Graduated compression stockings as an adjunct to low dose low molecular weight heparin in venous thromboembolism prevention in surgery

– a multi-centre randomised controlled trial [ISRCTN13911492]

GAPS Trial Investigators *

* GAPS Trial Investigators

J Shalhoub, J Norrie, C Baker, A W Bradbury, K Dhillon, T Everington, M S Gohel,

Z Hamady, F Heatley, J Hudson, B J Hunt, G Stansby, A Stephens-Boal, D Warwick,

A H Davies

For Correspondence

Alun H Davies

Professor of Vascular Surgery

Head, Academic Section of Vascular Surgery

Department of Surgery & Cancer

Imperial College London

4th Floor, East Wing, Charing Cross Hospital

Fulham Palace Road

London, W6 8RF, UK

E-mail: a.h.davies@imperial.ac.uk

Tel: +44 (0) 20 3311 7320

Fax: +44 (0) 20 3311 7362

Word Count3974 Words

1

AbstractBackground:

The evidence base upon which current global venous thromboembolism (VTE)

prevention recommendations have been made is not optimal. The cost of purchasing

and applying Graduated Compression Stockings (GCS) in surgical patients is

considerable and has been estimated at £63.1 million each year in England alone.

Objective:

To determine whether low dose low molecular weight heparin (LMWH) alone is non-

inferior to a combination of GCS and low dose LMWH for the prevention of VTE.

Methods:

A randomised controlled Graduated compression as an Adjunct to

Pharmacoprophylaxis in Surgery (GAPS) Trial [ISRCTN 13911492] will randomise

adult elective surgical patients identified as being at moderate and high risk for VTE

to receive either the current ‘standard’ combined thromboprophylactic LMWH with

GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH

pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for

the primary endpoint of all VTE within 90 days, 2236 patients are required.

Recruitment will be from seven UK centres. Secondary outcomes include quality of

life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH-

related complications (including bleeding).

Recruitment commenced in April 2016 with the seven UK centres coming ‘on-line’ in

a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is

funded by the National Institute for Health Research Health Technology Assessment

in the UK [14/140/61].

Key WordsRandomised controlled trial, venous thromboembolism, deep vein thrombosis,

graduated compression stockings, low molecular weight heparin, thromboprophylaxis

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IntroductionVenous thromboembolism (VTE) encompasses a range of clinical presentations,

including deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE is the

primary preventable cause of death in hospitalized patients1. Furthermore, DVT

carries a considerable burden of morbidity, sometimes long-term due to chronic

venous insufficiency and the development of a post-thrombotic limb (characterized by

chronic pain, swelling, skin changes and ulceration), which impacts on quality of life

and consumes 2% of the UK National Health Service (NHS) budget2. Reducing VTE

is therefore a clinical priority within the NHS2, particularly amongst individuals

undergoing surgery where the risks are significant.

In the Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery

(GAPS) Trial, our primary hypothesis is that there is no clinical benefit from the

addition of GCS to thromboprophylactic LMWH when compared to

thromboprophylactic LMWH alone in surgical patients at moderate and high risk for

VTE.

Thus, we are embarking upon a randomised clinical trial to compare VTE outcomes

in surgical patients assessed as being at moderate or high risk who are prescribed

GCS in addition to low dose LMWH and those prescribed low dose LMWH alone.

The trial will also address issues of complications, adherence and compliance with

GCS, and will support future guidance and policy in VTE prevention. We expect that

the results will influence peri-operative care internationally.

Guidelines for venous thromboembolism risk assessment and prevention

At present in the UK, the National Institute for Health and Care Excellence (NICE)

recommends that surgical patients who are deemed at moderate or high risk for VTE,

in whom there are no contraindications and who are at low risk of major bleeding,

should receive both pharmacological thromboprophylaxis and mechanical

thromboprophylaxis in the form of graduated compression stockings (GCS)2. This

recommendation was based on a cost-effectiveness analysis informed by network

meta-analysis; there were no studies included directly comparing pharmacological

thromboprophylaxis using LMWH with pharmacological thromboprophylaxis using

LMWH and GCS – this weakens the strength of this recommendation2.

