Draft Guideline on Prevention of Vte for Public Consultation

7/30/2019 Draft Guideline on Prevention of Vte for Public Consultation

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CliniCal praCtiCe guideline

or t prvntion o vnous trobobolis(dp vin trobosis and pulonary bolis)

in patints adittd to Australian ospitals

DRAFT FORPUBLIC CONSULTATION

2009


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Commonwealth o Australia 2009

Electronic documents

This work is copyright. You may download, display, print and reproduce this material in unaltered ormonly (retaining this notice) or your personal, non-commercial use, or use within your organisation.Apart rom any use as permitted under the Copyright Act 1968, all other rights are reserved.

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Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals | iii

Draft for Public Consultation

NATIONAL heALTh AND meDICAL ReSeARCh COUNCIL

Tabl o contnts

ecutiv Suary v

1 Introduction 11.1 Background 1

1.2 Clinical nd or tis Guidlin 1

1.3 Purpos o tis Guidlin 2

1.4 Intndd usrs 2

1.5 Scop o tis Guidlin 2

1.6 mtods usd to dvlop tis Guidlin 3

1.7 Scduld rviw o tis Guidlin 4

1.8 Funding 4

2 Options or trobopropylais in Australia 5

3 Issus to b considrd in using tis Guidlin 73.1 Diagnosis o VTe 7

3.2 endpoints or VTe prvntion 7

3.3 Applicability o vidnc issus to considr 7

3.4 Balancing risks 8

4 Patint risk 94.1 VTe risk 94.2 Blding risk 10

4.3 VTe risk assssnt 10

5 Suary o rcondations 115.1 Surgical patints 12

5.2 Anastsia 15

5.3 mdical patints 16

5.4 Cancr patints 16

5.5 Prgnancy and cildbirt 17

6 evidnc and rcondations 196.1 Surgical patints evidnc and rcondations or VTe propylais 19

6.1.1 Total ip rplacnt 196.1.2 hip ractur surgry 246.1.3 Total kn rplacnt 276.1.4 Kn artroscopy 306.1.5 Lowr lg racturs and injuris wit iobilisation 316.1.6 Gnral surgry 346.1.7 Urological surgry 366.1.8 Gynacological surgry 37

6.1.9 Abdoinal surgry 396.1.10 Cardiac, toracic and vascular surgry 416.1.11 Nurosurgry 436.1.12 Traua surgry or spinal surgry 44


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iv | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals



6 evidnc and rcondations (continud)6.2 Anastsia 46

6.3 mdical patints evidnc and rcondations or VTe propylais 48

6.3.1 Strok 486.3.2 myocardial inarction (mI) 506.3.3 Gnral dical 51

6.4 Cancr patints evidnc and rcondations or VTe propylais 54

6.5 Prgnancy and cildbirt evidnc and rcondations or VTe propylais 56

7 Aras or utur rsarc 597.1 Risk o VTe 59

7.2 ectivnss o trobopropylactic agnts 59

7.3 Aras wit littl vidnc or ctiv trobopropylais 59

7.4 Otr issus 59

8 Rrncs 61

9 Appndics 81Appndi A: VTe Prvntion Guidlin Adaptation Coitt 81

A.1: mbrsip o t VTe Prvntion Guidlin Adaptation Coitt 81A.2: Dclarations o Intrst o t VTe Prvntion Guidlin Adaptation Coitt 82A.3: Trs o Rrnc o t VTe Prvntion Guidlin Adaptation Coitt 84

Appndi B: Ovrviw o t guidlin dvlopnt procss 87

B.1: Appointing t Coitt 88B.2 Dclaration o intrst procss 88B.3: Stps in t dvlopnt o an NhmRC clinical practic guidlin 89B.3i Dvloping structurd clinical qustions 89B.3ii Slcting ig quality sourc guidlins to us or adaptation 89B.3iii Dvloping a sarc stratgy and sarcing t litratur 90B.3iv Assssing t ligibility o studis 90B.3v Inclusion critria 90B.3vi Critically appraising includd studis 93B.3vii Suaris and wr appropriat statistically pool t rlvant data 93B.3viii Assss t body o vidnc and orulat rcondations 93

Appndi C: Clinical qustions 94Appndi D: evidnc tabls 97

Appndi e: NhmRC evidnc Statnt For 98

Appndi F: Abbrviations and glossary o trs 101

Appndi G: Acknowldgnts 109

dscm

Tis docunt is a gnral guid to appropriat practic, to b ollowd subjct to t clinicians judgnt and patintsprrnc in ac individual cas. T guidlin is dsignd to provid inoration to assist dcision-aking and is basdon t bst vidnc availabl at t ti o dvlopnt o tis publication .


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Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals | v



ecutiv suaryAlthough eective pharmacological and mechanical preventive options have existed or decades,

venous thromboembolism (VTE) remains a major cause o morbidity and a signicant cause omortality in hospitalised patients across Australia and internationally. Data rom research andclinical audits suggest that the available preventive options are under-utilised and inconsistentlyapplied. Variations in practice and the emergence o new anticoagulants underline the needor an evidence-based VTE prevention guideline suited to the Australian healthcare context.

This Guideline provides recommendations on thromboprophylaxis or adult patients admittedto Australian hospitals. It covers patients undergoing all major types o surgery, patients withacute medical illnesses, trauma patients, patients admitted to intensive care units, cancer patients,and patients hospitalised during pregnancy and the puerperium.

The Guideline was prepared largely through critical appraisal and adaptation o existing

high-quality international VTE prevention guidelines, in preerence to a re-examination oprimary research publications and systematic reviews. From the critical appraisal, the main sourceo evidence selected was a guideline produced in 2007 by the National Institute or Healthand Clinical Excellence (NICE) in the UK. The adaptation o existing guidelines expeditedthe development o this Guideline, a consultation drat o which was produced withinapproximately 12 months.

A multidisciplinary VTE Prevention Guideline Adaptation Committee, comprising experts in theprevention o VTE and a consumer representative, was appointed by the NHMRC to provideadvice on the ollowing: the questions that directed the search or evidence; the selection oguidelines or adaptation; the adaptation process; the interpretation o primary research ndings

where existing guidelines did not provide sucient evidence; and the raming o the clinicalpractice recommendations.

In assessing the evidence rom the existing guidelines and other sources, the Committee tookaccount o potential biases in clinical trials. These biases resulted rom the dierent methodsused or the diagnosis o VTE and the dierent endpoints taken as refecting the occurrenceo VTE. The Committee also examined the applicability o the evidence to current Australianhospital practice.

In raming the Guideline recommendations, the Committee placed great emphasis onbalancing the risks o VTE in hospitalised patients against the actual and perceived risks opharmacological thromboprophylaxis and patients tolerance o pharmacological (especiallyinjectable) and mechanical prophylaxis. Bleeding is the major complication o pharmacologicalthromboprophylaxis, and is a potential side-eect o all anticoagulants. The risks o both VTE

and bleeding vary with individual patient actors, the presence o acute medical illnesses, typeso surgical procedures, and duration and nature o immobilisation. The consequences o bleedingalso vary with dierent surgical procedures and dierent anatomical sites.

The pharmacological options considered in the Guideline are unractionated heparin, lowmolecular weight heparin, ondaparinux, danaparoid (a heparinoid), rivaroxaban, dabigatranetexilate, aspirin and wararin. The mechanical options are graduated compression stockings,intermittent pneumatic compression devices and oot pumps.

The Guideline contains 64 recommendations. Each recommendation is assigned a grade romA to D. A reers to a recommendation based on a body o evidence that can be trusted toguide practice. B reers to a recommendation based on a body o evidence that can be trusted

to guide practice in most situations. Grade C means that the body o evidence provides somesupport or the recommendation, but care should be taken in its application. Grade D means


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vi | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals



that the body o evidence is weak and the recommendation should be applied with caution.Where no good-quality evidence was available but there was consensus among Committeemembers, consensus-based recommendations are given. Such recommendations are calledGood Practice Points. Within the Guideline, recommendations are presented by clinicalprocedure (e.g. total hip replacement, hip racture surgery, general surgery, gynaecologicalsurgery) and medical condition (e.g. stroke, myocardial inarction). Specic sections are includedor cancer patients surgical and non-surgical) and pregnancy and childbirth. A summary oall the recommendations is provided insection 5. The evidence or each recommendation ispresented by clinical procedure and set out in a summary withinsection 6. Finally, the Guidelinesets out a short list o areas or uture research.

The recommendations are intended to encapsulate the available evidence on the preventiono VTE. However, they should only be ollowed subject to the judgement o clinicians caringor individual patients and patients own preerences.


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Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals | 1



1 Introduction

1.1 BackgroundDeep vein thrombosis (DVT) and pulmonary embolism (PE) are two aspects o one disease processknown as venous thromboembolism (VTE). In DVT, a thrombus (blood clot) orms in the deep

veins o the leg or pelvis where it may cause pain, tenderness and swelling o the leg. In PE,some or all o the thrombus becomes detached and moves rom the vein through the right side othe heart to lodge in one or more pulmonary arteries. PE may cause shortness o breath, bloodysputum, chest pain, aintness and heart ailure. Massive PE leads to death.

