thrombosis as a cause of stump swelling in two lower extremity amputee patients. Arch Phys Med Rehabil 1993; 74: 1002–3.

16 Lastória S, Rollo HA, Yoshida WB, Giannini M, Moura R, Maffei FH. Prophylaxis of deep vein thrombosis after lower extremity amputation: comparison of low molecular weight heparin with unfractionated heparin. Acta Cir Bras 2006; 21: 184–6. Epub 2006 May 26 .

17 Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of ve-nous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl): 381S–453S.

18 Tschoe M, Kim HS, Brotman DJ, Streiff MB. Retrievable vena cava filters: a clinical review. J HospMed 2009; 4: 441–8.

90 Chapter 7

19 Velmahos GC, Kern J, Chan LS, Oder D, Murray JA, Shekelle P. Prevention of venous thromboem-bolism after injury: an evidence-based report; part II. Analysis of risk factors and evaluation of the role of vena caval filters. J Trauma 2000; 49: 140–4.

20 Struijk-Mulder MC, Ettema HB, Verheyen CC, Büller HR. Comparing consensus guidelines on thromboprophylaxis in orthopedic surgery. J Thromb Haemost 2010; 8: 678–83. Epub 2009 December 21.

8

Venous thromboembolism during hip plaster cast immobilisation:

Review of the literature

MC Struijk-Mulder1, HB Ettema1, RAJ Heyne2, J J Rondhuis1, HR Büller3, CCPM Verheyen1

1 Department of Orthopaedic Surgery and Traumatology, Isala Clinics, the Netherlands2 Department of Pulmonology, Ziekenhuis Rivierenland, Tiel, the Netherlands

3 Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands

Neth J Med. 2014 Jan;72(1):17-19.

92 Chapter 8

ABSTRACT

Introduction

There is a paucity of data regarding the risk of deep vein thrombosis during hip plas-ter cast immobilisation. The purpose of this article is to review the available evidence regarding the incidence of symptomatic venous thromboembolism (VTE) during hip plaster cast immobilisation.

Methods and Materials

All papers describing hip plaster cast immobilisation published in English literature retrieved from PubMed, EMBASE and the Cochrane database were reviewed. Articles regarding children, hip dysplasia, congenital hip dislocation and Legg-Calvé-Perthes were excluded. A total of three papers were available for analysis. We also describe a case of pulmonary embolism during hip cast immobilisation.

Results

The overall incidence of symptomatic VTE during hip plaster cast immobilisation was 0% in 343 patients. The incidence of symptomatic VTE in hip cast brace was 2,3% (range 0-3%).

Discussion

Our systematic review of literature showed a paucity of data regarding the incidence of VTE during hip plaster cast immobilisation. We described the first case of pulmonary embolism during hip plaster cast immobilisation. We recommend that patients who are fitted with a hip plaster cast should be routinely screened for additional risk fac-tors. When risk factors are present, patients should be considered for pharmacological thromboprophylaxis.

Venous thromboembolism during hip plaster cast immobilisation 93

8

InTRODuCTIOn

There is a paucity of data regarding the risk of deep vein thrombosis during hip plas-ter cast immobilisation. The purpose of this article is to review the available evidence regarding the incidence of symptomatic venous thromboembolism (VTE) during hip plaster cast immobilisation.Furthermore, we describe a case of pulmonary embolism in a hip plaster cast. To our knowledge, this has not been documented before. Clinicians should be aware of the risk of venous thromboembolism (VTE) when treating a patient with plaster cast im-mobilisation. A meta-analysis reported a mean rate of VTE during lower leg plaster cast immobilisation without thromboprophylaxis of 17.1% [1].

MATERIAL AnD METHODS

A systematic search strategy was used to identify all papers describing symptomatic venous thromboembolism (deep venous thrombosis and pulmonary embolism) during hip cast immobilisation published in English before October 18th 2013. We used the PRISMA statement for systematic reviews [2]. We performed an electronic PubMed, Cochrane and EMBASE database search. The terms plaster cast or hip cast brace or pan-taloon cast or spica cast were used. Articles regarding children, dysplasia, congenital hip dislocation, Legg-Calvé-Perthes and immobilisation with plaster cast restricted to the lower limb were excluded. From the retrieved articles, the reference lists were screened for any relevant papers. Full text copies of these articles were obtained and assessed for eligibility. Articles which did not describe the type of cast or brace and articles concern-ing treatment with traction or prolonged bed rest prior to bracing were excluded. All papers selected were analysed for incidence of DVT and pulmonary embolism.

RESuLTS

We reviewed 180 papers describing plaster cast immobilisation (Figure 1). There were no randomized controlled trials or non-randomized comparative studies. Two review articles by the same author were identified [3,4]. One article described the thesis of the author, including the other review article. The systematic review included three studies with a hip plaster cast test for surgical decision making in 120 chronic low back pain patients [3]. One of those three studies did not involve immobilisation of the hip. Rask et al. included 45 patients and the immobilisation period was 4 weeks initially and became two weeks later on [5]. Markwalder et al. immobilized 25 patients for two weeks [6]. In

94 Chapter 8

both studies, no VTE complications were described and the use of thromboprophylaxis was not reported. Data of the review were supplemented by a prospective cohort study with 257 patients [3]. Casts were applied for 3-6 weeks. The use of thromboprophylaxis was not described and no VTE complications were reported. It was concluded that in patients without prior spine surgery a hip plaster cast test with substantial pain relief suggests a favourable outcome of lumbar fusion compared to conservative manage-ment.The third article of our search described a cohort of 67 patients with a hip cast brace after primary and revision hip replacement in order to prevent hip dislocation [7]. Two patients developed deep venous thrombosis. This brace allowed 70 degrees of flexion and a variable range of abduction in the hip joint, however. The hip cast in our case re-port is designed to immobilize the hip joint in a fixed 10 degrees of flexion. The purpose of this cast is to simulate lumbar fusion. The same type of soft-cast brace was applied in the fourth article to 21 patients, to conservatively treat hip dislocation after total hip arthroplasty during three months [8]. No VTE was reported. The fifth article reported on 16 patients who were treated with a hip plaster cast for six weeks for dislocated total hip arthroplasty [9]. Three patients underwent additional revision hip arthroplasty before the cast was applied. No thromboembolic complications were described.

Figure 1. Algorithm showing search methods, according to PRISMA methodology

Figure 1. Algorithm showing search method, according to PRISMA methodology

PubMed search: 54 articles EMBASE search: 125 articles

Cochrane search: 1 article

172 articles after duplicates removed

172 articles screened 144 articles excluded

28 full text articles assessed for eligibility

25 full text articles excluded Exclusion criteria:

• < 18 years • Lower leg

immobilisation only • Type of cast or brace is

not described • Traction or prolonged

bedrest prior to casting in femoral fractures

5 studies included in qualitative synthesis


8

In summary, the overall incidence of symptomatic VTE during hip plaster cast immo-bilisation was 0%. The incidence of symptomatic VTE in hip cast brace was 2.3% (range 0-3%).

CASE REPORT

A 29-year-old woman with radiographically confirmed discopathy at level L4 to S1 was immobilized with a trial hip plaster cast immobilisation to simulate lumbosacral fusion. Pain relief would aid in the decision for lumbar fusion. The patient was on oral contra-ceptive medication (OCM) (ethinylestradiol 20 microgram, desogestrel 150 microgram). No other risk factors for the development of VTE were found. (Patient’s BMI was 24). After 11 days of plaster cast immobilisation, the patient became dyspnoeic. Two days later, the cast was removed and the following day, she presented to the emergency department with persistent dyspnoea and mid-sternal pain. There were no evident symptoms of deep venous thromboembolism of the legs. The diagnosis of pulmonary embolism was determined by means of a D-dimer of 15 mg/L in combination with multiple perfusion defects on a perfusion scan; confirmed by CT angiography that showed a massive em-bolus in the right pulmonary artery and a central embolus in the left pulmonary artery. She was treated with low molecular weight heparin (LMWH) (nadroparine 5700 IE twice daily sc) and started with a vitamin K antagonist (VKA) (acenocoumarol). Once the inter-national normalized ratio (INR) was between 2.5 and 3.5, LMWH was discontinued and VKA was continued for three months. The patient was discharged home after 14 days of hospital stay. Two years later, a ventral spondylodesis at levels L4-S1 was performed.

DISCuSSIOn

Our systematic review of literature did not show any symptomatic venous thromboem-bolic event during hip plaster cast immobilisation in 343 patients. Symptomatic DVT was reported in 2.3% (range 0-3%) of 88 patients immobilised with a hip brace.The risk of VTE in patients with plaster cast immobilisation is not properly documented. A meta-analysis regarding six studies on lower leg plaster cast immobilisation, showed a highly significant and clinically relevant reduction in asymptomatic events with LMWH prophylaxis compared to placebo or untreated controls (RR 0,58, CI 0.39-0,86, p= 0,006).[1] The mean rate of VTE was reduced from 17.1% to 9.6% with the use of LMWH.The authoritative ACCP guidelines give a grade 2C recommendation (based on low quality evidence) not to use pharmacological thromboprophylaxis in patients with iso-lated lower-leg injuries requiring leg immobilisation [10]. They suggest that results from

96 Chapter 8

higher-risk populations may, however, be reasonably extrapolated to patients at higher risk of DVT (who were excluded from the studies), particularly those with prior VTE.Several grading systems to identify risk factors for VTE have been developed, which are subject of debate. Limitations of these risk assessment models include lack of prospec-tive validation, applicability only to high-risk subgroups, inadequate follow-up time, and excessive complexity, according to the 9th ACCP guidelines regarding non-surgical pa-tients [11-14]. To our knowledge, no clinical trials evaluating VTE prophylaxis for medical outpatients have yet been published [15].Generally, immobilisation is considered a major risk factor for VTE. In our case the im-mobilisation induced by the hip plaster cast, combined with the use of OCM puts our patient in the high-risk category.Therefore we recommend that patients who are fitted with a hip plaster cast should be routinely screened for additional risk factors such as OCM use and a history of VTE. When risk factors are present, patients should be considered for pharmacological thrombopro-phylaxis.

What is known on this topic What this paper adds

• Immobilisation is a major risk factor for VTE • A systematic review on the incidence of symptomatic VTE during hip plaster cast immobilisation is presented

• A meta-analysis on lower leg plaster cast immobilisation showed a highly significant and clinically relevant reduction in asymptomatic events with LMWH prophylaxis compared to placebo or untreated controls

• The first case of pulmonary embolism during hip plaster cast immobilisation is described

• We recommend that patients who are fitted with a hip plaster cast should be routinely screened for additional VTE risk factors

• When risk factors are present, patients should be considered for pharmacological thromboprophylaxis


8

REFEREnCES

1. Ettema HB, Kollen BJ, Verheyen CCPM, Büller HR. Prevention of venous thromboembolism in patients with immobilisation of the lower extremity. A meta-analysis of randomised controlled trials. J Thromb Hemost. 2008;6:1093-1098.