In the United States, the Caprini scoring system has been developed3. The factors

which are considered in the Caprini scoring system mirror those highlighted in the

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Department of Health VTE risk assessment tool4. However, whilst the Department of

Health tool would identify an individual as high risk, based on the presence of one or

more patient-related or procedure-related factors, the Caprini scoring system gives

different ‘weight’ to different patient-related or procedure-related factors (scoring 1, 2,

3 or 5 points each). The total Caprini risk factor score would place patients in low,

moderate, higher or highest risk groups. The higher risk group patients are

recommended pharmacological thromboprophylaxis plus or minus mechanical

thromboprophylaxis (IPC). The highest risk individuals are recommended

pharmacological thromboprophylaxis plus mechanical thromboprophylaxis (IPC).

For moderate risk patients, the American College of Chest Physicians (ACCP)

recommends pharmacological thromboprophylaxis (Grade 2B) or mechanical

thromboprophylaxis, preferably intermittent pneumatic compression (Grade 2C)5. The

ACCP recommends a combination of pharmacological and mechanical

thromboprophylaxis for high risk surgical patients (Grade 2C recommendation for the

addition of mechanical thromboprophylaxis)5.

In 2013, the International Union of Angiology (IUA) generated a consensus statement

which recommends pharmacological thromboprophylaxis or mechanical

thromboprophylaxis in moderate risk patients6. For high risk patients the general

recommendation is for pharmacological thromboprophylaxis, stating that this ‘may be

combined with mechanical methods, particularly in the presence of multiple risk

factors’6. ‘Patients undergoing bariatric surgical procedures should receive dose

adjusted LMWH alone or in combination with GEC [graduated elastic compression]

and IPC’6. High risk patient undergoing plastic surgery should receive

pharmacoprophylaxis 24 hours after surgery, or in combination with mechanical

prophylaxis (level of evidence: low)6.

To summarise, the current recommendations vary across international guidelines,

reflecting the poor quality of evidence which currently exists in this clinical area.

Uptake of current venous thromboembolism guidance

In England, the Department of Health mandated adherence to the NICE guidelines

and this subsequently came under the Commissioning for Quality and Innovation

(CQUIN) payment framework. CQUIN who initially set a target of 90% of patients to

receive risk assessment and appropriate thromboprophylaxis for VTE prevention: this

was increased to 95% in the second year. Data compiled by NHS England reveals

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that, for all providers of NHS funded acute care, VTE risk assessment rates rose

from 47% in July 2010 to 91% in December 20117. In the financial year 2014/15, VTE

risk assessment was fixed to the NHS Contract and there is currently a penalty of

£200 per patient if the proportion assessed falls below 95%. This systematic

approach to prevention of healthcare-acquired thrombosis has resulted in an 8% fall

in death due to VTE in England8, 9.

Evidence relating to graduated compression stockings in venous thromboembolism

prevention

Existing evidence for the additional benefit of GCS in VTE prevention is weak, and

this has been highlighted by our group10 and others11, 12. In addition to the limited

evidence and variation in recommendations, there remains (despite guidelines) some

variation in practice across England. For example, one centre has adopted a

pharmacological prophylaxis policy (without GCS) that has been used for high risk

surgical patients; the incidence of hospital-acquired thrombosis in that centre is 1.3-

2.9 per 1000 admissions (as measured per quarter over a 2 year period), which is

comparable to centres elsewhere in England13.

Complications and compliance of graduated compression stockings

VTE risks need to be balanced against the risks of preventative measures, both

mechanical and pharmacological. Patient experience of stockings in the ‘real world’ is

poor14. In particular, the use of GCS is known to be associated with a number of

undesired effects for the patient, including discomfort, pressure necrosis, rolling down

and creating a constrictive band15. The use of GCS on legs with impaired arterial flow

can worsen ischemia16, 17. Patients who are allergic to the stocking material may

develop contact dermatitis, skin discoloration and blistering as highlighted in the

CLOT studies18. Textile properties, including fabric roughness, thermoregulation and

dye, may contribute to skin reactions19.