Hospitalised patients are over 100 times more likely to develop a DVT or PE compared with therest o the community.1 Each year approximately 30,000 people are hospitalised in Australia as aconsequence o VTE, and an estimated 2,000 die rom VTE.2 The majority o VTE cases requiringhospitalisation are related to previous hospital admission or surgery or acute illness. Many o thesecases are preventable.2 PE is one o the commonest causes o death in hospital, accounting or10 percent o all hospital deaths.3 Other signicant long-term morbidity, costs and consequencesare also associated with the occurrence o VTE.3

The options or thromboprophylaxis comprise pharmacological agents (anticoagulants) andmechanical methods, alone or in combination. The most commonly-used pharmacological agentsin Australia are the heparins (low molecular weight heparin and unractionated heparin sodium).Other agents include ondaparinux, danaparoid, wararin and aspirin. The direct thrombin inhibitordabigatran etexilate and the selective direct actor Xa inhibitor rivaroxaban were approved bythe Therapeutic Goods Administration (TGA) or limited indications in late 2008. Mechanicalprophylaxis options include thigh or knee length graduated compression stockings, pneumatic

venous pumping devices that intermittently compress the cal muscles and devices that stimulate

lower-limb muscle contraction. All the thromboprophylactic options that were considered orinclusion in this Guideline are described insection 2.

1.2 Clinical nd or tis Guidlin

A strong evidence base exists or VTE prevention, and VTE prevention in hospitalised patientshas been widely acknowledged in Australia and internationally as a major opportunity to improvepatient saety.4,5 Although several Australian and international VTE prevention guidelines have beenpublished in recent years,6-12 no guidelines or the prevention o VTE have been endorsed by theNational Health and Medical Research Council (NHMRC).

Eective VTE prevention measures have been widely reported to be under-utilised andinconsistently applied.13,14 For example, a recent UK survey reported that 71 percent o hospitalisedpatients judged to be at moderate or high risk o DVT did not receive any orm o prophylaxis.15

VTE leads to short and long term morbidity and mortality and is costly to treat. In addition todiagnostic tests, patients with VTE require treatment with anticoagulants and a longer hospital stay.They oten require urther diagnostic tests and prolonged treatment to manage the complications o

VTE post-discharge.16

An evidence-based prevention guideline that sets out clear nationally-agreed recommendationssuitable or the Australian clinical context will help to reduce the incidence o VTE, the occurrenceo chronic sequelae, and subsequent costs associated with managing VTE.


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2 | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals



1.3 Purpos o tis Guidlin

The purpose o this Guideline is to provide practical, evidence-based recommendations orthe prevention o VTE in adult surgical and medical patients and pregnant women admitted to

Australian metropolitan, regional and rural hospitals. The recommendations should be ollowedsubject to the judgement o clinicians caring or individual patients and patients own preerences.

1.4 Intndd usrs

This Guideline is intended or doctors, nurses, pharmacists and allied health proessionals. It alsoprovides useul inormation or consumers and those responsible or the quality and saety ohealth care.

1.5 Scop o tis Guidlin

This Guideline provides recommendations on thromboprophylaxis or adult patients admittedto Australian hospitals in the ollowing categories:

patients undergoing surgery including orthopaedic, major general, major gynaecological,urological, cardiothoracic, vascular and neurosurgery

patients with acute medical illnesses, including myocardial inarction, stroke, and othermedical conditions

trauma patients

patients admitted to intensive care units

cancer patients (active or occult, with or without cancer treatment)

patients admitted during pregnancy and the puerperium.

This Guideline does not provide recommendations on thromboprophylaxis or:

patients under the age o 18 years

patients attending hospital as outpatients

patients who present to emergency departments but are not admitted

elderly or immobile patients cared or at home or in external residential accommodation(unless admitted to hospital)

patients in long-term hospital rehabilitation

patients who have not been hospitalised

travel-related VTE.


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1.6 mtods usd to dvlop tis Guidlin

The National Institute o Clinical Studies (NICS), an institute o the NHMRC, developed thisGuideline in accordance with NHMRC guideline development processes.17-19

In July 2008, NICS convened a multidisciplinary committee comprising proessional groupmembers with specic expertise in VTE prevention and a consumer representative. Details o themembership o the VTE Prevention Guideline Adaptation Committee (the Committee) are providedinAppendix A.1and the process or their appointment can be ound inAppendix B.1. The termso reerence or the Committee are provided inAppendix A.3.

As a number o high quality international VTE prevention guidelines were already available, NICSdeveloped this Guideline using an established guideline adaptation methodology (ADAPTE) ratherthan developing a new guideline de novo.20 ADAPTE seeks to reduce duplication in guidelinedevelopment by using existing high-quality guidelines as the basis or a local guideline.

Following the ADAPTE process, the Committee considered that the 2007 publication rom theUKs National Institute or Health and Clinical Excellence (NICE)8 best met the criteria or a highquality source guideline. This guideline was selected using the Appraisal o Guidelines Researchand Evaluation instrument (AGREE),21 which measures the extent to which the potential biaseso guideline development have been adequately addressed, internal and external validity o therecommendations, and easibility or practice, but does not assess the content o the guideline.

Although the 2007 NICE VTE prevention guideline was considered the most comprehensive reviewo available evidence, its structure was unsuitable or direct adaptation into an Australian guideline.The NICE guideline grouped all surgical procedures together, and the Committee considered thatthis would not be clinically meaningul in the Australian context. The Committee also consideredthat the evidence or individual surgical procedures needed to be examined separately, as the

patient risk prole or each procedure diered and overall recommendations or practice were notexpected to be clinically relevant to practitioners rom dierent surgical and medical specialties.

The Committee consulted the American College o Chest Physicians (ACCP) VTE Prevention Guidelineto assist in raming the clinical questions as its structure was regarded more clinically useul.7

As the adaptation process progressed, the Committee ound that evidence and recommendationscould not be taken rom existing guidelines (i.e. the ADAPTE process could not be ollowed entirely).Thereore, the Committee resolved to use a modied guideline adaptation process based in principleon ADAPTE but incorporating elements o de novo guideline development. Consequently, theevidence in the NICE guideline was re-ordered and re-analysed to match the desired structure o thisNHMRC Guideline and the Committee ormulated recommendations based on these new analyses.

The Guideline recommendations were developed using procedures outlined in the NHMRCadditional levels o evidence and grades or recommendations or developers o guidelines:Stage 2 consultation 2008-2010.22 Each recommendation was assigned a grade by the Committee,taking into account the volume, consistency, generalisability, applicability and clinical impact othe body o evidence supporting each recommendation. The table inAppendix B.3viiisets outthe evidence gradings.22 A standardised evidence statement orm used to ormulate and gradethe recommendations can be ound inAppendix E.22 Good practice points were used when theconventional grading o evidence was not possible. These points represent consensus views o the

VTE Prevention Guideline Adaptation Committee and are identied throughout by the abbreviationGPP (in place o a recommendation grading).

A detailed report on the modied ADAPTE process used to develop this Guideline is provided

inAppendix B.


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1.7 Scduld rviw o tis Guidlin

NHMRC recommends that guidelines be reviewed and revised no more than ve years ater initialpublication. However, the evidence base on which this Guideline was developed is likely tochange sooner. Thereore, the Committee will be re-convened to review relevant sections o thisGuideline i any o the ollowing occur within ve years:

registration by the Australian Therapeutic Goods Administration o any new drugs or theprevention o VTE in hospitalised patients

a change in the indications registered by the Australian Therapeutic Goods Administration orany drug included in this Guideline

publication o any new major randomised controlled trials or systematic reviews that potentiallyhave a bearing on the recommendations in this Guideline

emergence o any major saety concerns relevant to this Guideline.

1.8 Funding

The development o this Guideline was unded by the National Health and Medical ResearchCouncil (NHMRC).


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2 Options or trobopropylais in AustraliaAdequate hydration and early mobilisation are simple measures that should be applied as standard

practice to prevent VTE. Other important options or VTE prophylaxis include pharmacologicalor mechanical methods. Their eectiveness varies depending upon the clinical procedure andpatient-related risk actors.

The pharmacological options considered or this Guideline were:

subcutaneously administered unractionated heparin (UFH) or low molecular weightheparins (LMWH)

subcutaneously administered pentasaccharide ondaparinux which is a selectiveinhibitor o activated Factor X (Xa)

subcutaneously administered heparinoid, danaparoid

orally administered direct actor Xa inhibitor, rivaroxaban

orally administered direct thrombin inhibitor, dabigatran etexilate

orally administered aspirin

orally administered vitamin K antagonist, wararin.

Low molecular weight heparin, unractionated heparin, ondaparinux, danaparoid, rivaroxaban,dabigatran etexilate, aspirin and wararin were treated as separate classes o agents or thepurposes o the review o evidence or this Guideline.