2. Moher D, Liberati A, Tetzlaff J et al. The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS medicine 2009 6;e100097

3. Willems PC, Elmans L, Anderson PG et al. The value of a pantaloons cast test in surgical decision making for chronic low back pain patients: a systematic review of the literature supplemented with a prospective cohort study. Eur Spine J. 2006;15:1487-1494.

4. Willems P. Decision making in surgical treatment of chronic low back pain: the performance of prognostic tests to select patients for lumbar spinal fusion. Acta Orthop Suppl. 2013 Feb;84(349):1-35.

5. Rask B, Dall BE. Use of the pantaloon cast for the selection of fusion candidates in the treatment of chronic low back pain. Clin Orthop Relat Res. 1993 Mar;(288):148-57.

6. Markwalder TM, Reulen HJ. Diagnostic approach in instability and irritative state of a “lumbar motion segment” following disc surgery—failed back surgery syndrome. Acta Neurochir (Wien). 1989;99(1-2):51-7.

7. Mallory TH, Vaughn BK, Lombardi AV Jr, Kraus TJ. Prophylactic use of a hip cast-brace following primary and revision total hip arthroplasty. Orthopaedic Review.1988;17:178-183.

8. Stewart HD. The hip cast-brace for hip prosthesis instability. Ann R Coll Surg Engl. 1983 Nov;65(6):404-6.

9. Williams JF, Gottesman MJ, Mallory TH. Dislocation after total hip arthroplasty. Treatment with an above-knee hip spica cast. Clin Orthop Relat Res.1982 Nov-Dec;(171):53-8.

10. Falck-Ytter Y, Francis CW, Johanson NA et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physi-cians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-325S.

11. Cohen AT, Alikhan R, Arcelus JI et al. Assessment of venous thromboembolism risk and the ben-efits of thromboprophylaxis in medical patients. Thromb Haemost.2005;94(4):750-759.

13. Spyropoulos AC. Risk assessment of venous thromboembolism in hospitalized medical patients. Curr Opin Pulm Med.2010;16(5):419-425.

14. Spyropoulos AC, Anderson FA Jr, Fitzgerald G et al. Predictive and associative models to identify hospitalized medical patients at risk for venous thromboembolism. Chest, 2011;140(3):706-714.

15. Kahn SR, Lim W, Dunn AS et al. American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;Feb;141(2 Suppl):e195S-226S.

16. Stashenko GJ, Tapson VF. Prevention of venous thromboembolism in medical patients and outpa-tients. Nat Rev Cardiol May. 2009;6(5):356-363.

9

Incidence of deep venous thrombosis after shoulder arthroplasty

Systematic review of literature

Struijk-Mulder MC1, Ettema HB1, Büller HR2, Verheyen CC1

1 Department of Orthopedic Surgery and Traumatology, Isala Klinieken, Zwolle, the Netherlands2 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands

Submitted

100 Chapter 9

ABSTRACT

Introduction

There is a paucity of data regarding the risk of deep vein thrombosis after shoulder arthroplasty. The purpose of this article is to review the available evidence regarding incidence of and risk factors for symptomatic venous thromboembolism (VTE) following shoulder arthroplasty. Mortality after shoulder arthroplasty was also assessed.We hypothesized that the incidence of VTE after shoulder arthroplasty might be higher than the previously reported incidence of VTE after shoulder arthroscopy (VTE: 0.038%, deep venous thrombosis (DVT) 0.029%, pulmonary embolism (PE) 0.017%) and lower than the incidence of VTE after major orthopedic surgery.


All papers describing symptomatic VTE after shoulder arthroplasty published in English literature retrieved from PubMed were reviewed. Case reports, primary upper limb thrombosis and other non-shoulder surgery-related causes were excluded. A total of five papers were available for analysis: all were large retrospective case series.

Results

The incidence of VTE was 0.59% in 47.998 shoulder arthroplasties. 0.33% of 22.461 procedures which were performed for non-traumatic indications (mostly osteoarthritis and cuff tear arthropathy) and 0.95% from 7.759 procedures for fractures of the proximal humerus. The 90-day incidence of PE (0.28%) was comparable to the 90-day incidence of DVT (0.32%). The mortality rate after shoulder arthroplasty was 0.49%; 0,43% for elective procedures and 3.0% in traumatic indications. The most common risk factors for VTE were comorbidities, traumatic indication for arthroplasty and advanced age.

Conclusions

This review shows that the incidence of VTE and the mortality rate following shoulder arthroplasty is relatively modest but not insignificant. The 90-day incidence of PE was comparable to the 90-day incidence of DVT. Mortality rate was nine times higher for traumatic indications than after elective arthroplasty. The risk of VTE after shoulder arthroplasty is higher than the previously reported risk of VTE after shoulder arthros-copy. Significant risk factors for VTE were the presence of comorbidities and a traumatic indication for shoulder arthroplasty.

Incidence of deep venous thrombosis after shoulder arthroplasty 101

9

InTRODuCTIOn

Early literature showed that without prophylaxis, the risk of venographically detected deep vein thrombosis (DVT) ranges from 40% to 70% following major orthopedic proce-dures, such as total hip and knee arthroplasty [1]. Therefore, following lower extremity joint replacement, it became standard practice to use pharma cological thromboprophy-laxis[2-4]. Literature from 1980 onwards shows lower venous thromboembolism (VTE) rates, probably because of early mobilization protocols and a significant reduction in the length of hospital stay and maybe because of pharmacological thromboprophylaxis with higher efficacy. The estimated 35-day symptomatic VTE rate without thrombopro-phylaxis after major orthopedic surgery is currently 4.3% (2.8% DVT and 1.5% pulmo-nary embolism (PE))[2]. When using thromboprophylaxis by means of LMWH, VTE rate is estimated to be 1.8% (1.25% DVT and 0.55% PE) [2].Shoulder arthroplasty is considered to cause less immobilization than lower extremity joint arthroplasty, but the procedure is more extensive than uncomplicated shoulder arthroscopy. There is a possibility that the incidence of thromboembolic events may actually be increased following shoulder arthroplasty vs. routine arthroscopy, which is supported by retrospective case series [5-9]. One study suggested that the rate of asymptomatic VTE may be as high as observed following total hip replacement[10].The aim of the present review is to evaluate the available evidence regarding incidence of and risk factors for symptomatic venous thromboembolism (VTE) following shoulder arthroplasty. Mortality after shoulder arthroplasty was also assessed. We hypothesized that the incidence of VTE after shoulder arthroplasty is higher than the baseline VTE risk of medical patients; higher than the previously reported incidence of VTE after shoulder arthroscopy and lower than the incidence of VTE after major orthopedic surgery.

MATERIAL AnD METHODS

A systemic search strategy was used to identify all papers describing symptomatic venous thrombo-embolism (deep venous thrombosis and pulmonary embolism) in shoulder arthroplasty published in English before august 8th 2013. We used the PRISMA statement for systematic reviews [11]. We performed an electronic PubMed, Cochrane and EMBASE database search. The terms (venous) thrombosis, thromboembolism, pulmonary embo-lism, shoulder surgery and shoulder arthroplasty were used. From the retrieved articles, the reference lists were screened for any relevant papers. Full text copies of these articles were obtained and assessed for eligibility. Case reports, shoulder arthroscopy, primary upper limb thrombosis and other non-shoulder surgery-related causes were excluded.

102 Chapter 9

All papers selected were analyzed for incidence of DVT and pulmonary embolism, risk factors and mortality.

RESuLTS

We reviewed 149 papers describing VTE after shoulder arthroplasty (Figure 1).There were no randomized controlled trials or non-randomized comparative studies.Two prospective studies were found [10-12], which actively screened for asymptomatic DVT. In both studies, thromboprophylaxis was giving by means of pneumatic compres-sion devices intra-operatively and aspirin post-operatively. These studies were not in-cluded in the analysis, as we defined symptomatic VTE as the primary outcome measure.Three review articles were identified [13-15]. from which the relevant studies were already included in our analysis and two papers described guidelines [16,17]; all five were excluded.Seven level II retrospective database analyses (describing prospectively collected data) were found, of which 3 studies described the same patient population[6,18,19].Ultimately, 5 studies[5-9] were eligible for this review (Table 1). Four studies described the 90-day VTE rate, and one study[9] described VTE rate during surgical admission only (4.7 days).

Incidence of VTE

The overall incidence of symptomatic VTE after shoulder arthroplasty was 0.59% in 47.998 procedures and ranged from 0.24 to 6.8% (Table 1). The 90-day incidence of PE (0.28%) was comparable to the 90-day incidence of DVT (0.32%). All but one study reported the incidence of VTE to be higher after hemi arthroplasty than after elective total shoulder arthroplasty. The VTE rate was higher in shoulder arthroplasty for trau-matic indications (0.95%) than after elective arthroplasty (0.33%). Mortality rate was also higher for traumatic indications (3.0%) than after elective arthroplasty (0.43%) (Table2).

Risk factors

Risk factors for VTE in the studied articles are shown in Table 3. Most common statistically significant risk factors were the presence of comorbidities and a traumatic indication for shoulder arthroplasty.

Diagnosis of VTE

In all 5 studies, the method of detection of DVT and PE was not documented. Diagnostic codes (ICD-9-CM and ICD-10) were used to extract diagnoses of DVT and PE from the


9

Tabl

e 1.

Sym

ptom

atic

ven

ous

thro

mbo

embo

lic c

ompl

icat

ions

of s

houl

der a

rthr

opla

sty

Proc

edur

es (n

)V

TED

VT

PE

Auth

orTo

tal

TSP

(n,%

)H

A(n

,%)

Tota

l(n

,%)

TSP

HA

Tota

l(n

,%)

TSP

HA

Tota

l(n

,%)

TSP

HA

Excl

uded

pat

ient

sSe

ttin

gPe

riod

(yrs

)

Nav

arro

2574

1388

(54)

1186

(46)

26 (1

.01)

1610

13(0

.51)

85

14(0

.54)

86

Prio

r VTE

Thro

mbo

prop

hyla

xis

< 2w

ks b

efor

e op

erat

ion

30 c

entr

es5

Sing

h40

19(3

480

patie

nts)

2588

(64)

1431

(36)

47 (1.2

)-

-13 (0.3

)-

-24 (0.6

)-

--

1 ce

ntre

32

Fang

h15

288

5044

(33)

1024

4(6

7)91 (0.6

)32

59-

--

--

-M

alig

nanc

yPr

ior s

houl

der s

urge

ry1

stat

e10

Jam

eson

1235

840

61(3

3)82

97(6

7)30

(0.2

4)8

2211

(0.0

9)0

1123

(0.1

9)8

15Pr

ior V

TEN

HS

3,5

Lym

an13

759

4931

(36)

8828

(64)

94 (6.8

)30

6469 (5.0

)20

4932 (2.3

)13

19-

1 st

ate

18

Tota

l (n,

%)

4799

818

012

(38)

2998

6(6

2)28

3(0

.59)

86(0

.56)

155

(0.5

4)10

6(0

.32)

28(0

.27)

65(0

.35)

93(0

.28)

29(0

.28)

40(0

.22)

VTE

= ve

nous

thro

mbo

embo

lism

DVT

= d

eep

veno

us th

rom

bosi

sPE

= p

ulm

onar

y em

bolis

mTS

P =

tota

l sho

ulde

r art

hrop

last

yH

A =

hem

i art

hrop

last

yN

HS

= N

atio

nal H

ealth

Ser

vice

104 Chapter 9

Tabl

e 2.