Previously, advice on VTE prevention in stroke patients was extrapolated from small

trials showing that GCS reduce the risk of DVT18. However the large randomised

CLOTS 1 trial found no statistically significant difference in symptomatic or

asymptomatic femoro-popliteal DVT in individuals admitted to hospital with acute

stroke, with an absolute risk reduction 0.5% (95% CI -1.9% to 2.9%)18. Importantly,

CLOTS 1 also identified that skin breaks, ulcers, blisters, and skin necrosis were

significantly more common in patients allocated to GCS than in those allocated to

avoid their use (5.1% versus 1.3%)18. Thus this trial has challenged the widespread

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use of GCS12, 20 and limited their use in stroke patients.

Furthermore, the non-compliance rate for GCS has been reported to be 30%–65%21-

25. Additionally, the partial non-compliance (‘most days’ or ‘less often’) rate has been

shown to be 16%21. Commonly cited reasons include pain, discomfort, difficulty

donning the stockings, perceived ineffectiveness, excessive heat, skin irritation, cost

and cosmesis15, 16, 21, 26.

Financial impact of graduated compression stockings for venous thromboembolism

prevention in surgical patients

The additional cost of the combination of pharmacological and mechanical

thromboprophylaxis is considerable as this matter is relevant to large numbers of

patients in all English hospitals offering surgical services. Based on 2012-2013

Hospital Episode Statistics data, excluding day cases, there are 3.6 million adult

surgical NHS hospital admissions annually27, of which 13.9% are assessed as being

at low risk for VTE13, 28. The unit cost of a pair of GCS is £6.3629. At 2014 rates (£84

per hour), the cost of 10 minutes of in hospital nurse to patient contact is £1430.

Therefore, the annual cost of purchasing and applying GCS stockings to surgical

inpatients assessed as being moderate or high risk for VTE in England is estimated

at £63.1 million.

The need for a randomised clinical trial to determine the need for graduated

compression stockings in surgical patients

The efficacy of GCS as an adjunct to LMWH in VTE prevention in surgical patients is

poorly estimated, GCS are responsible for complications and there are substantial

costs related to their use. There is a real need to conduct a trial to examine whether

GCS further reduces VTE incidence in surgical patients receiving prophylactic dose

LMWH.

MethodologyEthics approval has been granted (National Research Ethics Service reference

16/LO/0015) for a seven-centre, UK-wide, open, randomised controlled trial. The trial

has a non-inferiority, group sequential design. The study design is shown in Figure 1.

The null hypothesis is that the single therapy (LMWH alone) is worse than the

combination therapy for VTE at 90 days by at least 3.5% over the 6% assumed for

the combination therapy. The rate of VTE confirmed by imaging of 6% is derived from

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a recent systematic review10. The study population comprises adult patients

presenting for elective surgery at the recruiting centres. The inclusion and exclusion

criteria are outlined in Table 1. Patients from a variety of surgical specialties will be

included in this pragmatic trial. Orthopaedic surgical procedures are not excluded per

se, however a number of these procedures require thromboprophylaxis beyond the

time of admission, or cast or brace use, which are exclusion criteria for entry into the

trial.

Each trial centre will be encouraged to use the LMWH preparation and

thromboprophylactic dose that has been adopted and established locally from

admission to discharge from hospital. GCS, either below-knee or above-knee,

providing compression of 18mmHg at the ankle, 14mmHg at the calf, and 10mmHg

at the knee are used31 from admission (if randomised to the combined

thromboprophylactic LMWH with GCS mechanical thromboprophylaxis arm) to the

point of discharge from hospital.

Primary endpoint

The study primary endpoint is VTE within 90 days. This is a composite endpoint

including duplex ultrasound-proven new lower-limb DVT up to 90 days post-surgery

(symptomatic or asymptomatic) plus symptomatic PE (imaging confirmed) up to 90

days post-surgery. This 90 day endpoint is in line with the NHS Standard Contract for

Acute Services which specifies that root cause analysis should be performed for all

cases of hospital-associated VTE – defined as cases arising within 90 days of a

hospital stay32.