Immobility can lead to the development o DVT as normal venous pump unction o skeletalmuscles is greatly reduced. Patients may be immobilised through connement to bed, as aconsequence o a surgical procedure, because o local immobilisation (e.g. a plaster cast or

traction applied to a limb), or a combination o these. Mechanical methods o prophylaxis ocuson reducing venous stasis and blood stagnation by promoting venous blood fow through externalcompression (with graduated compression stockings, intermittent pneumatic compression or

venous oot pumps, used alone or in combination).

The mechanical options considered or this Guideline were:

knee or thigh length graduated compression stockings (GCS)

knee or thigh length intermittent pneumatic compression (IPC)

venous oot pumps including oot impulse technology (FIT) and oot impulse devices (FID).

For urther inormation on indications, contraindications and precautions relating to theagents used or preventing VTE, reer to the Australian Medicines Handbook,23 or individualmanuacturers instructions.


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3 Issus to b considrd in using tis Guidlin

3.1 Diagnosis o VTeA clinical diagnosis o DVT is usually conrmed by compression ultrasonography. Some o therandomised controlled trials that ormed the evidence base or this Guideline relied on compressionultrasound as the primary method o detecting or excluding a DVT in both the intervention andcontrol groups as ultrasound is non-invasive. Most trials used ascending venography, considered to bethe gold standard diagnostic tool. Venography has a greater sensitivity than compression ultrasoundor distal (below-knee) DVT, but is an invasive technique and rarely used in clinical practice.

PE is usually diagnosed or excluded by computed tomographic (CT) pulmonary angiography(helical CT) or ventilation-perusion isotope scan. Routine screening or PE was not usuallyperormed in the randomised controlled trials reviewed in this Guideline. Instead, trial subjects

were assessed only on clinical suspicion o PE, based on symptoms, signs and other investigations.Thereore, the actual incidence o PE may have been underestimated.

When reviewing evidence, the Committee discounted diagnostic methods that are incompletelyvalidated (e.g. Magnetic Resonance Imaging or DVT) or have limited accuracy or sub-clinical DVT(e.g. impedance plethysmography).

3.2 endpoints or VTe prvntion

The Committee accepted evidence on the ecacy o prophylaxis derived using objectivelydocumented outcome measures across the ull spectrum o VTE, including asymptomatic, distalor proximal DVT detected by venography or ultrasound imaging, as well as symptomatic and

conrmed DVT or PE (non-atal or atal).

The Committee acknowledges the continuing debate on the clinical relevance o asymptomaticdistal DVT as an indicator o the ecacy o VTE prophylaxis. Some experts have argued thatguideline committees should consider evidence only on symptomatic VTE or only symptomatic PE.This Committees decision to consider outcomes across the broad spectrum was based on the actthat VTE is a spectrum o disease, rom asymptomatic distal DVT to PE, and most DVTs (and PE)are initially asymptomatic.

3.3 Applicability o vidnc Issus to considr

The Committee recognised a number o issues concerning the applicability o the evidence to

current practice in Australia.

Early comparisons o active VTE prevention (usually using unractionated or low molecularweight heparin) with a placebo or no intervention were undertaken decades ago, when surgicaltechniques, anaesthesia and postoperative management were very dierent. Importantly, theemphasis on early postoperative mobilisation was not as strong as it is today. The results o earlystudies o VTE prevention may thereore not always apply to contemporary practice. It seemslikely that contemporary clinical management may have led to reductions in the risk o VTE, evenin the absence o specic prophylactic measures. Nevertheless, VTE remains a major complicationo hospitalisation and the existing guidelines are a response to that risk.

Therapeutic regimens in clinical trials may dier rom those in current practice. For example, a

preoperative low molecular weight heparin dose is required by many VTE prevention trials inorthopaedic surgery but is almost never administered in current practice in Australia.


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The risk o bleeding related to surgery is the main complication o pharmacological prophylaxis.Major bleeding, as variously dened in clinical trials, bears a limited relation to major bleedingas perceived by surgeons or patients. Diering perceptions o risk or major bleeding stronglydetermine surgeons attitudes to various orms o prophylaxis even though recorded likelihoodo major bleeding has been small in clinical trials.

These perceptions may also infuence the choice between pharmacological and mechanical ormso VTE prophylaxis that enhance venous return and/or prevent venous stasis (e.g. with variousintermittent pneumatic compression devices).

Finally, there are ar ewer studies o mechanical than pharmacological prophylaxis, and ewerstudies where one was ollowed by the other. A lack o available evidence in important areasnecessarily limits the scope o evidence-based recommendations.

3.4 Balancing risks

The risk o VTE in hospitalised patients must be balanced against the actual and perceived riskso pharmacological thromboprophylaxis and patients tolerance o pharmacological (especiallyinjectable) or mechanical prophylaxis. Evidence presented throughout this Guideline shows thatthe risk o major bleeding associated with anticoagulant agents is low.

With major orthopaedic surgery, reported 30-day rates o major bleeding in patients receivingheparins were 0.2-1.7 percent; similar to placebo rates in the same trials o 0.2-1.5 percent.24,25However, clinicians and patients perceive the bleeding risk as signicant. In particular, surgeonsmay be understandably reluctant to expose patients to the risk o excessive intra- or postoperativebleeding and the subsequent complications, especially in procedures such as joint replacement

where bleeding can lead to severe inections and a need to explant prostheses.

This Guideline is intended to assist clinicians in balancing the risks o death and serious morbidityrom VTE against the complications and disadvantages o prophylaxis.


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4 Patint risk

4.1 VTe riskThe likelihood o developing a VTE is increased by well-recognised risk actors. However, there areew population-based studies on VTE risk in hospitalised patients, and estimates o the magnitudeo risk are sometimes contradictory or outdated (or example, by changes in surgical techniques orpatient characteristics).

There are no evidence-based algorithms or assigning a patient to low or high risk categories,based on single risk actors or combinations o risk actors. Known risk actors are listed below,and their presence or absence should inorm clinical decisions on the use o thromboprophylaxis.

The risk actors are grouped into the ollowing categories: individual patient risk actors; risksrelated to an acute medical illness; and risks related to an injury or a surgical procedure. Risks

related to the individual may be either inherited or exogenous. Depending on their magnitudethe risk actors related to an injury, a surgical procedure, or an acute medical illness oten exerta dominating infuence or their duration.

Individual patient risk actors:1.

age (the annual incidence o VTE rises with each decade over the age o orty) 26-28

pregnancy and the puerperium 29

active or occult malignancy 27,28,30-32

previous VTE 27,32

varicose veins 32

marked obesity 32-34

prolonged severe immobility (prolonged bed rest, immobilisation in a plaster cast orbrace or prolonged travel resulting in limited movement and subsequent venous stasis)30,35

use o oestrogen-containing hormone replacement therapy or oral contraceptivesin women32,33,36

inherited or acquired thrombophilia (conditions that carry a high risk o VTE includeinherited deciency o antithrombin, protein C or protein S, homozygosity or doubleheterozygosity or actor V Leiden or the G20120A prothrombin gene mutation, thephospholipid antibody syndrome).33

Risks related to an acute medical illness:2.

acute or acute on chronic chest inection 32

heart ailure 30,32

myocardial inarction 32

stroke with immobility 37

some orms o cancer chemotherapy 28,30

acute infammatory bowel disease. 32

Risks related to an injury or surgical procedure:3.

all surgical procedures but especially abdominal, 38 pelvic,8 thoracic or orthopaedic surgicalprocedures39-42

risk is determined by the type o surgery (major joint surgery carries a very high risk, 39-42

as does curative surgery or cancer43), the type o anaesthesia,44 the likely duration oimmobility (including duration o surgery),30,35 and surgical complications

leg injury that requires surgery or prolonged immobilisation. 45


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4.2 Blding risk

The risk o bleeding is elevated in the presence o certain risk actors and when certain proceduresare undertaken. Pharmacological thromboprophylaxis may add to these risks.

Patient-related risk actors or bleeding include abnormal blood coagulation or low platelet count.Pharmacological VTE prophylaxis may also be contraindicated in patients with the ollowingcharacteristics:

recent central nervous system bleeding

intracranial or spinal lesion at high risk or bleeding

current active major bleeding, dened as requiring at least two units o blood or blood productsto be transused in 24 hours

current chronic, clinically signicant and measurable bleeding over 48 hours

thrombocytopenia (platelets < 50,000/l)

severe platelet dysunction

recent major surgical procedure at high risk or bleeding

underlying coagulopathy or coagulation actor abnormalities

regional axial anaesthesia or recent lumbar puncture or any reason

high risk o alls.

By nature o its mechanism o action, pharmacological prophylaxis may increase the risk o surgicalbleeding. With pharmacological prophylaxis, bleeding risk can be related to dose and treatmentschedule (especially the timing o prophylaxis relative to surgery). An assessment o bleeding riskis an essential step in deciding on appropriate prophylaxis or individual patients.

4.3 VTe risk assssnt

It is essential to perorm and record a VTE risk assessment in each patient beore deciding whetheror not to use preventive measures and on the most appropriate measures to use.