VTE

inci

denc

e an

d m

orta

lity

by p

roce

dure

type

and

pro

cedu

re in

dica

tion

Inci

denc

e of

VTE

Mor

talit

y

Elec

tive

proc

edur

eTr

aum

a pr

oced

ure

Elec

tive

proc

edur

eTr

aum

a pr

oced

ure

Auth

orTo

tal

TSP

(n,%

)H

A(n

,%)

Tota

l(n

,%)

TSP

HA

Tota

l(n

,%)

TSP

HA

Tota

l(n

,%)

TSP

HA

Nav

arro

16/1

988

(0.8

0)15

/134

2(1

.12)

1/64

6(0

.15)

10/5

86(1

.71)

1/46

(2.1

7)9/

540

(1.6

7)4/

1988

(0.2

0)3/

1342

(0.2

2)1/

646

(0.1

5)9/

586

(1.5

4)1/

46(2

.17)

8/54

0(1

.48)

Fang

h41

/102

44(0

.40)

--

50/5

044

(0.9

9)*

--

54/1

0244

(0.5

3)-

-14

5/50

44(2

.87)

*-

-

Jam

eson

16/1

0229

(0.1

6)8/

4061

(0.2

0)8/

6168

(0.1

3)14

/212

9(0

.66)

-14

/212

9(0

.66)

38/1

0229

(0.3

7)9/

4061

(0.2

2)29

/616

8(0

.47)

80/2

129

(3.7

6)-

80/2

129

(3.7

6)

Tota

l (n,

%)

73/2

2461

(0.3

3)74

/775

9(0

.95)

96/2

2461

(0.4

3)23

4/77

59(3

.0)

VTE

= ve

nous

thro

mbo

embo

lism

TSP

= to

tal s

houl

der a

rthr

opla

sty

HA

= h

emi a

rthr

opla

sty

* si

gnifi

cant

diff

eren

ce (P

<0,

05)


9

Table 3. Risk factors for VTE

Risk factors

Author Age Femalegender

ObesityBMI 25.5-29.9

History of DVT/PE

Comorbidity(Charlson Index)

Indication(trauma vs. elective)

Procedure type (hemi vs. TSP)

Navarro - - - Excluded - NS NS

Singh >70 * * * * ≥ 1 * * *

Fangh - - - - > 1 * * -

Jameson NS - - Excluded 1 *≥ 2 *

- -

Lyman 10-year increase in age *

NS - - NS * NS

* significant difference (P <0,05); NS = no significant differenceBMI = Body Mass IndexDVT = deep venous thrombosisPE = pulmonary embolismTSP = total shoulder prosthesis

Figure 1. Algorithm showing search methods, according to PRISMA methodologyFigure 1. Algorithm showing search method, according to PRISMA methodology

PubMed search: 108 articles EMBASE search: 52 articles

Cochrane search: 0 articles

149 articles after duplicates removed

149 articles screened 131 articles excluded

18 full text articles assessed for eligibility

13 full text articles excluded Exclusion criteria:

• Case reports • Non-shoulder surgery-

related causes • Shoulder arthroscopy • Primary upper limb

thrombosis • Articles regarding same

study population

5 studies included in qualitative synthesis

106 Chapter 9

databases. When a DVT was present, the location of the thrombus was reported by only one study [5]: 7 upper limb (1 contra-lateral) and 6 lower limb DVTs were described.

Prophylaxis

Three studies did not mention if thromboprophylaxis was used. Singh et al. [6] noted that thromboprophylaxis was not routinely used. Jameson and colleagues [8] reported that the majority of patients should get thromboprophylaxis according to the NHS guidelines.

DISCuSSIOn

Main findings

The overall 3-month incidence of symptomatic VTE after shoulder arthroplasty was 0.59% in 47.998 procedures and ranged from 0.24 to 6.8%. The 90-day incidence of PE (0.28%) was comparable to the 90-day incidence of DVT (0.32%). All but one study reported the incidence of VTE to be higher after hemi arthroplasty than after total shoul-der arthroplasty. The VTE rate was higher in shoulder arthroplasty for traumatic indica-tions (0.95%) than after elective arthroplasty (0.33%). The mortality rate was higher for traumatic indications (3.0%) than after elective arthroplasty (0.43%).The most common significant risk factors were the presence of comorbidities (such as cardiac, pulmonary, renal, diabetes, etc,) and a traumatic indication for shoulder arthro-plasty.The data were retrieved from five level II retrospective database analyses. Data were comparable, as their study design for the main outcomes (VTE, type of prosthesis) were almost identical. One study [6] did not describe the difference in type of prosthesis (hemi vs. total arthroplasty). Data on indication for surgery (traumatic vs. elective) and mortality could only be retrieved from three of the five studies.

An interesting finding is, that the incidence of PE (0.28%) was comparable to the inci-dence of DVT (0.32%). Lyman et al. [9] described higher DVT rates, probably because they described VTE rate during admission only (4.7 days on average). After total hip and total knee replacement, reported DVT rate is always much higher than PE rate. The main difference between upper extremity and lower extremity surgery may be explained by adequate early mobilization, causing less DVTs after shoulder surgery. The question remains why the incidence of PE is relatively high after shoulder arthroplasty. Would intramedullary reaming of the upper extremity lead to more PEs? The overall PE rate after shoulder surgery without thromboprophylaxis is lower than the PE rate after lower extremity arthoplasty [2]. The location of the thrombus might be a risk factor for de-


9

veloping pulmonary embolism after shoulder surgery. We are not able to comment on this matter, as only one study [5] documented this: seven upper extremity and six lower extremity DVTs were found. Willis et al. previously reported six asymptomatic DVTs in the upper extremity and seven situated in the lower extremity. Although in general, upper extremity DVTs account for only 4% of all DVTs [20], both upper and lower extremity DVTs have shown a similarly high rate (36%) of asymptomatic pulmonary embolism [21]. In patients with proven upper extremity DVT, 9% showed angiographically-proven symptomatic pulmonary embolism [22,23].

The incidence of thrombosis after shoulder arthroplasty will probably be underesti-mated, as this review included only symptomatic VTE. The incidence of asymptomatic DVT, as detected by ultrasound, is described to be as high as 13% in 100 patients, up to 12 weeks after surgery [10]. There is a relation between asymptomatic DVT and symp-tomatic VTE [24,25]. It remains unclear which percentage of asymptomatic lower leg thrombi propagate proximally from where they might cause pulmonary embolism. (In symptomatic calf vein clots, 20% propagate proximally [26] and asymptomatic proximal DVTs have demonstrated a risk of symptomatic PE in 40% [27]. Both phenomena (VTE/DVT) are symptoms of the same disease process of hypercoagulability, a condition we believe should be prevented.

Compared to shoulder arthroscopy, VTE rates after shoulder arthroplasty are higher. In their systematic review, Datani et al. described an overall VTE rate of 0.038% in 92440 patients, a PE rate of 0.017% and a DVT rate of 0.029% after shoulder arthroscopy. This risk is similar to the VTE risk in the general population [28].The higher VTE rate after shoulder arthroplasty could be explained by several factors. First, the mean age of patients undergoing arthroplasty is higher. Increased age is a known risk factor for VTE [2]. The duration of the operation is substantially longer in arthroplasty. Operations lasting more than 60 minutes are also described as an indepen-dent risk factor for VTE [2]. Arthroplasty is performed in beach chair position, while in shoulder arthroscopy both beach chair and lateral decubitus positions can be chosen. Beach chair position may lead to more VTE’s, due to venous stasis in the legs [29]. Con-trary to this statement, in their review Datani et al. found more upper extremity DVTs during lateral decubitus position (14 cases) than in beach chair position (4 cases) during arthroscopy of the shoulder, based on small numbers [13,30]. The incidence of upper extremity DVT may be attributed to traction and subsequently reduced limb perfusion [31]. Intramedullary reaming during arthroplasty placement may lead to (fatty) embolus formation [32]. Finally, intimal damage to the axillary vein during arthroplasty through (in)direct trauma may be caused by traction, repeated rotation of the humerus or direct pressure of retractors [10,33,34].

108 Chapter 9

Limitations

General limitations for retrospective database analysis of prospectively collected data apply: The diagnosis of VTE was extracted from ICD codes. Coding errors could occur. The exact method of detection of VTE (Doppler/CT angiogram/ventilation perfusion scan) is not described. There are no data on the location of the thrombus (upper or lower extremity).Data concern admitted or re-admitted patients within 90 days after shoulder arthro-plasty: there are no data on the outpatients diagnosed with and treated for DVT. (One study only included patients with VTE during surgical admission) [9].There are no data on the use or type of VTE prophylaxis. No data on cause of death are available. Patients who died at home are not accounted for.However, when a rare complication, such as VTE is investigated, large database studies are needed, because prospective, single centre studies would have to include thousands of patients and would take many years to perform. While randomized controlled trials are not available (for this same reason), the interpretation of database analyses is justi-fied.Recommendations regarding the use of thromboprophylaxis following shoulder arthro-plasty cannot be made based on this review. A randomized controlled trial should be performed, including sufficient patients to detect a difference between the incidence of VTE with (0.25%) and without thromboprophylaxis (0.59%).

COnCLuSIOn

The purpose of our study was to review the available evidence regarding incidence of and risk factors for symptomatic venous thromboembolism (VTE) following shoulder arthroplasty. Mortality was also investigated. The five retrospective database studies indicate a variable, low incidence of VTE and low mortality after shoulder arthroplasty. Mortality rate was nine times higher for traumatic indications than after elective arthro-plasty.Significant risk factors for VTE were the presence of comorbidities and a traumatic indication for shoulder arthroplasty. Recommendations regarding the use of thrombo-prophylaxis following shoulder arthroplasty cannot be made based on this review.


9

REFEREnCES

1. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW; American College of Chest Physicians (2008) Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Jun;133(6 Suppl):381S-453S.

2. Falck-Ytter Y, Francis CW, Johanson NA et al; American College of Chest Physicians (2012) Preven-tion of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Throm-bosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest Feb;141(2 Suppl):e278S-325S.

3. Mont MA, Jacobs JJ, Boggio LN et al. AAOS (2011) Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg Dec;19(12):768-76.

4. Struijk-Mulder MC, Ettema HB, Verheyen CCPM et al. (2010) Comparing consensus guidelines on thromboprophylaxis in orthopedic surgery. J Thromb Haemost Apr;8(4):678-83.