Telephone or online review (according to patient preference) will be performed one

week after surgery or at discharge, and at 90 days. Imaging will be initiated at any

point if there is clinical suspicion of a DVT or PE. Routine bilateral full lower limb

duplex ultrasonography will be performed between 14 days and 21 days post-

operatively to capture peak VTE incidence33, 34. We expect to capture >95% of VTE

since the average time-point for post-operative thrombosis is seven days for DVT

and 21 days for PE, with the vast majority of events being DVT. The range of dates

offered is to prevent restricting scanning to a single date. Routinely scanning patients

only once reduces cost, and limits the time and inconvenience to the enrolled study

subjects (ethical consideration, improve recruitment and reducing drop-outs and loss

to follow-up). There is no pre-operative duplex for these same reasons and also

because asymptomatic pre-operative DVTs should be accounted for by equal

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distribution in the two study arms by the randomisation process. If patients are

inpatients at the time of their routine bilateral full lower limb duplex ultrasonography

at between 14 days and 21 days post-operatively, or if any inpatient duplex imaging

is prompted by clinical suspicion, GCS will be removed prior to imaging to ensure

optimum blinding of those undertaking the imaging18.

Secondary and safety endpoints

Secondary endpoints include quality of life which will be assessed upon arrival, upon

discharge and at follow-up using the EQ-5D. EQ-5D is widely used and well

validated, and is currently employed as part of the routine collection of Patient

Reported Outcome Measures (PROMs) for the NHS in England35.

Compliance with stockings during their admission will be assessed by issuing

patients with a VTE diary where they can document their GCS use, as well as any

adverse outcomes related to GCS or LMWH use. Compliance with LMWH will be

assessed by review of the patient’s medication chart. Overall mortality data will be

collected as a secondary endpoint.

Safety endpoints include GCS-related complications, bleeding complications and

adverse reactions to LMWH during admission. These will be determined by review of

medical notes and patient-reported comments in their VTE diary.

Sample size

With a one-sided test at 2.5% level of significance (equivalent to a 2-sided test at 5%)

the study has 90% power to conclude that the single pharmacological intervention is

non-inferior to the combined intervention (pharmacology and stockings) assuming an

event rate of 6% of VTE at 90 days in the combined group and a non-inferiority

margin of 3.5%, and a conservative loss to follow up (i.e. non-evaluable for the

primary outcome) rate of 10%. The maximum sample size required under this group

sequential design, including allowance for loss to follow up, is 2236.

Data monitoring

The independent Data Monitoring Committee (iDMC) will formally examine data at

25%, 50%, 75% and finally 100% accrual of the information for effectiveness using a

Lan-DeMets alpha spending function (<0.001, 0.002, 0.010, and 0.025 cumulative

alpha spent) and at 50% for futility (0.02 of the 0.10 total cumulative beta spent). The

study at full size expects to observe around 156 VTE episodes at 90 days under the

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null hypothesis (that the single intervention is not non-inferior to the combined) and

around 121 events under the alternative hypothesis (that the single intervention is

non-inferior to the combined). In information time the interim data reviews will be

scheduled to around 40 (25%), 80 (50%, including the single futility look as well) and

120 (75%) 90-day primary outcome events recorded. We will also schedule a

meeting of the iDMC when approximately n=200 subjects have achieved mature 90-

day follow up to check on the assumptions about the event rate. The full details of the

iDMC’s remit (including the stopping rules for effectiveness and futility) have been

agreed at the first meeting of the iDMC before any unblinded data are available or

seen. The expected sample size under the null hypothesis is 1546 and under the

alternative hypothesis 1673 (having allowed for the 10% assumed to be missing

primary outcome data).

Data analysis

The final sample size will be determined by the pre-specified group sequential

design, and there will be a single final analysis and reporting of the trial at that point.