VTE risk actors are thought to be additive so the presence o multiple risk actors leads to ahigher risk o developing VTE. The presence o multiple risk actors may signal the need or moreecacious VTE prophylactic regimens.

A VTE risk assessment should ollow the ollowing steps:

Step 1 Assess the patients baseline risk o VTE, taking into account inherited andacquired risk actors such as those listed insection 4.1.

Step 2 Assess the patients additional risk o VTE, taking account o the reasons orhospitalisation (surgical procedures, trauma or specic medical illness).

Step 3 Assess the patients risk o bleeding.

Step 4 Formulate an overall risk assessment (with consideration o VTE risk and bleeding risk).

Step 5 Select appropriate methods o thromboprophylaxis based on the risk assessment.


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5 Suary o rcondationsThis summary section provides a list o the evidence-based recommendations detailed in the

text osection 6. Each o the recommendations is given an overall grading based on the NHMRCadditional levels o evidence and grades o recommendation (2008-2010). When no Level I or IIevidence was available but there was consensus among the committee, recommended best practicepoints have been provided, and can be identied throughout the guideline with the ollowing:Good practice point (GPP)

Consensus recommendations and recommendations or urther research have not been graded.

g of

commo dsco

a Body o vidnc can b trustd to guid practic

B Body o vidnc can b trustd to guid practic in ost situations

C Body o vidnc provids so support or rcondation(s) but car sould b takn inits application

d Body o vidnc is wak and rcondation ust b applid wit caution

na Not applicabl unabl to grad body o vidnc

gpp Good practic point consnsus-basd rcondations

Interpreting guideline recommendationsWhere the words use or recommended are used in this Guideline, the Committee judgedthat the benets o the recommended approach clearly exceed the harms, and that the evidencesupporting the recommendation was trusted to guide practice.

Where the words should be considered are used, either the quality o evidence wasunderpowered, or the available studies demonstrated little clear advantage o one approach overanother or the balance o benets to harm was unclear.

Where the words not recommended are used, there is either a lack o appropriate evidence, orthe harms outweigh the benets.

The ull evidence tables supporting the recommendations can be ound in Appendix D and

or details on contraindications to thromboprophylaxis reer to the 2009 Australian MedicinesHandbook.23

The ollowing tables provide a summary o the recommendations or the prevention o VTE byclinical procedure. For urther inormation on the evidence rom which these recommendations arebased, as well as dose, duration, timing and precautions, please reer tosection 6.


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5 Suary o rcondations (cont.)

5.1 Surgical patints

rcommos by cc oc g

evc

sco

to h cm

Us trobopropylais or all patints adittd to ospital or total ip rplacnt.1. gpp 6.1.1

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly and continu or up to 35 days ollowing total ip rplacnt surgr y.Us on o t ollowing:

low olcular wigt parinondaparinurivaroabandabigatran tilat.

aBBB

6.1.16.1.16.1.16.1.1

Proprativ adinistration o trobopropylais is not rcondd or patints3.undrgoing total ip rplacnt surgry.

C 6.1.1

Us graduatd coprssion stockings or intrittnt pnuatic coprssion ollowing4.total ip rplacnt until t patint is ully obil, wtr or not paracologicaltrobopropylais is usd.

I possibl, us graduatd coprssion stockings wit a oot pup wr paracologicaltrobopropylais is not usd.

B

B

6.1.1

6.1.1

Unractionatd parin is not rcondd or trobopropylais ollowing total ip5.rplacnt. Only use unractionated heparin i recommended thromboprophylactic

options are not availabl.

B 6.1.1

Aspirin is not rcondd as t sol agnt or trobopropylais ollowing total6.ip rplacnt.

C 6.1.1

Wararin is not rcondd or trobopropylais ollowing total ip rplacnt7.cpt wr usd or traputic rasons.

In ts cass us adjustd traputic doss or our to v wks.

C

C

6.1.1

6.1.1

In patints wit parin-inducd trobocytopania, us parinoids suc as danaparoid as an8.altrnativ trobopropylactic option.

B 6.1.1

rcommos by cc oc gevc sco

H fc sy

Us trobopropylais or all patints adittd to ospital or ip ractur surgr y.1. gpp 6.1.2

In t absnc o contraindications, conc paracological trobopropylais and2.continu or up to 35 days or ip ractur surgry. Us on o t ollowing:

ondaparinulow olcular wigt parin.

B

B

6.1.26.1.2

I low olcular wigt parin is usd, considr t addition o low dos aspirin.3. B 6.1.2

Aspirin is not rcondd as t sol agnt or trobopropylais ollowing ip4.

ractur surgry.

B 6.1.2


18/112




rcommos by cc oc g

evc

sco

H fc sy (cont)

Unractionatd parin is not rcondd or trobopropylais ollowing ip5.ractur surgry.

B 6.1.2

Wararin is not rcondd or trobopropylais ollowing ip ractur surgry.6. B 6.1.2

I paracological trobopropylais is contraindicatd or not availabl, us on o t7.ollowing until t patint is ully obil:

oot pupintrittnt pnuatic coprssion.

C 6.1.2

In patints wit parin-inducd trobocytopania, us parinoids suc as danaparoid as an8.

altrnativ trobopropylactic option.

B 6.1.2

rcommos by cc oc g

evc

sco

to k cm

Us trobopropylais or all patints adittd to ospital or total kn rplacnt.1. gpp 6.1.3

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly and continu or up to 14 days ollowing total kn rplacnt surgry.

Us on o t ollowing:low olcular wigt parinondaparinurivaroabandabigatran tilat.

a

B

B

B

6.1.36.1.36.1.36.1.3

Us on o t ollowing wtr or not paracological trobopropylais is usd, until t3.patint is ully obil:


C 6.1.3

Aspirin alon is not rcondd or trobopropylais ollowing total kn rplacnt.4. C 6.1.3

Wararin is not rcondd or trobopropylais ollowing total kn rplacnt.5. B 6.1.3

K hoscoy

Trobopropylais is not rcondd ollowing kn ar troscopy.1.

Considr trobopropylais or patints wit additional VTe risk actors, in t absnco contraindications.

B

gpp

6.1.4

6.1.4

low fcs js

Us low olcular wigt parin or all patints adittd to ospital wit a lowr lg ractur1.or injury wit iobilisation in a brac or a plastr cast. Trobopropylais sould bcontinud or t ntir priod o iobilisation.

a 6.1.5



19/112




rcommos by cc oc g

evc

sco

g sy

Us trobopropylais or all patints adittd to ospital or gnral surgry.1. gpp 6.1.6

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly and continu or up to on wk or until t patint is ully obil ollowingajor gnral surgry. Us on o t ollowing:

low olcular wigt parinunractionatd parin.

B

a6.1.66.1.6

Us graduatd coprssion stockings or all gnral surgical patints, wtr or not3.paracological trobopropylais is usd, until t patint is ully obil.

B 6.1.6

I rcondd trobopropylais is contraindicatd or not availabl, us a oot pup4.ollowing gnral surgry, until t patint is ully obil.

C 6.1.6

uooc sy

Considr trobopropylais or patints adittd to ospital or urological surgry basd on1.an assssnt o t patints risk o VTe and blding.

gpp 6.1.7

rcommos by cc oc g

evc

sco

gycooc sy

Us trobopropylais or all patints adittd to ospital or ajor gynacological surgry.1. gpp 6.1.8

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly and continu or up to on wk or until t patint is ully obil ollowingajor gynacological surgry. Us on o t ollowing:


B 6.1.8

Considr t additional us o graduatd coprssion stockings or otr canical3.trobopropylais ollowing ajor gynacological surgry, spcially i paracologicaltrobopropylais is contraindicatd.

gpp 6.1.8

Wararin is not rcondd or trobopropylais ollowing ajor gynacological surgry.4. C 6.1.8

abom sy

Us trobopropylais or all patints adittd to ospital or ajor abdoinal surgr y.1. gpp 6.1.9

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly wit low olcular wigt parin and continu or at last v to nin days.

B 6.1.9

Fondaparinu is not rcondd or trobopropylais ollowing ajor abdoinal surgry.3. C 6.1.9

Us graduatd coprssion stockings or all patints ollowing abdoinal surgry, wtr or4.not paracological trobopropylais is usd, until t patint is ully obil.

B 6.1.9



20/112




rcommos by cc oc g

evc

sco

Cc, hocc vsc sy

Us trobopropylais or all patints adittd to ospital ollowing cardiac, toracic or1.vascular surgry.

gpp 6.1.0

In t absnc o contraindications, conc paracological trobopropylais2.postoprativly and continu or up to on wk or until t patint is ully obil ollowingcardiac, toracic, or vascular surgry. Us on o t ollowing:


B 6.1.0

Us on o t ollowing or all patints ollowing cardiac, toracic, or vascular surgry, wtr3.

or not paracological trobopropylais is usd, until t patint is ully obil:graduatd coprssion stockingsintrittnt pnuatic coprssion.