5. Navarro RA, Inacio MCS, Burke MF, Costouros JG, Yian EH (2013) Risk of thromboembolism in shoulder arthroplasty: effect of implant type and traumatic indication. Clin Orthop Relat Res 471:1576-1581.

6. Singh JA, Sperling J, Cofield R (2012) Cardiopulmonary complications after primary shoulder arthroplasty: a cohort study. Semin Arthritis Rheum April 41(5):689-697.

7. Farng E, Zingmond D, Krenek L, Soohoo NF (2011) Factors predicting complication rates after primary shoulder arthroplasty. J Shoulder Elbow Surg 20:557–563.

8. Jameson SS, James P, Howcroft DW, et al. (2011) Venous thromboembolic events are rare after shoulder surgery: analysis of a national database. J Shoulder Elbow Surg 20:764–770.

9. Lyman S, Sherman S, Carter TI, et al. (2006) Prevalence and risk factors for symptomatic thrombo-embolic events after shoulder arthroplasty. Clin Orthop Relat Res 448:152–156.

10. Willis AA, Warren RF, Craig EV, et al. (2009) Deep vein thrombosis after reconstructive shoulder arthroplasty: a prospective observational study. J Shoulder Elbow Surg 18:100–106.

11. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS medicine 6;e100097

12. Widmer BJ, Bassora R, Warrender WJ, Abboud JA (2001) Thromboembolic events are uncommon after open treatment of proximal humerus fractures using aspirin and compression devices. Clin Orthop Relat Res. Dec;469(12):3332-6.

13. Dattani R, Smith CD, Patel VR (2013)The venous thromboembolic complications of shoulder and elbow surgery: a systematic review. Bone Joint J Jan;95-B(1):70-4.

14. Ojike NI, Bhadra AK, Giannoudis PV, Roberts CS (2011) Venous thromboembolism in shoulder surgery: a systematic review. Acta Orthop Belg Jun;77(3):281-9.

15. Saleh HE, Pennings AL, Elmaraghy AW (2013) Venous thromboembolism after shoulderarthro-plasty: a systematic review. J Shoulder Elbow Surg Oct;22(10):1440-8. Epub 2013 Aug 21.

16. Anakwe RE, Middleton SD, Beresford-Cleary N, McEachan JE, Talwalkar SC (2013) Preventing ve-nous thromboembolism in elective upper limb surgery. J Shoulder Elbow Surg. Mar;22(3):432-8.

17. Izquierdo R, Voloshin I, Edwards S, Freehill MQ, Stanwood W, Wiater JM, Watters WC 3rd, Goldberg MJ, Keith M, Turkelson CM, Wies JL, Anderson S, Boyer K, Raymond L, Sluka P; American Academy of Orthopedic Surgeons (2010) Treatment of glenohumeral osteoarthritis. J Am Acad Orthop Surg Jun;18(6):375-82.

110 Chapter 9

18. Hoxie SC, Sperling JW, Cofield RH (2007) Pulmonary embolism after operative treatment of proxi-mal humeral fractures. J Shoulder Elbow Surg Nov-Dec;16(6):782-3.

19. Sperling JW, Cofield RH (2002) Pulmonary embolism following shoulder arthroplasty. J Bone Joint Surg Am Nov;84-A(11):1939-41.

20. Horattas MC, Wright DJ, Fenton AH, Evans DM, Oddi MA, Kamienski RW & Shields EF (1988) Changing concepts of deep venous thrombosis of the upper extremity—report of a series and review of the literature. Surgery 104: pp. 561-567

21. Prandoni P, Polistena P, Bernardi E, Cogo A, Casara D, Verlato F, Angelini F, Simioni P, Signorini GP, Benedetti L, Girolami A (1997) Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med Jan 13;157(1):57-62.

22. Lee J, Zierler BK, Zierler RE (2012) The Risk Factors and Clinical Outcomes of Upper Extremity Deep Vein Thrombosis. Vac endovasc surg 46: 2;139-144.

23. Muñoz FJ, Mismetti P, Poggio R, Valle R, Barrón M, Guil M, Monreal M; RIETE Investigators (2008) Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE Registry. Chest Jan;133(1):143-8.

24. Turpie AG, Bauer KA, Eriksson BI et al. (2004) Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest 126:501–508.

25. Segers AE, Prins MH, Lensing AW et al. (2005) Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies? J.Thromb.Haemost 3:1099-1102.

26. Philbrick J, Becker D (1988) Calf vein thrombosis: a wolf in sheeps clothing? Arch Int Med 148:2131-2138

27. Kelly J, Rudd A, Lewis RR et al. (2001) Screening for subclinical deep-vein thrombosis. Q J Med 94:511-519.

28. Sweetland S, Green J, Liu B et al. (2009) Duration and magnitude of the postoperative risk of the hospital incidence of venous thromboembolism in middle aged women: prospective cohort study. BMJ 339:4583.

29. Mansfield AO. (1972) Alteration of fibrinolysis associated with surgery and venous thrombosis. Br. J. Surg 59:754-757.

30. Kuremsky MA, Cain L, Fleischli J (2007) Thromboembolic events after arthoscopic shoulder sur-gery: a case series of unusual complications. Arthroscopy 16(suppl):18-19.

31. Hennrikus WL, Mapes RC, Bratton MW, Lapoint JM (1995) Lateral traction during shoulder arthro-scopy: it’s effects on tissue perfusion measured by pulse oximetry. Am J Sports Med 23:444-446.

32. Parmet JL, Horrow JC, Keykhah MM, Sirianni A, Singer R, Weiss A (1995) Accumulation of a right ventricular mass during shoulder hemiarthroplasty. Anesth Analg Mar;80(3):614-6.

33. Arcand M, Burkhead WZ, Zeman C (1997) Pulmonary embolism caused by thrombosis of the axil-lary vein after shoulder arthroplasty. J Should Elbow Surg 6:486-490.

34. Saleem A, Markel DC (2001) Fatal pulmonary embolus after shoulder arthroplasty. J. Arthroplasty 16:400-403.

10

Incidence of deep venous thrombosis after arthroplasty of the shoulder Study protocol and preliminary

results of INDRA-P study

MC Struijk-Mulder1, HB Ettema1, CCPM Verheyen CC1, JJAM van Raaij2, PC Rijk3, HR Büller4

1 Department of Orthopedic Surgery and Traumatology, Isala Klinieken, Zwolle, the Netherlands2 Department of Orthopedic Surgery, Martini Ziekenhuis, Groningen, the Netherlands

3 Department of Orthopedic Surgery, Medisch Centrum Leeuwarden, Leeuwarden, the Netherlands4 Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

Study in progress

112 Chapter 10

ABSTRACT

Background

A paucity of data exists on the risk of deep venous thrombosis after shoulder arthro-plasty. Currently there are few level II retrospective studies regarding the incidence of symptomatic venous thromboembolism (VTE) following shoulder arthroplasty. The incidence ranges from 0.24 to 6.8%. Symptomatic deep venous thrombosis (DVT) was found in 0.09 to 5.0 %. Symptomatic 90-day pulmonary embolism (PE) rates ranged from 0.54 to 2.3%. The highest percentages reported are even higher than those following lower extremity arthroplasty. This is the first study on the incidence of asymptomatic DVT after shoulder arthroplasty without prophylaxis.

Methods and design

A prospective cohort of 100 consecutive patients who are scheduled for shoulder ar-throplasty for non-traumatic indications will be included. All eligible patients will be assessed clinically for VTE and screened for DVT by bilateral complete c-ompression ultrasonography (CCUS) of both legs and the operated arm at day 14 postoperatively. No thromboprophylaxis will be given.

Preliminary results

The first eight included patients did not show DVT nor had symptoms of pulmonary embolism.

Discussion

This study first aims to establish the incidence of asymptomatic deep venous thrombo-sis as detected by ultrasound. If the incidence of VTE will be substantial, a randomized controlled clinical trial comparing pharmacological thromboprophylaxis and placebo will follow, to identify risk factors for VTE patients undergoing shoulder arthroplasty and to investigate the need for thromboprophylaxis.

Incidence of deep venous thrombosis after arthroplasty of the shoulder 113

10

BACKGROunD

Early literature showed that without prophylaxis, the risk of venographically detected deep vein thrombosis (DVT) ranges from 40% to 70% following major orthopedic proce-dures, such as total hip and knee arthroplasty.1 Therefore, following lower extremity joint replacement, it is standard practice to use pharma cological thromboprophylaxis.2-4 Literature from 1980 onwards shows lower venous thrombo embolism (VTE) rates, prob-ably because of early mobilization protocols and a significant reduction in length of hospital stay. The estimated 35-day symptomatic VTE rate without thromboprophylaxis after major orthopedic surgery is currently 4.3% (2.8% DVT and 1.5% pulmonary embo-lism (PE)).2

Shoulder arthroplasty is considered to cause less immobilization than lower extremity joint arthroplasty, but the procedure is far more extensive than uncomplicated shoulder arthroscopy. There is a genuine possibility that the incidence of thromboembolic events is substantially higher following shoulder arthroplasty vs. routine arthroscopy, which is supported by retrospective case series5-9.The incidence of symptomatic VTE was only investigated in level II retrospective data-base studies.5-9 The incidence ranges from 0.24 to 6.8 %. Two studies prospectively re-ported incidences of asymptomatic deep venous thrombosis after shoulder arthroplasty of respectively 0 and 13%. However, both studies used pharmacological prophylaxis with aspirin in addition to mechanical thromboprophylaxis10-11 and had sample sizes of respectively 10 and 100 patients studied.To our knowledge, this is the first study on the incidence of symptomatic VTE and a-symptomatic DVT after shoulder arthroplasty without prophylaxis. There is no consensus regarding the need for perioperative pharmacological thromboprophylaxis following shoulder arthroplasty within and amongst guidelines.15

PuRPOSE

The aim of our study is to establish the inci dence of venous thrombo-embolic complica-tions as detected by bilateral complete compression ultrasonography after shoulder arthroplasty without thromboprophylaxis.We hypothesize that the incidence of VTE after shoulder arthroplasty will be higher than the baseline VTE risk of medical patients; higher than the previously reported incidence of VTE after shoulder arthroscopy and lower than the incidence of VTE after major ortho-pedic surgery. This is the first step to determine whether routine thromboprophylaxis is warranted after shoulder arthroplasty.

114 Chapter 10

METHODS AnD DESIGn

This Dutch multi-center study has started at the Isala Klinieken Zwolle and will also com-mence soon at the Martini Ziekenhuis, Groningen and Medisch Centrum Leeuwarden.All consecutive patients aged 18 years or older, scheduled for shoulder arthroplasty will undergo complete compression ultrasonography (CCUS) of both legs and the operated arm approximately 14 days post-procedure. Clinical data including date of birth, sex, race, weight and height are recorded at entry. Patients meeting one of the following criteria are excluded from the study: fracture of proximal humerus, inability or unwilling-ness to give writ ten informed consent, inability to be followed-up, ongoing treatment with anticoagulant therapy (excluding aspirin) and a history of VTE. Exclusion criteria are limited, to keep selection bias to a minimum.