As a non-inferiority design, both an Intention to Treat (ITT) and a suitably specified

Per Protocol analysis will be presented, with primacy given to the ITT approach. The

primary outcome will be analysed using a mixed effects logistic regression, with

centre as a random effect, VTE risk (moderate vs. high) and other to be pre-specified

baseline factors as covariates. Secondary outcomes will be assessed in a similar

fashion with generalised linear models appropriate to the distribution of the outcome.

The level of statistical significance will be taken to be a nominal 0.05.

Recruitment

Recruitment commenced in April 2016 with the seven UK centres coming ‘on-line’ in

a staggered fashion. Recruitment will be over a total of 18 months.

AcknowledgementsThe GAPS trial is funded by the National Institute for Health Research Health

Technology Assessment in the UK [14/140/61]. The views and opinions expressed

therein are those of the authors and do not necessarily reflect those of the HTA,

NIHR, NHS or the Department of Health.

Conflicts of Interest

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Professor David Warwick has no current conflicts of interest. He gave a paid lecture

on behalf of Oped, a manufacturer of intermittent compression therapy, in September

2015.

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References

1. Committee HoCH. The Prevention of Venous Thromboembolism in Hospitalised Patients. 2005.2. Venous thromboembolism : reducing the risk : reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. London: National Institute for Health and Clinical Excellence; 2010.3. Bahl V, Hu HM, Henke PK, Wakefield TW, Campbell DA, Jr. and Caprini JA. A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg. 2010;251:344-50.4. Health Do. Risk Assessment for Venous Thromboembolism. 2010.5. Guyatt GH, Akl EA, Crowther M, Gutterman DD and Schuunemann HJ. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:7S-47S.6. Nicolaides AN, Fareed J, Kakkar AK, Comerota AJ, Goldhaber SZ, Hull R, et al. Prevention and treatment of venous thromboembolism--International Consensus Statement. Int Angiol. 2013;32:111-260.7. Department of Health NE. VTE Risk Assessment Data Collection. 2012.8. Alikhan R and Cohen AT. Heparin for the prevention of venous thromboembolism in general medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev. 2009:CD003747.9. Kopcke D, Harryman O, Benbow EW, Hay C and Chalmers N. Mortality from pulmonary embolism is decreasing in hospital patients. J R Soc Med. 2011;104:327-31.10. Mandavia R, Shalhoub J, Head K and Davies AH. The additional benefit of graduated compression stockings to pharmacologic thromboprophylaxis in the prevention of venous thromboembolism in surgical inpatients. J Vasc Surg: Venous and Lym Dis. 2015;3:447-455.11. Zareba P, Wu C, Agzarian J, Rodriguez D and Kearon C. Meta-analysis of randomized trials comparing combined compression and anticoagulation with either modality alone for prevention of venous thromboembolism after surgery. Br J Surg. 2014;101:1053-62.12. Whittaker L, Baglin T and Vuylsteke A. Challenging the evidence for graduated compression stockings. Bmj. 2013;346:f3653.13. Roberts LN, Porter G, Barker RD, Yorke R, Bonner L, Patel RK, et al. Comprehensive VTE prevention program incorporating mandatory risk assessment reduces the incidence of hospital-associated thrombosis. Chest. 2013;144:1276-81.14. May V, Clarke T, Coulling S, Cowie L, Cox R, Day D, et al. What information patients require on graduated compression stockings. British journal of nursing. 2006;15:263-70.15. Lim CS and Davies AH. Graduated compression stockings. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2014;186:E391-8.16. Palfreyman SJ and Michaels JA. A systematic review of compression hosiery for uncomplicated varicose veins. Phlebology. 2009;24 Suppl 1:13-33.17. Callam MJ, Ruckley CV, Dale JJ and Harper DR. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. British medical journal. 1987;295:1382.18. Dennis M, Sandercock PA, Reid J, Graham C, Murray G, Venables G, et al. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet. 2009;373:1958-65.