C 6.1.0

rcommos by cc oc g

evc

sco

nosy

Us intrittnt pnuatic coprssion ollowing nurosurgry, until t patint is ully obil.1. a 6.1.11

Us paracological trobopropylais wit tr caution in patints ollowing2.

nurosurgry, du to t ig risk o blding.

gpp 6.1.11

Wr paracological trobopropylais is appropriat and not contraindicatd, us low3.olcular wigt parin or unractionatd parin.

B 6.1.11

Considr t us o graduatd coprssion stockings ollowing nurosurgry (alon or in4.cobination wit paracological trobopropylais).

C 6.1.11

tm sy o s sy

Us trobopropylaxis or all patints adittd to ospital or traua surgry or spinal surgry.1. gpp 6.1.12

I2. n t absnc o contraindications, us a oot pup ro ospital adission wit t addition olow olcular wigt parin v days atr adission or traua patints undrgoing surgry.

C 6.1.12

5.2 Anastsia

rcommo g

evc

sco

Considr cntral nural blockad as an altrnativ to gnral anastsia i asibl.1.

I cntral nural blockad is usd tr is a risk o dvloping an pidural aatoa. To iniistis risk, tiing o paracological trobopropylais sould b carully plannd and discussdin advanc wit t anasttist.

a

gpp

6.2

6.2



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5.3 mdical patints

rcommos by mc coo g

evc

sco

Sok

Considr t us o trobopropylais or all patints adittd to ospital wit iscaic1.strok basd on an assssnt o t patints dgr o iobility and risk o blding.

B 6.3.1

Paracological trobopropylais is not rcondd or aorragic strok patints du2.to t risk o intracranial blding.

gpp 6.3.1

Wr trobopropylais is appropriat and not contraindicatd, us low olcular wigt3.parin or patints wit iscaic strok.

I low olcular wigt parin is contraindicatd or not availabl, us unractionatd parin.

B

B

6.3.1

6.3.1

Myoc fco

Us trobopropylais or patints adittd to ospital or yocardial inarction, wr ull1.anticoagulation is not in us.

C 6.3.2

In t absnc o contraindications, us unractionatd parin or trobopropylais ollowing2.yocardial inarction.

C 6.3.2

g mc

Considr t us o trobopropylais or patints adittd to ospital or dical conditions1.basd on an assssnt o t patints risk o VTe and blding.

gpp 6.3.3

In t absnc o contraindications, us on o t ollowing:2.low olcular wigt parinunractionatd parin.

B 6.3.3

5.4 Cancr patints

rcommos fo sc o-sc cc s g

evc

sco

Use thromboprophylaxis or all cancer patients undergoing general surgical procedures1.

including abdoinal or plvic surgry or nurosurgry, providd tr ar no contraindications.

Conc paracological trobopropylais postoprativly and continu or at lastsvn to 10 days ollowing ajor gnral surgr y or cancr. Us on o t ollowing:

low olcular wigt parinunractionatd parin

gpp 6.4

Considr using tndd troopropylais wit low olcular wigt parin or up to2.28 days atr ajor abdoinal or plvic surgry or cancr, spcially in patints wo ar obs,slow to obilis or av a past istory o VTe.

gpp 6.4

In t absnc o otr signicant risk actors, trobopropylais is not rcondd or3.cancr patints undrgoing ad and nck surgr y.

gpp 6.4

In non-surgical cancr patints in t absnc o contraindications, conc4.trobopropylais on adission and continu until discarg. Us on o t ollowing:


gpp 6.4

For bot non-surgical and surgical cancr patints, us graduatd coprssion stockings i5.paracological trobopropylais is contraindicatd.

gpp 6.4



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5.5 Prgnancy and cildbirt

rcommos g

evc

sco

miniis iobilisation o won during prgnancy, labour and t purpriu and nsur1.adquat ydration at all tis.

gpp 6.5

All won wo dlivr by casaran sction ar at incrasd risk o VTe and sould b2.obilisd proptly atr surgry.

gpp 6.5

Wr paracological trobopropylais is appropriat and not contraindicatd, us low3.olcular wigt parin atr casaran dlivry or v to svn days, or until t patint isully obil.

gpp 6.5

etnd paracological trobopropylais wit low olcular wigt parin or adjustd4.dos wararin to si wks or ig-risk won, atr casaran or vaginal dlivry.

gpp 6.5

Considr t us o graduatd coprssion stockings i paracological trobopropylais is5.contraindicatd or not usd.

gpp 6.5

Considr t us o intrittnt pnuatic coprssion during casaran and in t6.postoprativ priod or up to 24 ours.

gpp 6.5



23/112




Suary o availability o vidnc or us o trobopropylacticagnts by clinical catgory

UFh

LmWh

hePARANOID

RIVAROxABAN

DABIGATRAN

FONDAPARINUx

WARFARIN

ASPIRIN

GCS

IPC

FOOTPUmP

Total ip rplacnt x x x

us witGCS

hip ractur surgry x x +

Total kn rplacnt

x x Kn artroscopy x

Lowr lg racturs and injuris

Gnral surgry

Urological surgry x

Gynacological surgry x

Abdoinal surgry x

Cardiac, toracic and vascular surgry Nurosurgry

Traua surgry and spinal surgry at

day 5

+us witLmWh

Iscaic strok

myocardial inarction

mid dical

Cancr

Prgnancy and cildbirt

evidnc supports us o tis agnt or trobopropylais or tis clinical catgory

evidnc supports us o tis agnt or trobopropylais wit or witout otr

trobopropylactic agnts or tis clinical catgory

+evidnc supports us o tis agnt or trobopropylais only in addition wit anotr

trobopropylactic agnt or tis clinical catgory

x evidnc dos not support us o tis agnt or trobopropylais or tis clinical catgory

x Tis agnt is not rcondd or tis clinical catgory

Tr is no vidnc about tis or o trobopropylais or tis clinical catgory


24/112




6 evidnc and rcondation

6.1 Surgical patints evidnc and rcondations orVTe propylais

6.1.1 to h cm

This section summarises the evidence rom systematic reviews and individual trials considered orthe prevention o VTE in patients undergoing total hip replacement. Full evidence tables on whichthese summaries are based are provided in Appendix D (tables 1-30, 61, 62 and 65).

The recommendations given below were based on the body o evidence, with consideration othe strength o evidence, consistency across studies, likely clinical impact, and generalisability

and applicability o study ndings in the Australian context. Details o this process are providedinAppendix B. Explanations are given or those recommendations that are inconsistent with thecorresponding evidence summaries. Where necessary, some additional explanation has beenprovided to help interpret the recommendations in light o the evidence presented.

No recommendations were made where the evidence was o poor quality or not relevant to thecurrent Australian healthcare context. Diculties in interpreting the evidence are summarised insection 3.

Good Practice Points (GPP) are consensus-based, and are provided where the available evidencewas inadequate or could not be applied in the Australian healthcare context.

Vteohycc

evinc summy - homboohyxis fo o hi cmn ins lv rfcs

Rivaroaban In two ulti-cntr intrnational RCTs, rivaroaban (10g orally onc pr dayor 35 days) was or ctiv at rducing t occurrnc o DVT tan LmWh(40g onc pr day, itr or 35 days or 14 days). Tr wr no signicantdirncs in t rats o Pe or advrs vnts, including dat, btwn trivaroaban and LmWh ars.

I 46,47

Dabigatrantilat

In on ulti-cntr intrnational RCT, tr wr no signicant dirncs in ratso DVT or Pe wit dabigatran tilat (220g or 150g) copard wit LmWh(40g daily). Tr wr no signicant dirncs in t rats o advrs vnts

btwn t two groups.

I 48

Fondaparinu In two RCTs o patints wo rcivd itr LmWh (40g onc pr day)or ondaparinu (2.5g onc daily) or up to nin days, t group rcivingondaparinu ad signicantly lowr rats o VTe or DVT. howvr, ondaparinuwas associatd wit signicantly igr rats o ajor blding tan LmWh.

I 49,50


25/112




Vte

ohycc


LmWh Pooling o svn RCTs coparing LmWh wit no tratnt sowd signicantlywr asyptoatic DVTs wit LmWh. Tr wr no dirncs in toccurrnc o advrs vnts, suc as wound aatoa or ajor blding,btwn t groups rciving LmWh and no tratnt. Various doss o LmWhwr usd across t RCTs.

I 51-57

In a systatic rviw o si RCTs, tndd duration o propylais wit LmWh(to 2835 days postoprativly) rsultd in signicantly lowr rats o botproial and syptoatic DVT and lowr rats o Pe copard wit tnddplacbo. etndd duration o propylais was not associatd wit an incrasdrat o advrs vnts.

I 58

In on RCT, tr was no advantag in proprativ adinistration o LmWh

copard wit postoprativ adinistration. A urtr tr RCTs invstigatddosag cts o LmWh. Fro tis vidnc, igr doss o LmWh rducd trat o asyptoatic and distal DVT, but did not act t rat o syptoatic orproial DVT.