Peri-operative management

Patients are operated in beach-chair position. We use a standard deltopectoral ap-proach. All types of shoulder prosthesis are eligible: total shoulder arthroplasty, hemi-arthroplasty, resurfacing shoulder arthroplasty and reversed shoulder prosthesis. Concomitant treatments such as rotator cuff repair, and operative time will be recorded. An intra-articular drain is inserted, and removed on the first post-operative day.

Post-operative management

A shoulder immobilizer is applied for 6 weeks. On the first post-operative day, patients are instructed by a physiotherapist regarding wrist and elbow movements, to be repeated every hour. No limitations are imposed regarding ambulatory status. A pain protocol starting with paracetamol is initiated and patients are allowed to use non-steroid anti-inflammatory drugs according to their need. Physiotherapy is continued for 6 months. Routinely patients will be admitted for two days; the day of operation and the first post-operative day. No thromboprophylaxis is given; neither during hospital stay nor after discharge. Mechanical thromboprophylaxis is also not used.Two follow-up contacts are scheduled; when CCUS will be performed (2 weeks) and after 6 weeks in the outpatient clinic. Patients will be asked if they had had any clinical signs or symp toms of VTE following the operation. The clinical signs documented are pain, tenderness, swelling or redness of the legs, dyspnea, chest pain and hemoptysis. In ad-dition, patients are instructed to contact the hospital if one of these signs or symptoms occur prior to a follow-up contact. If clinical symptoms of VTE occur, the patient will be referred to the department of internal medicine and either CCUS, for suspected DVT or a CT angiogram, for suspected PE will be performed. If VTE is detected, nadroparin 5700 IE s.c. will be administered twice daily for at least 5 days, until adequate INR of 2,5 -3,5 will be reached with vitamin K antagonists, according to hospital protocols.


10

Complete compression ultrasonography

Three experienced ultrasound technicians perform CCUS of the leg veins and operated arm veins. All of them received a supervised period of training before participating as a sonographer in this study. The ultrasound device used is a linear L9-3 MHz sono-graphic scanner (Philips IU22). A stan dardized protocol for complete compression ultra-sonography is applied16 requiring an examination time of approximately 40 minutes for both legs and 20 minutes for the arm.The criterion for the diagnosis of DVT is inability to compress the veins with the ultra-sound transducer. Ultrasonography findings are recorded as normal (negative), abnor-mal (posi tive), or inadequate for interpretation if a complete vein or segment of a vein could not be visualized. A venous thrombus of the legs is classified as proximal throm-bosis (with or without concomitant calf vein thrombosis), isolated calf vein thrombosis or muscle vein thrombosis. The proximal venous system of the leg is defined as the deep veins in the pelvis, the thigh, and the popliteal region cephalad to the trifurcation of the calf veins. A venous thrombosis of the operated arm is classified as a proximal thrombo-sis (with of without concomitant lower arm thrombosis), or lower arm thrombosis. The proximal venous system of the arm is defined as truncus brachiocephalica, subclavian vein, axillary vein and brachial vein.

Outcome measures

The primary outcome measure of the study is the combined incidence of symptomatic and asymptom atic venous thromboembolic complications after shoulder arthroplasty during the 2-week follow-up period (as diagnosed by a single postoperative complete compression ultrasound sonography, CCUS). The secondary outcome measure is the incidence of symp tomatic venous thromboembolic complications and mortality after shoulder arthroplasty during the 6 weeks of postoperative follow-up. The principal safety outcome measure is the cumulative incidence of major and clinically relevant non-major bleeding events. A major bleeding event is defined as a clinically overt hemorrhage associated with a decrease in hemoglobin requiring transfusion, a bleeding event requiring re-intervention, or a haemarthrosis with joint drainage of more than 250 mL. A clinically relevant non-major bleeding event is defined as a haemarthrosis with joint drainage of 100 to 250 mL that did not require re-intervention.

Ethics

This is an observational cohort study but since an ultrasound is performed, written in-formed consent is requested and the study was approved by the local ethics committee of all participating hospitals.

116 Chapter 10

Statistical analysis

As the expected incidence of DVT after shoulder arthroplasty is unknown, we calculated the sample size, presuming an incidence of 10%. With a sample size of 100 patients, a sufficiently narrow confidence interval will be reached with a power of 80% and a signifi-cance level of 5%. The analysis is based on intention to treat. Incidences are presented as a proportion of the studied population. 95% confidence intervals are calculated using CIA software, (BMJ books, London) using the exact method. Continuous variables are compared using Stu dent’s t-test or, in the case of an abnormal distri bution, the Mann-Whitney U test. Categorical data are compared with cross tabulation (Chi-square, Fisher’s exact test).

Study period and data dissemination

The study has started in November 2012 at the Isala Clinics, Zwolle and will soon commence at the other two hospitals. The recruitment period will be one year. Study completion includes submission to relevant national and international conferences and peer reviewed publications.

PRELIMInARy RESuLTS

During the study period, 12 consecutive patients were scheduled for shoulder ar-throplasty, one of which underwent bilateral shoulder arthroplasty in two separate operations. Three patients were excluded: use of anticoagulant therapy (1 patient), inability to provide informed consent (1 patients), and the anesthetists disapproval of participation of one patient with a biological heart valve replacement, who did not use anti-coagulants. One patient did not present for the ultrasonography investigation. Thus 8 patients were included and gave their consent. The mean duration of hospital stay was 3.5 days (range, 2 to 6 days). Ultimately, 8 patients (9 operations) were included for the analysis of the primary and secondary outcome parameters. The baseline characteristics of the 8 patients (9 procedures) who completed the ultrasonography studies are listed in Table 1.The first eight included patients did not show any DVT on extended CUS examination, which was performed approximately 17 days after the procedure (range, 14 to 22 days). All ultrasonography scans were evaluated as adequate. Also, no symptomatic VTE epi-sodes were reported. Regarding the principal safety outcome, no major bleeding events occurred. The patients did not require transfusions, and no bleeding events requiring re-intervention were observed. Post-thrombotic syndrome was not observed in our patient group.


10

DISCuSSIOn

To our knowledge, this is the first study on the incidence of symptomatic VTE and asymptomatic DVT after shoulder arthroplasty without prophylaxis. There is no con-sensus regarding the need for perioperative pharmacological thromboprophylaxis fol-lowing shoulder arthroplasty within and amongst guidelines.15 When the incidence will be substantial, a randomized controlled clinical trial comparing thromboprophylaxis

Table 1. Baseline demographic and operation characteristics

(n=9)*

Age in yrs, mean ± SD 68.7 ± 9.1

BMI, mean ± SD 29.1 ± 3.8

Gender, n (%) Male 5 (56)

Female 4 (44)

Ethnicity, n (%) European 9 (100)

Side, n (%) Left 3 (33)

Right 6 (67)

Medication, n (%) Aspirin 1 (11)

Paracetamol 3 (33)

Antihypertensives 4 (44)

Malignancy -

Contraceptives, n (%) Current use -

Previous use 1 (11)

HRT, n (%) Current use -

Previous use 1 (11)

Family history of VTE, n (%) -

Varicosis, n (%) 2 (22)

Thrombophilic factors -

Anesthesia, n (%) Loco regional 1 (11)

General 2 (22)

Both 6 (67)

Type of prosthesis, n (%) Hemi 2 (22)

Total shoulder 5 (56)

Reversed 1 (11)

Resurfacing 1 (11)

Duration of Operation(min, Mean ± SD)

95 ± 28

BMI, body mass index; HRT, hormone replacement therapy; VTE, venous thrombo embolism* n = 9 operations in 8 patients.

118 Chapter 10

and placebo will follow, to determine risk factors for VTE patients undergoing shoulder arthroplasty and to investigate the need for thromboprophylaxis.

Shoulder arthroplasty is considered to cause less immobilization than lower extremity joint arthroplasty, but the procedure is far more extensive than uncomplicated shoulder arthroscopy. There is a genuine possibility that the incidence of thromboembolic events is substantially higher following shoulder arthroplasty vs. routine arthroscopy, which is supported by retrospective case series.5-9

A paucity of data exists on the risk of deep venous thrombosis after shoulder arthro-plasty. Currently there are few level II retrospective studies regarding the incidence of symptomatic VTE following shoulder arthroplasty.5-9 The incidence ranges from 0.24 to 6.8 %. Symptomatic DVT was found in 0.09 to 5.0 %. Symptomatic 90-day PE rate ranged from 0.54 - 2.3%. The highest percentages reported are even higher than those follow-ing lower extremity arthroplasty.Two studies prospectively investigated the incidence of asymptomatic deep venous thrombosis after shoulder arthroplasty. Incidences of 0 to 13% of DVT, using both aspirin and mechanical thromboprophylaxis, were detected by color-flow Doppler ultrasound.10-11 Widmer et al.10 included 10 patients who underwent hemi arthroplasty after a proximal humeral fracture and the ultrasound was performed at postoperative day 14. Willis et al.11 included 100 patients: in all patients the ultrasound was performed at postoperative day 2, and in 50 patients the ultrasound was repeated at week 12.Likewise, no randomized controlled clinical trials on VTE after shoulder arthroscopy could be found in literature. Only four retrospective case series after shoulder arthroscopy could be found, with incidences of symptomatic VTE ranging from 0.011 to 0.38%. (DVT: 0.0046-0,38; PE: 0.008-0.26).9,12-14

Limitations

One potential limitation of our study is the rela tively small number of patients, even if completed to 100 cases. Because of this, a risk factor analysis for the development of VTE in our population will be limited. Secondly, ultrasonography was chosen over contrast venography to assess the inci-dence of deep venous thrombosis, potentially underestimating the actual incidence. Contrast venography is a more sensitive method for detecting DVT and considered to be the golden standard.2,17,18 Venography is invasive however. Up to 20% of venograms is considered inadequate for evaluation,19 a considerable degree of intra-observer and inter-observer variation is present19 and the clinical relevance of small thrombi is un-certain.20 Therefore, the use of venography as a screening test in unselected patients is undesirable. Ultrasound is non-invasive, and repeatable. The accuracy of ultrasound is somewhat reduced for the calf veins however, and it is operator dependent.19 Sensitivity


10

and specificity for the detection of symptomatic DVT with ultrasound is equivalent to venography.21 However, combined data from 11 level 1 studies investigating the utility of various US techniques for the diagnosis of asymptomatic DVT in orthopedic patients demonstrated a sensitivity of 62% for proximal and 48% for below-knee DVTs. Reduced sensitivity can be explained by the fact that asymptomatic thrombi are more likely to be fresh, smaller and non-occlusive than their symptomatic counterparts.22-24

The presence of pre-operative asymptomatic thrombi will not be determined in this study. However, a low baseline risk in this patient group without prior history of VTE can be assumed.Furthermore we will exclude patients with a history of VTE potentially causing a further underestimation of the risk of VTE. Finally, results from prospective cohort studies have shown that most asymptomatic thrombi in patients undergoing hip or knee replacement remain clinically silent. These results raise questions about the clinical relevance of asymptomatic DVT detected by ultrasound. There is, however, a relation between asymptomatic DVT and symptomatic VTE.25,26 It remains unclear which percentage of asymptomatic lower leg thrombi propa-gates proximally from where they might cause pulmonary embolism. (In symptomatic calf vein clots, 20% propagate proximally20 and asymptomatic proximal DVTs have dem-onstrated a risk of symptomatic PE in 40%).27 Both phenomena (VTE/DVT) are symptoms of the same disease process of hypercoagulability, a condition we believe should be prevented.