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19. Wollina U, Abdel-Naser MB and Verma S. Skin physiology and textiles - consideration of basic interactions. Current problems in dermatology. 2006;33:1-16.20. Welfare M. NICE's recommendations for thromboembolism are not evidence based. Bmj. 2011;343:d6452.21. Raju S, Hollis K and Neglen P. Use of compression stockings in chronic venous disease: patient compliance and efficacy. Annals of vascular surgery. 2007;21:790-5.22. Shingler S, Robertson L, Boghossian S and Stewart M. Compression stockings for the initial treatment of varicose veins in patients without venous ulceration. Cochrane Database Syst Rev. 2011:CD008819.23. Shingler S, Robertson L, Boghossian S and Stewart M. Compression stockings for the initial treatment of varicose veins in patients without venous ulceration. Cochrane Database Syst Rev. 2013;12:CD008819.24. Chant ADB, Davies LJ, Pike JM and Sparks MJ. Support stockings in practical management of varicose veins. Phlebology. 1989;4:167–9.25. Coughlin LB, Gandy R, Rosser S and de Cossart L. Pregnancy and compression tights for varicose veins: a randomised trial. Phlebology. 2001;16:47.26. Ziaja D, Kocelak P, Chudek J and Ziaja K. Compliance with compression stockings in patients with chronic venous disorders. Phlebology. 2011;26:353-60.27. Centre HaSCI. Hospital Episode Statistics.28. Lang KJ, Barker RD, Roberts LN, Yorke R, Bonner L, Patel RK, et al. The value of computerised VTE assessments: findings from retrospective audit of 2474 non-consecutive electronic patient records in a VTE exemplar centre. Br J Haematol. 2012;157:31.29. Excellence NIfHaC. Venous thromboembolism: reducing the risk. Costing report. Implementing NICE guidance. 2010.30. Curtis L. Unit Costs of Health and Social Care. 2014.31. Best AJ, Williams S, Crozier A, Bhatt R, Gregg PJ and Hui AC. Graded compression stockings in elective orthopaedic surgery. An assessment of the in vivo performance of commercially available stockings in patients having hip and knee arthroplasty. J Bone Joint Surg Br. 2000;82:116-8.32. Arya R and Hunt BJ. Venous Thromboembolism Prevention - A Guide for Delivering the CQUIN Goal. 2010.33. Sweetland S, Green J, Liu B, Berrington de Gonzalez A, Canonico M, Reeves G, et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. Bmj. 2009;339:b4583.34. Warwick D and Rosencher N. The ''critical thrombosis period'' in major orthopedic surgery: when to start and when to stop prophylaxis. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2010;16:394-405.35. Health Do. Guidance on the routine collection of Patient Reported Outcome Measures (PROMs) for the NHS in England. 2008.

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Figure 1:Design of the GAPS trial

GCS, graduated compression stockings; IPC, intermittent pneumatic compression;

IVC, inferior vena cava; LMWH, low molecular weight heparin; NICE, National

Institute for Health and Care Excellence; PE, pulmonary embolism; VTE, venous

thromboembolism

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Table 1:GAPS Trial inclusion and exclusion criteria

GCS, graduated compression stockings; IPC, intermittent pneumatic compression;

IVC, inferior vena cava; LMWH, low molecular weight heparin; NICE, National

Institute for Health and Care Excellence; VTE, venous thromboembolism

Inclusion Criteria Exclusion Criteria

Elective surgical inpatients assessed

as being at moderate or high risk of

VTE according to the widely-used UK

Department of Health VTE Risk

Assessment for Venous

Thromboembolism 4 (based upon the

NICE recommendations 2).

Able to give informed consent to

participate in the study after reading

the patient information documentation

Age >18 years

Contraindications to LMWH

Contraindications to GCS, including

peripheral arterial disease, stroke

patients, individuals undergoing lower

limb surgery

Documented or known thrombophilia

or thrombogenic disorder

Individuals requiring therapeutic

anticoagulation

Previous VTE

Patients having IPC beyond theatre

and recovery

Patients requiring IVC filter

Pregnancy

Patients requiring extended

thromboprophylaxis

Application of a cast or brace in

theatre

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