I 59-62

LmWhor UFh

Across si RCTs, rats o asyptoatic DVT did not dir btwn patintsrciving LmWh or UFh. howvr, in tr o t si RCTs, patints rcivingLmWh ad lowr rats o proial DVT. T occurrnc o advrs vnts,including blding, did not dir btwn LmWh and UFh groups.

I 63-68

GCS Pooling o igt RCTs sowd signicantly lowr rats o asyptoatic DVT wntotal ip rplacnt patints wor graduatd coprssion stockings copardwit no tratnt. Graduatd coprssion stockings wr sown to av anadditional bnt wn addd to ctiv paracological propylais (owvr,

not wn addd to ondaparinu). 69

I 51,70-76

IPC In on RCT o patints not on ctiv paracological propylais, signicantlywr asyptoatic DVT wr dtctd in t intrittnt pnuatic

coprssion (IPC) group copard wit t group rciving no tratnt.77 Inon sall RCT o patints rciving IPC or LmWh, rats o proial DVT did not

dir btwn t groups.78 In two RCTs, continuous nancd circulation trapy

was t or o IPC valuatd.79,80Ts trials wr cludd ro analysis as ttod o trobopropylais is not availabl in Australia.

I 77-80

GCS or IPC Two sall RCTs coparing graduatd coprssion stockings wit IPC wrinconclusiv. On RCT suggstd a bnt o adding IPC to LmWh copardwit adding GCS to LmWh or asyptoatic DVT but not otr outcos. 81

I 81,82

Foot pup In on RCT o patints not rciving paracological propylais, t addition oa oot pup to graduatd coprssion stockings was or ctiv in prvntingVTe tan t stockings alon. Two sall unblindd studis coparing LmWh wita oot pup wr inconclusiv.

I 83-85

Danaparoid In two RCTs, danaparoid was or ctiv in prvnting DVT (including proialDVT) tan UFh, or no tratnt.

I 86,87

Aspirin In two RCTs tr wr no signicant dirncs in t rats o proial DVT,distal DVT, Pe and t rats o advrs vnts btwn groups givn aspirin orno tratnt.

I 88,89


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Vte

ohycc


Wararin In two RCTs, tr wr no dirncs in t rat o DVT and t rats oadvrs vnts btwn groups givn wararin and no tratnt.

I 90,91

In tr RCTs, tr was a sall but non-signicant dirnc in t rat o DVTbtwn groups givn wararin or aspirin; tis avourd wararin.

I 92-94

In two RCTs, adjustd traputic doss o wararin wr or ctiv tan d,low-dos wararin in prvnting VTe.

I 95,96

In on RCT o patints rciving standard traputic doss o wararin, tnddduration (28-35 days) was or ctiv tan sortr-tr adinistration owararin or prvnting VTe.

I 97

RCTs coparing IPC wit wararin wr not applicabl to t Australianaltcar contt.

I 98-101

Discussion about the evidence and basis for recommendations for total hip replacement

Patients undergoing total hip replacement are in the highest risk category or VTE, on the basis othe procedure itsel,30,102 and in the absence o thromboprophylaxis, risk o VTE is high ollowingtotal hip replacement.103,104

rcommo

g

Us trobopropylais or all patints adittd to ospital or total ip rplacnt.1. gpp

Low molecular weight heparin, ondaparinux, rivaroxaban and dabigatran etexilate are all eectiveVTE prophylactic agents ollowing total hip replacement. RCTs have shown that rivaroxaban(10mg daily) or ondaparinux (2.5mg daily) signicantly reduced VTE compared with lowmolecular weight heparin46,47,49,50 while the eectiveness o dabigatran etexilate (220mg or 150mgdaily) and low molecular weight heparin was similar.48 Importantly, the rates o adverse events,including bleeding were similar or rivaroxaban and dabigatran etexilate compared with lowmolecular weight heparin. Low molecular weight heparin was more eective than unractionated

heparin63-68

or wararin.105-107

The choice o thromboprophylactic agent to be used ater total hip replacement should be basedon availability, cost and individual patients risk characteristics and preerences.

Rivaroxaban and dabigatran etexilate are oral thromboprophylactic agents that were registered bythe Therapeutic Goods Administration and became available in Australia in late 2008. Post-marketingsurveillance or adverse events has not been completed or rivaroxaban or dabigatran, so both shouldbe used with caution. The lack o inormation on post-marketing surveillance or rivaroxaban anddabigatran, along with the number o available RCTs infuenced the grading o the recommendation.

When this inormation becomes available, the recommendation should be reviewed.

In RCTs where low molecular weight heparin was compared with ondaparinux or nine days,

ondaparinux signicantly reduced DVT but also caused signicantly more bleeding.49,50 Fondaparinuxshould be used with caution as it may cause bleeding, particularly in those weighing less than 50kg,in the rail, the elderly and those with renal impairment.


27/112




Duration o thromboprophylaxis: The risk o late-occurring DVT ollowing total hip replacementremains high until at least day 35 ater surgery.108 In trials o extended duration low molecular

weight heparin, thromboprophylaxis was more eective when administered or up to 35 daysater surgery than or shorter durations, with no signicant increase in bleeding.58 Thereore,pharmacological prophylaxis has been recommended or up to 35 days ollowing total hipreplacement surgery.

Timing o thromboprophylaxis: Preoperative administration o pharmacological prophylaxis wasshown to provide no additional benet compared with postoperative administration.59 Based onthis and the practical diculties o preoperative administration in the context o the increasingrequency o same-day admissions, all pharmacological thromboprophylaxis should only beadministered postoperatively ollowing total hip replacement.

Dosage of thromboprophylaxis: In RCTs comparing low molecular weight heparin with no treatment,there were various doses o low molecular weight heparin used across the trials. I low molecular

weight heparin is chosen or thromboprophylaxis, it should commence postoperatively and dosage

should ollow manuacturers instructions.

rcommo

g

In t absnc o contraindications, conc paracological trobopropylais postoprativly and2.continu or up to 35 days ollowing total ip rplacnt surgry. Us on o t ollowing:

low olcular wigt parinondaparinu#rivaroaban*dabigatran tilat.*

Proprativ adinistration o trobopropylais is not rcondd or patints undrgoing total3.ip rplacnt surgry.

aBBB

C

* Rivaroaban and dabigatran tilat ar nwly approvd agnts and post-arkting survillanc on advrs vnts is notyt availabl.

#Us ondaparinu wit caution as it ay caus blding in tos wiging lss tan 50kg, in t rail, t ldrly and toswit rnal ipairnt.

Mechanical methods reduce the risk o VTE ollowing total hip replacement70-75,83 and arerecommended whether or not pharmacological prophylaxis is used. In one RCT o patients wearinggraduated compression stockings and not on eective pharmacological prophylaxis, the additiono a oot pump was associated with a signicant decrease in the rate o DVT (including proximal

DVT).83 Graduated compression stockings or intermittent pneumatic compression do not increasethe risk o bleeding. The eectiveness o graduated compression stockings can be increased iused in conjunction with a oot pump. RCTs comparing graduated compression stockings withintermittent pneumatic compression were inconclusive.81,82

Intermittent pneumatic compression signicantly reduced the occurrence o asymptomatic DVTcompared with no treatment77 and there was some suggestion rom a small study rom 1996 thatintermittent pneumatic compression could be used as an alternative to low molecular weightheparin.78 Studies comparing oot pump with low molecular weight heparin were inconclusive84,85but there was some suggestion that intermittent pneumatic compression added to low molecular

weight heparin reduces asymptomatic DVT.81 Intermittent pneumatic compression is also an optioni pharmacological prophylaxis is contraindicated.


28/112




rcommo

g

Us graduatd coprssion stockings or intrittnt pnuatic coprssion ollowing total ip rplacnt4.until t patint is ully obil, wtr or not paracological trobopropylais is usd.

I possibl, us graduatd coprssion stockings wit a oot pup wr paracologicaltrobopropylais is not usd.

B

B

In two RCTs, the rates o VTE did not dier between groups o patients given aspirin and nothromboprophylactic treatment ollowing total hip replacement.88,89 Consequently, aspirin is notrecommended as the sole orm o thromboprophylaxis. Similarly, the rates o VTE did not dierbetween groups o patients given wararin and no treatment.90,91 Wararin may be used by somepatients or therapeutic reasons other than thromboprophylaxis. In the cases where wararin useis unavoidable, adjusted therapeutic doses are more likely to be eective in preventing VTE thanxed low-dose wararin.95,96

Given the availability o more ecacious options, wararin, unractionated heparin and aspirinshould not be used or thromboprophylaxis ollowing total hip replacement.

rcommo

g

Unractionatd parin is not rcondd or trobopropylais ollowing total ip rplacnt. Only5.us unractionatd parin i rcondd trobopropylactic options ar not availabl.

Aspirin is not rcondd as t sol agnt or trobopropylais ollowing total ip rplacnt.6.Wararin is not rcondd or trobopropylais ollowing total ip rplacnt cpt wr usd7.or traputic rasons. In ts cass, us adjustd traputic doss or our to v wks.