120 Chapter 10

REFEREnCES

1. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW; American Col-lege of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S.

2. Falck-Ytter Y, Francis CW, Johanson NA et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S.

3. Mont MA, Jacobs JJ, Boggio LN et al. AAOS. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011 Dec;19(12):768-76.

4. Struijk-Mulder MC, Ettema HB, Verheyen CCPM et al. Comparing consensus guidelines on throm-boprophylaxis in orthopedic surgery. J Thromb Haemost. 2010 Apr;8(4):678-83.

5. Navarro RA, Inacio MCS, Burke MF, Costouros JG, Yian EH. Risk of thromboembolism in shoul-der arthroplasty: effect of implant type and traumatic indication. Clin Orthop Relat Res 2013; 471:1576-1581.

6. Singh JA, Sperling J, Cofield R, Cardiopulmonary complications after primary shoulder arthro-plasty: a cohort study. Semin Arthritis Rheum. 2012;April 41(5):689-697.

7. Farng E, Zingmond D, Krenek L, Soohoo NF. Factors predicting complication rates after primary shoulder arthroplasty. J Shoulder Elbow Surg 2011;20:557–563.

8. Jameson SS, James P, Howcroft DW, et al. Venous thromboembolic events are rare after shoulder surgery: analysis of a national database. J Shoulder Elbow Surg 2011;20:764–770.

9. Lyman S, Sherman S, Carter TI, et al. Prevalence and risk factors for symptomatic thromboembolic events after shoulder arthroplasty. Clin Orthop Relat Res 2006;448:152–156.

10. Widmer BJ, Bassora R, Warrender WJ, Abboud JA. Thromboembolic events are uncommon after open treatment of proximal humerus fractures using aspirin and compression devices. Clin Or-thop Relat Res. 2011;469:3332-3336.

11. Willis AA, Warren RF, Craig EV, et al. Deep vein thrombosis after reconstructive shoulder arthro-plasty: a prospective observational study. J Shoulder Elbow Surg 2009;18:100–106.

12. Kuremsky MA, Cain EL, Fleischli JE. Thromboembolic phenomena after arthroscopic shoulder surgery. Arthroscopy 2011;27:1614–1619.

13. Brislin KJ, Field LD, Savoie FH. Complications after arthroscopic rotator cuff repair. Arthroscopy 2007;23:124–128.

14. Hoxie SC, Sperling JW, Cofield RH. Pulmonary embolism following rotator cuff repair. Int J Shoul-der Surg 2008;2:49–51.

15. Anakwe RE, Middleton SD, Beresford-Cleary N, McEachan JE, Talwalkar SC. Preventing venous thromboembolism in elective upper limb surgery. J Shoulder Elbow Surg.2013;22:432-438.

16. Schellong S M, Schwarz T, Halbritter K et al. Complete com pression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Hae most 2003; 89: 228-234.

17. Lausen I, Jensen R, Wille-Jørgensen P et al. Colour Doppler flow imaging ultrasonography versus venography as screening method for asymptomatic postoperative deep venous thrombosis. Eur J Radiol. 1995 Sep;20(3):200-4.


10

18. Bates SM, Jaeschke R, Stevens SM et al. American College of Chest Physicians. Diagnosis of DVT, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2)(suppl):e351-e418s.

19. Barnes RW, Nix ML, Barnes CL et al. Perioperative asymptomatic venous thrombosis: role of duplex scanning versus venography. J Vasc Surg. 1989 Feb;9(2):251-60.

20. Philbrick J, Becker D. Calf vein thrombosis: a wolf in sheeps clothing? Arch Int Med 1988;148:2131-2138

21. Polak JF, Cutter S, Oleary D. Deep veins of the calf: assessment with color Doppler flow imaging. Radiology 1989;171:481-485.

22. Lensing AW, Doris CI, McGrath FP et al. A comparison of compression ultrasound with color Dop-pler ultrasound for the diagnosis of symptomless postoperative deep vein thrombosis. Arch Int Med 1997; 157:765-768.

23. Wells PS, Lensing WA, Davidson BL et al. Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery. A meta-analysis. Ann Intern Med 1995; 122:47-53.

24. Nicolaides A, Kalkodi E. Duplex scanning in post-operative surgical patients. Haemostasis 1993;23 (suppl 1):72-79.

25. Turpie AG, Bauer KA, Eriksson BI et al. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest 2004;126:501–508.

26. Segers AE, Prins MH, Lensing AW et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies? J.Thromb.Haemost. 2005;3:1099-1102.

27. Kelly J, Rudd A, Lewis RR et al. Screening for subclinical deep-vein thrombosis. Q J Med 2001;94:511-519.

Appendices

Summary 125

A

SuMMARy

This thesis describes the use of thromboprophylatic modalities after total hip and total knee arthroplasty by Dutch orthopedic departments over a period of ten years and several uncertainties regarding thromboprophylaxis in other areas of orthopedic sur-gery. In this thesis some of these uncertainties are addressed: the incidence of venous thromboembolism after arthroscopic cruciate ligament reconstruction, lower extremity amputation, and shoulder arthroplasty and a case of pulmonary embolism during trial hip plaster cast immobilization.

In chapter 1 a general introduction and a short overview of the history of thrombopro-phylactic regimens in patients undergoing orthopedic surgery is presented.

Thromboprophylaxis and blood management in the netherlands

To asses changes in patterns in Dutch Orthopedic thromboprophylaxis practices, three surveys were conducted. In chapter 2, the results of the second survey, conducted in 2007, are described. The use of pharmacological prophylaxis after arthroplasty of the hip and knee as well as after fracture surgery around the hip and knee was common practice in the Netherlands in 2007. In five years time the widely used coumarin-derivates have largely been replaced by LMWH. Low molecular weight heparin was most frequently used (79%), followed by fondaparinux (13%).Chapter 3 summarizes the results of the third survey, performed in 2012. The use of thromboprophylaxis in and out of hospital was still the standard of care in the Neth-erlands after hip and knee surgery. Although currently low molecular weight heparin remains the most commonly used thromboprophylactic agent, the new oral anticoagu-lants are now used in 25% of all departments. In day-care surgery and arthroscopies either no prophylaxis was given (68% and 56% respectively), or a single shot of LMWH (23% and 39% respectively) was employed. There is a significant increase in the use of thromboprophylaxis during plaster cast immobilization and in the use of extended thromboprophylaxis after ACL surgery.In chapter 4, the use of blood saving modalities among Dutch orthopedic departments during a 10-year follow-up period is described. The use of intraoperative autologous retransfusion in revision hip (56 vs. 54%) as well as revision knee arthroplasty (26 vs. 24%) was virtually unchanged in 2012 compared to five years earlier. Postoperative autologous retransfusion is still used by the majority of departments after both primary arthroplasty and revision of hip (58/53%) and knee (65/61%). Currently, just as in 2007, the majority of Dutch orthopedic departments use erythropoietin, normothermia and postoperative autologous retransfusion with hip and knee arthroplasty. Other effective

Summary126

blood management modalities such as tranexamic acid have not been widely imple-mented.


In Chapter 5 eleven (inter)national guidelines on thromboprophylaxis from different countries are compared, and their differences analyzed. Eleven guidelines from nine dif-ferent countries and one international guideline were included. Few guidelines advice on thrombosis prophylaxis after plaster cast immobilization, (prolonged) arthroscopic surgery and isolated lower extremity trauma. Different opinions exist on the sole use of aspirin and mechanical prophylaxis and on the use of Vitamin K antagonists after major hip- and knee surgery. The grade of recommendation should ideally be based on the same level of evidence worldwide. It will be impossible to reach a consensus as long as there is no agreement on the relevance of different outcomes (e.g. asymptomatic DVT).


In chapter 6, the results of our study regarding the incidence of deep venous throm-bosis after arthroscopic cruciate ligament reconstruction are described. In total 9 of 100 patients (incidence 9%; 95% CI: 4.2-16.4) showed asymptomatic proximal or distal deep vein thrombosis on compression ultrasound, of whom 4 (incidence 4%; 95% CI: 1.1-9.9) were symptomatic. One patient developed a non-fatal pulmonary embolus dur-ing the 8-week follow-up period. This study shows that the incidence of VTE following arthroscopic ACL reconstruction is relatively high. Further research is recommended to assess the need for thromboprophylaxis in patients undergoing ACL reconstruction, especially when risk factors are present.


In the study, described in chapter 7, we prospectively determined the occurrence of deep venous thrombosis and pulmonary embolism both pre- and post-operatively after lower extremity amputation by means of duplex-ultrasonography and ventilation-perfusion lung scintygraphy. Forty-nine patients (53 amputations) were ultimately included in the intention-to-treat analysis. The total mortality rate was 12 of 53 amputa-tions (22.6%, 95% confidence interval (CI) 12.3-36.2). Six patients developed pulmonary embolisms (of which two were fatal) and one patient developed an asymptomatic contra lateral distal deep venous thrombosis resulting in a total VTE rate of 7 out of 53 amputations (13.2%, 95% CI 5.47-25.3). Lower extremity amputation is accompanied by a high mortality rate from sepsis, respiratory and vascular causes. This study shows that VTE substantially contributes to the morbidity and mortality after lower extremity amputation despite adequate pharmacological thromboprophylaxis in this vulnerable population.

Summary 127

A

Plaster cast immobilization

In chapter 8 a case of pulmonary embolism during trial hip plaster cast immobiliza-tion to simulate lumbosacral fusion is described and a review of literature is presented. Generally, immobilization is considered a major risk factor for VTE. In our case the immo-bilization induced by the hip plaster cast, combined with the use of oral contraceptive medication (OCM) puts our patient in the high-risk category. Therefore we recommend that patients who are fitted with a hip plaster cast should be routinely screened for ad-ditional risk factors such as OCM use and a history of VTE. When risk factors are present, patients should be considered for pharmacological thromboprophylaxis.


In chapter 9 a systematic review of literature regarding symptomatic thrombosis after shoulder arthroplasty is presented. The incidence of VTE was relatively low: 0.59% in 47,998 shoulder arthroplasties. The VTE rate for arthroplasty after fractures of the proxi-mal humerus was almost three times as high as the VTE rate for elective, non-traumatic indications; 0.95% vs. 0.33% respectively. The 90-day incidence of PE was comparable to the 90-day incidence of DVT. The mortality rate after shoulder arthroplasty was 0.49%; 0.43% for elective procedures and 3.0% in traumatic indications. The most common statistically significant risk factors for VTE were comorbidities, traumatic indication for arthroplasty and advanced age.Chapter 10 describes our study protocol regarding the incidence of asymptomatic venous thrombo embolic complications as detected by bilateral complete compression ultrasonography of both legs and the operated arm after shoulder arthroplasty without thromboprophylaxis. The first ten included patients did not show any DVT or pulmonary embolism. This study aims to establish the incidence of asymptomatic deep venous thrombosis as detected by ultrasound. If DVT is frequently encountered, a randomized controlled clinical trial comparing thromboprophylaxis and placebo will follow, to deter-mine risk factors for VTE patients undergoing shoulder arthroplasty and to investigate the need for thromboprophylaxis.

Samenvatting 129

A

SAMEnVATTInG

Dit proefschrift beschrijft het gebruik van trombose profylaxe na totale heup,- en totale knie prothesen door Nederlandse orthopedische vakgroepen over een periode van tien jaar, alsmede onzekerheden aangaande het profylaxebeleid voor wat betreft andere orthopedische ingrepen. In dit proefschrift wordt een aantal van deze onzekerheden belicht: de incidentie van veneuze trombose na arthroscopische voorste kruisband re-constructie, amputatie van de onderste extremiteit en schouder prothesiologie en een casus van een longembolie tijdens gipscorset met beenpijp immobilisatie.

In hoofdstuk 1 wordt een algemene introductie en een kort historisch overzicht gege-ven wat betreft tromboseprofylaxe regimes bij patiënten die orthopedische chirurgie ondergaan.

Tromboseprofylaxe en bloedmanagement in nederland

Om de veranderingen voor wat betreft Nederlandse orthopedische tromboseprofylac-tisch beleid in te schatten werden drie enquêtes gehouden. In hoofdstuk 2 worden de resultaten van de tweede enquête, verricht in 2007 beschreven. Het gebruik van farmacologische profylaxe na heup- en knieprothesiologie was common practice in Nederland in 2007. Binnen vijf jaar is het wijd verbreide gebruik van coumarine deriva-ten vervangen door laag moleculair gewicht heparines (LMWH). LMWH werd het meest gebruikt (79%), gevolgd door fondaparinux (13%).Hoofdstuk 3 vat de resultaten van de derde enquête samen, uitgevoerd in 2012. Het gebruik van tromboseprofylaxe tijdens opname en erna was nog steeds de standaard behandeling na heup- en knieprothesiologie. Hoewel op dit moment LMWH het meest gebruikte tromboseprofylacticum blijft, worden de nieuwe orale anticoagulantia (NOACs) thans gebruikt door een kwart van alle orthopedische vakgroepen. Bij dagbe-handelingen en artroscopieën wordt enerzijds geen profylaxe gegeven (68% en 56% respectievelijk), of er wordt een enkele gift LMWH gegeven (23% en 39% respectievelijk). Er is een significante toename in het gebruik van tromboseprofylaxe tijdens gipsimmo-bilisatie en in het gebruik van verlengde profylaxe na voorste kruisband reconstructie.In hoofdstuk 4, wordt het gebruik van bloed besparende maatregelen bij Nederlandse orthopedische vakgroepen gedurende een follow-up van tien jaar beschreven. De toepassing van peroperatieve autologe retransfusie bij zowel revisie heup prothesi-ologie (56 vs. 54%) als revisie knie prothesiologie (26 vs. 24%) is vrijwel niet veranderd in 2012 ten opzichte van vijf jaar geleden. Postoperatieve autologe retransfusie wordt nog steeds gebruikt door de meerderheid van de orthopedische vakgroepen na zowel primaire,- als revisie heup- (58/53%) en knieprothesiologie (65/61%). Op dit moment, evenals in 2007, gebruikt de meerderheid van de vakgroepen epoëtine, normothermie

Samenvatting130

en postoperatieve autologe retransfusie bij heup,- en knie prothesiologie. Andere ef-fectieve bloed besparende maatregelen, zoals tranexaminezuur, worden niet op grote schaal toegepast.

Internationale richtlijnen wat betreft trombose profylaxe

In hoofdstuk 5 worden elf (inter)nationale richtlijnen aangaande trombose profylaxe uit diverse landen vergeleken en hun verschillen geanalyseerd. Elf richtlijnen uit negen lan-den en één internationale richtlijn werden geïncludeerd. Slechts een aantal richtlijnen adviseren over trombose profylaxe na gips immobilisatie, (langdurige) arthroscopische ingrepen en geïsoleerd trauma van de onderste extremiteit. Verschillende meningen bestaan over het gebruik van aspirine en mechanische profylaxe en wat betreft het gebruik van vitamine K antagonisten na grote ingrepen aan de heup en de knie. De graad van aanbeveling zou idealiter gebaseerd moeten zijn op hetzelfde “level of evi-dence” wereldwijd. Het zal onmogelijk zijn om consensus te bereiken zolang er geen overeenstemming is voor wat betreft de relevantie van verschillende uitkomstmaten (zoals asymptomatische DVT).

Arthroscopische voorste kruisband reconstructie

In hoofdstuk 6 worden de resultaten van onze studie naar de incidentie van diep veneuze trombose na voorste kruisband reconstructie beschreven. In totaal werd bij 9 van de 100 patiënten (incidentie 9%; 95% BI: 4.2-16.4) asymptomatische proximale of distale diep veneuze trombose aangetoond middels compressie echografie, van wie 4 (incidentie 4%; 95% BI: 1.1-9.9) symptomatisch waren. Eén patiënt ontwikkelde een niet-fatale longembolie gedurende de 8-weekse follow-up periode. Deze studie toont aan dat de incidentie van veneuze tromboembolieën na arthroscopische voorste kruisband reconstructie relatief hoog is. Nader onderzoek wordt aangeraden om de noodzaak van tromboseprofylaxe bij patiënten die een voorste kruisband reconstructie ondergaan in te schatten, vooral wanneer risicofactoren voor trombose aanwezig zijn.

Amputatie van de onderste extremiteit

In de studie die in hoofdstuk 7 wordt beschreven, hebben we prospectief het vóórko-men van diep veneuze trombose en longembolieën bij patiënten die een amputatie van de onderste extremiteit hebben ondergaan door middel van een echo duplex en een ventilatie-perfusie scan onderzocht. Negenenveertig patiënten (53 amputaties) werden uiteindelijk geïncludeerd in de intention-to-treat analyse. De totale mortaliteit was 12 van de 53 amputaties (22.6%, 95% BI 12.3-36.2). Zes patiënten ontwikkelden een longembolie; twee longembolieën waren fataal. Eén patiënt ontwikkelde een asympto-matische contralaterale distale DVT, zodat het totale VTE aantal resulteerde in 7 van de 53 amputaties (13.2%, 95% BI 5.47-25.3). Amputatie van de onderste extremiteit gaat

Samenvatting 131

A

gepaard met een hoge mortaliteit door sepsis, respiratoire en vasculaire oorzaken. Deze studie toont aan dat VTE substantieel bijdraagt aan de morbiditeit en mortaliteit na am-putatie van de onderste extremiteit, ondanks een adequate farmacologische trombose profylaxe in deze kwetsbare populatie.

Gips immobilisatie

In hoofdstuk 8 wordt een casus beschreven van een longembolie tijdens een proef-periode met een gipscorset met beenpijp om lumbosacrale fusie te simuleren. Tevens wordt een overzicht van de literatuur hieromtrent gepresenteerd. In het algemeen wordt immobilisatie beschouwd als een grote risicofactor op het krijgen van VTE. De patiënt uit onze casus behoort door de immobilisatie met het gipscorset met beenpijp, gecombineerd met het gebruik van orale anticonceptiva tot de hoog-risico categorie. Daarom raden wij aan dat patiënten die van een gipscorset met beenpijp worden voor-zien routinematig worden gescreend op additionele risicofactoren, zoals het gebruik van orale anticonceptiva en VTE in de voorgeschiedenis. Indien risicofactoren aanwezig zijn, dient farmacologische profylaxe overwogen worden.

Schouder prothesiologie

In hoofdstuk 9 wordt een systematic review wat betreft symptomatische trombose na schouder prothesiologie gepresenteerd. De incidentie van VTE is relatief laag: 0.59% bij 47.998 schouder protheses. Het aantal VTE’s na proximale humerus fracturen was bijna drie keer zo hoog vergeleken met het aantal VTE’s bij electieve, niet-traumatische indica-ties: respectievelijk 0.95% vs. 0.33%. De 90-dagen incidentie van DVT was vergelijkbaar met de incidentie van PE. De mortaliteit na schouder prothesiologie was 0.49%: 0.43% bij electieve procedures en 3.0% bij traumatische indicaties. De meest voorkomende, statistisch significante, risicofactoren voor VTE waren co-morbiditeiten, een traumati-sche indicatie voor schouder prothesiologie en gevorderde leeftijd.Hoofdstuk 10 beschrijft ons onderzoeksprotocol betreffende de incidentie van symptomatische VTE en asymptomatische diep veneuze trombose, gedetecteerd door bilaterale complete compressie echografie van beide benen en de geopereerde arm na schouder prothesiologie zonder tromboseprofylaxe. De eerste acht geïncludeerde patiënten ontwikkelden geen DVT of longembolie. Deze studie heeft tot doel de inci-dentie van asymptomatische DVT na het plaatsen van een schouderprothese vast te stellen. Indien DVT frequent wordt aangetoond, zal een randomized controlled clinical trial volgen, waarbij tromboseprofylaxe met placebo wordt vergeleken om de risicofac-toren voor VTE en de noodzaak van tromboseprofylaxe te bepalen bij patiënten die een schouder prothese krijgen.

Publications 133

A

PuBLICATIOnS

This Thesis is based on the following articles:

Struijk-Mulder MC, Ettema HB, Büller HR, Verheyen CCPM. Incidence of deep venous thrombosis after shoulder arthroplasty. Systematic review of literature. Submitted.

Struijk-Mulder MC, Ettema HB, Büller HR, Verheyen CCPM. Ten-year follow-up on orthopaedic thromboprophylaxis in the Netherlands. DATA III survey. Submitted.

Struijk-Mulder MC, Ettema HB, Büller HR, Verheyen CCPM. Incidence of deep venous thrombosis after arthroplasty of the shoulder. Study protocol and preliminary results of INDRA-P study. Study in progress.

Struijk-Mulder MC, Ettema HB, Heyne RA, Rondhuis JJ, Verheyen CC. Venous throm-boembolism during hip plaster cast immobilisation: Review of the literature. Neth J Med. 2014 Jan;72(1):17-9.