B

CCC

Heparin-induced thrombocytopaenia (HIT) is the development o thrombocytopaenia(low platelet counts) due to the administration o the anticoagulant heparin, either in itsunractionated or low molecular weight orm. Upon diagnosis o HIT, treatment o HIT requiresboth protection rom thrombosis and choice o a thromboprophylactic agent that will not reducethe platelet count urther. The heparinoid danaparoid does not reduce the platelet count. In twoRCTs o patients undergoing total hip replacement, the heparinoid danaparoid was more eectiveor thromboprophylaxis than unractionated heparin or no treatment.86,87 Thereore, in patients

with heparin-induced thrombocytopaenia, heparinoids such as danaparoid are an alternativethromboprophylactic option ollowing total hip replacement surgery.

rcommo

g

In patints wit parin-inducd trobocytopania, us parinoids suc as danaparoid as an altrnativ8.trobopropylactic option.

B


29/112




6.1.2 H fc sy

This section summarises the evidence rom systematic reviews and individual trials or theprevention o VTE in patients undergoing surgery or hip racture. Full evidence tables on which

these summaries are based are provided in Appendix D (tables 31-49).

The recommendations were based on the body o evidence, with consideration o the strength oevidence, consistency across studies, likely clinical impact, and generalisability and applicabilityo study ndings in the Australian context. Details o this process are provided inAppendix B.Explanations are given or those recommendations that are inconsistent with the correspondingevidence summaries. Where necessary, some additional explanation has been provided to helpinterpret the recommendations in light o the evidence presented.

No recommendations were made where the evidence was o poor quality or not relevant tothe current Australian healthcare context. Diculties in interpreting the evidence are summarisedinsection 3.


Vte

ohycc

evinc summy homboohyxis fo hi fcu suy ins lv rfcs

Fondaparinu In on RCT coparing ondaparinu wit LmWh, tr wr signicantly lowrrats o total VTe and DVT (including proxial DVT) in patints rciving ondaparinux(and no dirncs in blding). Tr was no dirnc in t rats o Pe btwnt two groups.

I 109

In on RCT, tr wr signicantly lowr rats o VTe (including proial DVT andPe) in patints rciving ondaparinu or btwn 31 to 39 days copard wit upto igt days postoprativly. Tr was no dirnc in t occurrnc o blding.

I 110

LmWh A systatic rviw o v RCTs sowd tat rats o DVT (including proialDVT) wr lowr in patints rciving LmWh tan in tos rciving notratnt. Tr was no signicant dirnc in t rats o advrs vnts sucas wound aatoa, wound inctions or dat. T trials on proprativ vrsuspostoprativ adinistration o LmWh wr inconclusiv.

I 111

Foot pup orIPC

In an RCT o patints undrgoing ip ractur surgry and not on ctivparacological propylais, patints wit oot pups or IPC dvics applid adlowr rats o DVT and Pe tan tos rciving no tratnt. Tr wr no dirctcoparisons btwn IPC and oot pup. In a sparat RCT, rats o VTe did notdir btwn patints on IPC in addition to LmWh copard wit tos on

LmWh alon.112

I 111,112

Danaparoid Rats o DVT wr lowr in patints rciving danaparoid tan tos rciving

aspirin113 or wararin.114Tr was no dirnc in advrs vnts.

I 113,114

Wararin In our RCTs, patints rciving wararin ad lowr rats o DVT tan tos rcivingaspirin or no tratnt. In two o t our RCTs tat rpor td on ajor blding,tr was no signicant dirnc in t occurrnc o ajor blding btwn

wararin and no tratnt.115,116

I 115-118

Aspirin In t pulonary bolis prvntion trial (PeP), patints rciving aspirin(160g/day) along wit otr trobopropylactic agnts LmWh or UFh or

GCS, ad lowr rats o VTe tan tos wo did not rciv t addd aspirin.

I 89


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Vte

ohycc

evinc summy homboohyxis fo hi fcu suy ins lv rfcs

UFh In a systatic rviw tat includd 10 RCTs, tr wr signicantly lowr rats oDVT. No signicant dirncs or any Pe owvr or causs o dat otr tan Pe,tis just racd statistical signicanc in avour o no tratnt. Fro t RCTs tatcopard UFh wit LmWh, tr was insucint vidnc to rcond on inprrnc to t otr.

I 111

GCS On RCT copard GCS plus ondaparinu wit ondaparinu alon. Tis vidncwas discountd as it was a sub-group analysis wit vry w patints.

I 69

Discussion about the evidence and basis for recommendations for hip fracture surgery

Patients undergoing hip racture surgery are in the highest risk category or VTE, on the basis othe procedure itsel30,102,119 and in the absence o thromboprophylaxis, reported rates o VTE arehigh ollowing surgery or hip racture.102,104 Thromboprophylaxis has been shown to reduce therisk o PE and mortality.120 Thereore, all patients admitted to hospital or surgery or hip ractureshould receive thromboprophylaxis ollowing surgery.

rcommo

g

Us trobopropylais or all patints adittd to ospital or ip ractur surgr y.1. gpp

Whilst low molecular weight heparin,111 unractionated heparin,111 wararin115-118 and ondaparinux109were all eective in preventing VTE, only low molecular weight heparin and ondaparinux arerecommended or thromboprophylaxis ollowing hip racture surgery. Wararin has largely beenreplaced by more practical and saer options or thromboprophylaxis. Wararin requires closemonitoring and therapeutic dose adjustment, making it relatively costly. In addition, a ailure tomaintain the appropriate level o anticoagulation with wararin exposes the patient to an increasedrisk o thrombosis or bleeding.

One RCT showed that ondaparinux signicantly reduced DVT (including proximal DVT) inpreerence to low molecular weight heparin or thromboprophylaxis ollowing hip racturesurgery.109 However, ondaparinux should be used with caution as it may cause bleedingparticularly in patients weighing less than 50kg, the rail, the elderly and those with renalimpairment. In one trial o hip racture surgery patients, extended use o ondaparinux to between31 and 39 days compared with eight days signicantly reduced DVT and PE rates (with nosignicant increase in bleeding).121 From this evidence, ondaparinux should be commencedsix to eight hours ater surgery, and administered or 31 to 39 days (2.5mg once daily).

I low molecular weight heparin is chosen or thromboprophylaxis, it should commencepostoperatively and dosage should ollow manuacturers instructions (as the dosages o lowmolecular weight heparin varied across the RCTs considered).

The choice o thromboprophylactic agent to be used ater total hip replacement should be basedon availability, cost and individual patients risk characteristics and preerences.


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rcommo

g

In t absnc o contraindications, conc paracological trobopropylais and continu or up to2.35 days or ip ractur surgry. Us on o t ollowing:

ondaparinu#low olcular wigt parin.

BB

#Us ondaparinu wit caution as it ay caus blding in tos wiging lss tan 50kg, in t rail, t ldrly and toswit rnal ipairnt.

In the pulmonary embolism prevention trial (PEP),89 low dose aspirin (160mg/day) addedto other more ecacious options such as low molecular weight heparin or unractionatedheparin or graduated compression stockings ollowing hip racture surgery provided additionalthromboprophylactic benet. Importantly, in this trial aspirin alone was not eective. Thereore,low dose aspirin may be considered in combination with other more eective thromboprophylacticagents ollowing surgery or hip racture.

rcommo

g

I low olcular wigt parin is usd, considr t addition o low dos aspirin.3.

Aspirin is not rcondd as t sol agnt or trobopropylais ollowing ip ractur surgry.4.

B

B

rcommo

g

Unractionatd parin is not rcondd or trobopropylais ollowing ip ractur surgry.5.

Wararin is not rcondd or trobopropylais ollowing ip ractur surgry.6.

B

B

The use o either a oot pump or intermittent pneumatic compression is associated with asignicant reduction in the rates o DVT (including proximal DVT) and PE compared with notreatment.111 The use o either is recommended i pharmacological prophylaxis is contraindicatedor not available ollowing surgery or hip racture. From one small study comparing intermittentpneumatic compression and low molecular weight heparin, there was insucient evidenceto support one in preerence to another.122 There was no demonstration o benet in addingintermittent pneumatic compression to low molecular weight heparin.112

rcommo

g

I paracological trobopropylais is contraindicatd or not availabl, us on o t ollowing until t7.patint is ully obil:


B


32/112




Heparin-induced thrombocytopaenia (HIT) is the development o thrombocytopaenia (low plateletcounts) due to the administration o the anticoagulant heparin, either in its unractionated or lowmolecular weight orm. Upon diagnosis o HIT, treatment o HIT requires both protection romthrombosis and choice o a thromboprophylactic agent that will not reduce the platelet counturther. The heparinoid danaparoid does not reduce the platelet count. In two RCTs o patientsundergoing hip racture surgery, the heparinoid danaparoid was more eective than wararin114or aspirin.89 Thereore, in patients with heparin-induced thrombocytopaenia, heparinoids such asdanaparoid are an alternative thromboprophylactic option ollowing hip racture.

rcommo

g

In patints wit parin-inducd trobocytopania, us parinoids suc as danaparoid as an altrnativ8.trobopropylactic option.

B

6.1.3 to k cm

This section summarises the evidence rom systematic reviews and individual trials or theprevention o VTE in patients undergoing total knee replacement. Full evidence tables on whichthese summaries are based are provided in Appendix D (tables 50-60).

The recommendations provided were based on the body o evidence, with consideration othe strength o evidence, consistency across studies, likely clinical impact, and generalisabilityand applicability o study ndings in the Australian context. Details o this process are given in

Appendix B. Explanations are given or those recommendations that are inconsistent with thecorresponding evidence summaries. Where necessary, some additional explanation has been

provided to help interpret the recommendations in light o the evidence presented.

No recommendations were made where the evidence was o poor quality or not relevant tothe current Australian healthcare context. Diculties in interpreting the evidence are summarisedin section 3.


Vte

ohycc

evc smmy homboohyxs fo o k cm

sy s lv rfcs

Rivaroaban In two RCTs rivaroaban (10g orally onc pr day or two wks) was orctiv at rducing DVT (asyptoatic, syptoatic and distal DVT) tanLmWh (40g subcutanously onc pr day or two wks). Tr was nodirnc in non-atal Pe, dat or blding btwn rivaroaban and LmWh.

I 123,124

Fondaparinu In on RCT ondaparinu was or ctiv at rducing VTe and DVT (includingproial DVT) tan LmWh; owvr ondaparinu causd signicantly orajor blding tan LmWh.

I 125

Dabigatranetilat

In two RCTs tr was no signicant dirnc in rats o DVT or Pe witdabigatran tilat (220g or 150g) copard wit LmWh (40g daily).Tr was no signicant dirnc in any advrs vnts btwn dabigatrantilat and LmWh.

I 126,127


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Vte

ohycc

evc smmy homboohyxs fo o k cm

sy s lv rfcs

LmWh, UFhor IPC

In two RCTs tr wr signicantly wr DVT vnts (including proial DVT)

in tos rciving LmWh copard wit no tratnt or UFh25,128 or IPC.129Tr was no dirnc in advrs vnts or itr UFh or IPC copardwit LmWh.

I 128-132

Foot pupor IPC

In RCTs wr patints wr not on ctiv paracological propylais, t

us o oot pup133 or intrittnt pnuatic coprssion dvics134 conrrd

trobopropylactic bnts copard wit no tratnt or aspirin;135,136owvr tr wr no ad-to-ad coparisons o oot pups vrsus IPC soon cannot b rcondd in prrnc to t otr. Tr wr a nubr ostudis tat copard oot pup or IPC wit paracological propylais all o

wic wr inconclusiv.137-139

I 133-139

Aspirin In two RCTs intrittnt pnuatic coprssion was or ctiv at rducingDVT tan low-dos aspirin (rsults or ig dos aspirin not rlvant as tisdosag would not b usd in surgical patints). On RCT copard IPC plus

aspirin wit IPC plus wararin.139 Tis trial was cludd ro analysis as it ad asall sapl siz and was undrpowrd.

I 135,136,139

Wararin In tr RCTs, LmWh was or ctiv at rducing DVT tan wararin witno signicant dirnc in proial DVT, Pe or advrs vnts btwn LmWhand wararin.

I 140-142

In one RCT, there was no thromboprophylactic beneft in preoperative

wararin dosing.I 143

Discussion about the evidence and basis for recommendations for total knee replacement

Patients undergoing surgery or total knee replacement are in one o the highest risk categories orVTE, on the basis o the procedure itsel. 30,102,119 Thereore, all patients admitted to hospital or totalknee replacement surgery should receive thromboprophylaxis ollowing surgery.

rcommo

g

Us trobopropylais or all patints adittd to ospital or total kn rplacnt.1. gpp

Low molecular weight heparin,130,131 ondaparinux,125 rivaroxaban123,124 and dabigatran etexilate126,127are all eective VTE prophylactic agents ollowing total knee replacement. RCTs have shown thatrivaroxaban123,124 or ondaparinux125 reduce VTE in preerence to low molecular weight heparin,

while the eectiveness o dabigatran etexilate126,144 and low molecular weight heparin was similar.Importantly, there was no dierence in adverse events including bleeding or both rivaroxaban anddabigatran etexilate compared with low molecular weight heparin. Low molecular weight heparinreduced DVT signicantly compared with unractionated heparin128,132 eective at reducing DVT(with no dierence in proximal DVT or PE between the two agents).

Rivaroxaban and dabigatran etexilate are oral thromboprophylactic agents that were registeredby the Therapeutic Goods Administration and became available in late 2008. Post-marketing

surveillance or adverse events has not been completed or rivaroxaban or dabigatran, soboth should be used with caution. The lack o inormation on post-marketing surveillance or


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rivaroxaban and dabigatran, along with the number o available RCTs infuenced the gradingo the recommendation. When this inormation becomes available, the recommendation shouldbe reviewed.

While ondaparinux was more eective than low molecular weight heparin at reducing VTE(including total and proximal DVT), it also resulted in signicantly more bleeding.125 Fondaparinuxshould be used with caution as it may cause bleeding particularly in those weighing less than 50kg,in the rail, the elderly or those with renal impairment.

The choice o thromboprophylactic agent to be used ater total knee replacement should be basedon availability, cost and individual patients risk characteristics and preerences.

Duration o thromboprophylaxis: In the total knee replacement RCTs, low molecular weightheparin was provided or a period o up to 14 days25,130 as was rivaroxaban.123 Thereorepharmacological prophylaxis is recommended or a period o up to 14 days ollowing total kneereplacement. Its important to note that in the trial o ondaparinux compared with low molecular

weight heparin, prophylaxis was given or a period o between ve to nine days145

and in the trialso dabigatran etexilate, thromboprophylaxis was provided or between six to 10 days in one trial126and 14 days in a second trial.144

Dosage o thromboprophylaxis: Some o the trials comparing low molecular weight heparin withplacebo used a 60mg daily dosage o low molecular weight heparin; this dose is not availablein Australia. Given the variability in dosages o the thromboprophylactic agents across the trials,dosing o thromboprophylaxis is recommended according to manuacturers instructions ollowingsurgery or total knee replacement.

rcommo

g

In t absnc o contraindications, conc paracological trobopropylais postoprativly and2.continu or up to 14 days ollowing total kn rplacnt surgry. Us on o t ollowing:

low olcular wigt parinondaparinu#rivaroaban*dabigatran tilat.*

aB

BB

* Rivaroaban and dabigatran tilat ar nwly approvd agnts and post-arkting survillanc on advrs vnts is notyt availabl.

# Us ondaparinu wit caution as it ay caus blding in tos wiging lss tan 50kg, in t rail, t ldrly and toswit rnal ipairnt.

Low molecular heparin was more eective at reducing DVT than intermittent pneumaticcompression129 while studies comparing oot pump with low molecular weight heparin wereinconclusive.137,138 Application o a oot pump133 or intermittent pneumatic compression134 wasshown to be benecial in reducing DVT (including proximal DVT) compared with no treatment.Intermittent pneumatic compression was also shown to signicantly reduce DVT compared withaspirin.135,136 Thereore, the use o aspirin has not been recommended. A urther study evaluatedintermittent pneumatic compression plus low molecular weight heparin against intermittentpneumatic compression plus aspirin;139 however, no conclusions could be drawn about the benetso combination pharmacological prophylaxis with intermittent pneumatic compression as this study

was small in sample size and was underpowered.


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rcommo

g

Us on o t ollowing wtr or not paracological trobopropylais is usd, until t patint is3.ully obil:


B

rcommo

g

Aspirin alon is not rcondd or trobopropylais ollowing total kn rplacnt.4. C

Wararin is not recommended or thromboprophylaxis ollowing total knee replacement as it wasnot shown to be eective in RCTs compared with low molecular weight heparin.141,142,146 Onestudy o wararin timing suggests that preoperative wararin dosing does not provide additionalthromboprophylactic benet compared with postoperative dosing.143

rcommo

g

Wararin is not rcondd or trobopropylais ollowing total kn rplacnt.5. B

6.1.4 K hoscoy

This section summarises evidence rom systematic reviews and individual trials or the preventiono VTE in patients undergoing knee arthroscopy. The ull evidence tables on which thesesummaries are based are provided in Appendix D (table 68).

The recommendations provided were based on the body o evidence, with consideration othe strength o evidence, consistency across studies, likely clinical impact, and generalisabilityand applicability o study ndings in the Australian context. Details o this process are given in

Appendix B. Explanations are given or those recommendations that are inconsistent with thecorresponding evidence summaries. Where necessary, some additional explanation has been

provided to help interpret the recommendations in light o the evidence presented.No recommendations were made where the evidence was o poor quality or not relevant tothe current Australian healthcare context. Diculties in interpreting the evidence are summarisedin section 3.

Good Practice Points (GPP) are consensus-based, and are provided where the available evidencewas inadequate or could not

Draft Guideline on Prevention of Vte for Public Consultation

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