Struijk-Mulder MC, Horstmann WG, Verheyen CCPM, Ettema HB. Ten-year follow-up on Dutch Orthopaedic blood management. DATA III survey. Archives of Orth and Trauma Surg. 2014 Jan;134(1):15-20.

Struijk-Mulder MC, Ettema HB, Verheyen CCPM, Büller HR. Deep vein thrombosis follow-ing arthroscopic cruciate ligament reconstruction: a prospective cohort study of 100 patients. Arthroscopy. 2013 Jul;29(7):1211-1216.

Struijk-Mulder MC, Van Wijhe W, Ettema HB, Sze YK, Knollema S, Baars ETC, Verheyen CC, Büller HR, Fritschy WM. Death and venous thromboembolism after lower extremity amputation. J Thromb Haemost. 2010 Dec;8(12):2680-4.

Struijk-Mulder MC, Ettema HB, Verheyen CCPM, Büller HR. Comparing consensus guidelines on thromboprophylaxis in orthopaedic surgery. J Thromb Haemost. 2010 Apr;8(4):678-83.

Ettema HB, Mulder MC, Nurmohamed MT, Büller HR, Verheyen CC.Dutch orthopaedic thromboprophylaxis: a 5-year follow-up survey. Acta Orthop. 2009 Feb;80(1):109-12.

Publications134

Other publications

Struijk-Mulder MC, Ettema HB. Orthopedische indicaties voor NOAC’s. In: Leidraad begeleide introductie nieuwe orale antistollingsmiddelen. Utrecht: Orde van Medisch specialisten; 2012. p.24-32.

Goosen JH, Mulder MC, Bongers KJ, Verheyen CC. High revision rate after treatment of femoral neck fractures with an optionally (un)cemented stem. Arch Orthop Trauma Surg. 2009 Jun;129(6):801-5.

Mulder MC, Jutte PC, Wiersma PH. Lumbar bilateral facet dislocation. Nederlands Tijd-schrift voor Traumatologie. 2006; 14(5):115-119.

Mulder MC, Verhaar JAN. Chronisch pijnlijke knie. In: Ensing GT, Knobben BAS, Houweling ST, Verhaar JAN, Van Horn JR. Probleemgeoriënteerd denken in de Orthopedie. Utrecht: De Tijdstroom Uitgeverij; 2004. p. 109-23.

Mulder MC, Eygendaal DE, Obradov M, Van Heerwaarden RJ. Een zwelling ter hoogte van het proximale tibio-fibulaire gewricht. Differentiële diagnostiek toegelicht aan de hand van een casus. Geneeskunde en sport. 2003 Jun;36(3):79-82.

Lefrandt JD, Mulder MC, Bosma E, Smit AJ, Hoogenberg K. Relation between auto-nomic function and blood glucose in the nondiabetic range. Diabetes Care. 2001 Nov;24(11):2017.

Sevre K, Lefrandt JD, Nordby G, Os I, Mulder MC, Gans RO, Rostrup M, Smit AJ. Autonomic function in hypertensive and normotensive subjects: the importance of gender. Hyper-tension. 2001 Jun;37(6):1351-6.

Lefrandt JD, Mulder MC, Bosma E, Smit AJ, Hoogenberg K. Inverse relationship be-tween blood glucose and autonomic function in healthy subjects. Diabetes Care. 2000 Dec;23(12):1862-4.

Dankwoord 135

A

DAnKWOORD

Met Kees Verheyen als machinist en Harmen Ettema als coachende conducteur was het prettig werken in de eerste klas coupé van de rijdende onderzoekstrein die Isala heet. Het trombose onderzoek van Harmen heb ik kunnen voortzetten. Ik leerde dat de weg der wetenschap je af en toe op een dood spoor brengt, waarbij onderzoeksprotocol-len helaas niet altijd tot uitvoering komen. Af en toe balen voor een rood sein, als een artikel wordt afgewezen, hoort erbij. Maar als die trein goed op stoom is, en artikelen gepubliceerd worden: wat een heerlijk gevoel! Kees en Harmen, hartelijk dank voor jullie supersnelle (en grondige) revisies van artikelen: dat hield de vaart er lekker in. De Zwolse wetenschapstrein rijdt verder: ik blijf aan boord om de INDRA P studie af te ronden en nieuwe wetenschappelijke reisplannen te maken met jullie.

Waarde professor Büller, beste Harry, tijdens teleconferenties en vooral tijdens de aan-gename wetenschaps-dinertjes met Kees en Harmen, was jij degene die door wat extra kolen op het vuur de inspiratie weer heerlijk kon doen oplaaien: een lichtend voorbeeld voor mij.

De leden van de promotiecommissie, professor Brandjes, professor Bulstra, professor Castelein, professor Van Dijk en professor Middeldorp ben ik zeer erkentelijk voor het beoordelen van mijn proefschrift.

Daarnaast veel dank aan mijn medeauteurs, orthopeden, chirurgen, radiologen, echolaboranten, verpleging, onderzoekscoördinatoren, secretaresses en patiënten uit de stations Isala Klinieken, het UMCG, het Martini Ziekenhuis en het Medisch Centrum Leeuwarden voor de participatie in alle studies.

Dankzij de Zwolse Onderzoeks Nerds kon de inclusie op “station Zwolle” doorgang vinden, terwijl ik in andere klinieken werkzaam was. Hartelijk dank Rob Rolink, Wybren Prins en met name Patricia Pasman. Dank ook aan de stationschefs te Leeuwarden: Bas Mollen, Thomas Tilkema en Baukje Dijkstra.

Collega AIOS uit het UMCG: railtenders en medereizigers, dank voor alle kopjes 1-2-start in de assistentenkamer, de gezellige lunches, etentjes en borrels. Marijke Oidtmann: onze bijklets-uren in jouw rode brikkie tussen Groningen en Enschede waren heerlijk relativerend.

Dankwoord136

Josien Jansen en Wendy Kelder, mijn paranimfen. Met jullie aan mijn zijde heb ik al veel mooie “treinreizen” in mijn leven mogen maken. Als getuigen bij mijn huwelijk en nu paranimfen bij mijn promotie: jullie zijn onmisbare vriendinnen.

Mijn ouders, jullie hebben mij op het juiste spoor gezet en gehouden. Dank voor de altijd beschikbare tussenstop op “Utrecht Centraal”.

Jan Evert, jij bent mijn belangrijkste reisgenoot in dit leven. Deze wetenschappelijke treinreis heb jij mij gegund en gelukkig heb je nooit aan de noodrem hoeven trekken. Samen met onze twee railrunners Carlijn en Thijs rijden we door: het avontuur tegemoet.

Curriculum Vitae 137

A

CuRRICuLuM VITAE

Marieke Struijk-Mulder was born on October 25th 1976 in Utrecht, the Netherlands. She attended the Cathedral Choir School Utrecht and graduated from the Christian Gymna-sium in 1995. In 1996 she received the propaedeutic diploma of veterinary medicine at the Rijksuniversitair Centrum Antwerpen. Medical school was started in 1996 at the Rijks-universiteit Groningen. The last two years of medical training were spent at the Deventer Ziekenhuis. After graduation in 2002, she worked as a resident orthopaedic surgeon at the Medisch Spectrum Twente, Enschede. In 2004 she started her surgical training at the Medisch Spectrum Twente, Enschede (head Dr. W.J.B. Mastboom). Between surgical and orthopaedic training, she was working as a resident orthopaedic surgeon at the St. Elisa-beth Hospital, Curaçao. The orthopaedic residency-training program was started in 2007 at the Isala Clinics, Zwolle (head Dr. N.J. A. Tulp). In 2007 she also started the research on this thesis at the Isala Clinics, supervised by Dr. H.B. Ettema, Dr. C.C.P.M. Verheyen and Prof. Dr. H.R. Büller from the Academic Medical Centre Amsterdam. Orthopaedic training continued in 2008 at the University Medical Centre Groningen (head Prof. Dr. S.K. Bulstra) and the Medisch Spectrum Twente, Enschede (head Dr. A.V.C.M. Zeegers). After completing her orthopaedic residency in 2011, she worked as an orthopaedic sur-geon at the St. Antonius Ziekenhuis, Nieuwegein, the Rijnland Ziekenhuis, Leiderdorp and Medinova Kliniek Klein Rosendael, Rozendaal. In order to develop her surgical skills regarding shoulder surgery, she was trained at the Reinier de Graaf Groep, Delft, by Max Hoelen in 2013. Marieke is married to Jan Evert Struijk. Currently, they live in Vleuten with their two wonderful children: Carlijn and Thijs.

Portfolio 139

A

PhD PORTFOLIO

Name PhD student: M.C. Struijk-MulderPhD period: 2007-2014Name PhD supervisor: Prof. Dr. H.R. Büller

PhD training

yearWorkload

(Hours)

General courses• VNVA Kadertraining• Reading Efficiently for medical doctors• Teach the teacher for AIOS

201020102008

641616

Specific courses• EBRO (Evidence-Based Guideline Development training)• Reference Manager, UMCG• Literature search using Pubmed, UMCG• Writing a scientific article, NTvG• Evidence-Based Surgery UMCG

20132011201020072007

816161616

Seminars, workshops and master classes• Powerpoint secrets: presentation and performance, DOLS 2010 2

Presentations• ROGO-dag Orthopaedie cluster Noord, Zwolle - Ten-year follow-up on Dutch orthopedic thrombopro-

phylaxis, DATA III survey. (presentation) - Deep vein thrombosis following arthroscopic cruciate

ligament reconstruction: a prospective cohort study of 100 patients. (presentation)

• Knee symposium Early Arthritis, Huizen. Thromboprophylaxis in lower extremity surgery. (presentation)

2013

2010

24

24

Portfolio140

(Inter)national conferences• Traumadagen, Nederlandse vereniging voor (orthopae-

dische) traumatologie, Amsterdam. Deep vein thrombosis following arthroscopic cruciate

ligament reconstruction: a prospective cohort study of 100 patients. (poster)

• International Society of Thrombosis and Haemostasis, Amsterdam.

Ten-year follow-up on Dutch orthopedic thromboprophy-laxis, DATA III survey. (e-poster presentation)

• Nordic Orthopaedic Federation, Amsterdam. Higher revision rate in optional cemented versus cemented hemiarthroplasty in hip fracture surgery. (presentation)

• EFORT, Nice. Higher revision rate in optional cemented versus cemented hemiarthroplasty in hip fracture surgery. (poster)

2013

2013

2008

2008

24

24

24

24


Thro

mboprophylaxis in

Orthopaedic Surgery

Thromboprophylaxis in O

rthopaedic Surgery

M

arieke C. Struijk-M

ulder

ISBN 978-94-6169-490-4

Documents

UvA-DARE (Digital Academic Repository) Thromboprophylaxis ... · Summary 125 Samenvatting 129 ... Curriculum Vitae 137 PhD Portfolio 139. 1 General introduction and outline of the