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Randomised clinical trial,observational study and assessmentof cost-effectiveness of the treatmentof varicose veins (REACTIV trial)

JA Michaels, WB Campbell, JE Brazier,JB MacIntyre, SJ Palfreyman, J Ratcliffe

and K Rigby

Health Technology Assessment 2006; Vol. 10: No. 13

HTA

Health Technology Assessment

NHS R&D HTA Programme

April 2006

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HTA

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Randomised clinical trial,observational study and assessmentof cost-effectiveness of the treatmentof varicose veins (REACTIV trial)

JA Michaels,1*WB Campbell,2JE Brazier,3

JB MacIntyre,4

SJ Palfreyman,1

J Ratcliffe3

and K Rigby1

1Academic Vascular Unit, University of Sheffield, UK2 Royal Devon and Exeter Hospital and Peninsula Medical School,

Exeter, UK3 School of Health and Related Research, University of Sheffield, UK4 Royal Devon and Exeter Hospital, Exeter, UK

* Corresponding author

Declared competing interests of authors: none

Published April 2006

This report should be referenced as follows:

Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

Randomised clinical trial, observational study and assessment of cost-effectiveness of the

treatment of varicose veins (REACTIV trial). Health Technol Assess 2006;10(13).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,

Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch) and

Current Contents/Clinical Medicine.

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liability for damages or losses arising from material published in this report.The views expressed in this publication are those of the authors and not necessarily those of theHTA Programme or the Department of Health.

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Dr Rob Riemsma and Dr Ken SteinManaging Editors: Sally Bailey and Sarah Llewellyn Lloyd

ISSN 1366-5278

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This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals providedthat suitable acknowledgement is made and the reproduction is not associated with any form of advertising.

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Objectives: To establish the cost-effectiveness of

surgery and sclerotherapy for the treatment of varicose

veins.

Design: Randomised controlled trials (RCTs) werecarried out for conservative treatment, sclerotherapy

and surgery for varicose veins. An economic analysis

was carried out alongside the randomised trial.

Economic modelling was undertaken based on the

primary data collection and a literature review

(database searches undertaken in April 2000 and

updated in March 2001).

Setting: Primary data collection was from a large

district general hospital and a teaching hospital both in

England over a 2-year period from January 1999. Cost-

effectiveness analysis and economic modelling were

carried out using an NHS perspective.

Participants:A total of 1009 patients were recruited.Interventions: Thirty-four patents were randomised

in Group 1 (minor varicose veins with no reflux,

randomised between conservative treatment and

sclerotherapy), 77 in Group 2 (moderate varicose veins

with reflux, randomised between surgery and

sclerotherapy) and 246 in Group 3 (severe varicose

veins with reflux, randomised between conservative

treatment and surgery). The remaining 652 patients

formed the observational part of the study.

Main outcome measures: The cost-effectiveness

analysis was based on NHS treatment costs for the

20023 financial year, and utilities based on the ShortForm 6D (SF-6D) preference-based health measure.

For the clinical trial, the outcome measures were

health-related quality of life (HRQoL) [Short Form with

36 Items (SF-36), EuroQol quality of life questionnaire

(EQ-5D), visual analogue scale (VAS) and standard

gamble], symptomatic relief, anatomical extent (for

which a new classification was developed andvalidated), patient satisfaction and the incidence of

complications.

Results: Of the RCTs, only the Group 3 trial was large

enough to provide clear results. This showed that

surgical treatment produced better results than

conservative treatment in terms of HRQoL,

symptomatic relief, anatomical extent and patient

satisfaction. Clinical outcomes of surgery and

sclerotherapy showed significant improvement in the

extent of varicose veins, symptomatic and HRQoL

parameters. Cost-effectiveness analysis based on the

Group 3 trial showed that the surgery produced an

estimated discounted benefit of 0.054 quality-adjustedlife-year (QALY) over a 2-year period, with an

additional discounted cost of 387.45, giving an

incremental cost-effectiveness ratio (ICER) of 7175

per QALY. Economic modelling suggested that surgery

produced a still greater benefit when considered with a

10-year time horizon, with an ICER of 1936 per

QALY. Injection sclerotherapy produced an incremental

benefit of approximately 0.044 QALY at a cost of 155

when compared with conservative treatment, giving an

ICER of 3500 per QALY. When surgery was compared

with sclerotherapy, surgery produced greater benefit

with a lower ICER (showing extended dominance).Conclusions: Standard surgical treatment of

varicose veins by saphenofemoral ligation, stripping

and multiple phlebectomies is a clinically effective and


iii

Queens Printer and Controller of HMSO 2006. All rights reserved.

Abstract

Randomised clinical trial, observational study and assessmentof cost-effectiveness of the treatment of varicose veins(REACTIV trial)

JA Michaels,1*WB Campbell,2JE Brazier,3JB MacIntyre,4 SJ Palfreyman,1J Ratcliffe3

and K Rigby1

1

Academic Vascular Unit, University of Sheffield, UK2 Royal Devon and Exeter Hospital and Peninsula Medical School, Exeter, UK3 School of Health and Related Research, University of Sheffield, UK4 Royal Devon and Exeter Hospital, Exeter, UK

* Corresponding author

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cost-effective treatment for varicose veins, with an

ICER well below the threshold normally considered

appropriate for the funding of treatments within

the NHS. Injection sclerotherapy also appears to be

cost-effective, but produces less overall benefit,

with a higher ICER than surgery for patients with

superficial venous reflux. In minor varicose veins

without reflux, sclerotherapy is likely to provide a small

average benefit with acceptable cost-effectiveness.

Research is needed into methods for accurate and

acceptable utility evaluations for conditions with

relatively minor effect on HRQoL and also for a

validated and standardised method of classification for

varicose veins.

Abstract

iv

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v

List of abbreviations .................................. vii

Executive summary .................................... ix

1 Introduction ............................................... 1The problem .............................................. 1

Aims of the study ....................................... 1The clinical effects of varicose veins .......... 2

Assessment of varicose veins ...................... 3

Treatments for varicose veins ..................... 4Other treatments ........................................ 5Important uncertainties ............................. 5Structure of the report ............................... 5

2 Review of existing evidence ....................... 7Prevalence and epidemiology of varicose

veins ............................................................ 7Treatment of varicose veins ........................ 9

3 Classification of varicose veins ................... 17Background ................................................ 17

Methods ...................................................... 17Results ........................................................ 17

4 Clinical trials .............................................. 21Methods ...................................................... 21Results ........................................................ 25Group 1 trial .............................................. 34Group 2 trial .............................................. 38Group 3 trial .............................................. 43Overall results of treatment ....................... 48

5 Economic analysis ...................................... 55Introduction ............................................... 55

Methods ...................................................... 55Results ........................................................ 56Patient preference: willingness to paystudy ........................................................... 66

6 Cost-effectiveness modelling ..................... 73Introduction ............................................... 73Method ....................................................... 73Model 1 ...................................................... 79Model 2 ...................................................... 83Model 3 ...................................................... 88

7 Discussion and conclusions ........................ 97Introduction ............................................... 97

Classification .............................................. 97Clinical trial recruitment ............................ 97Group 1 trial .............................................. 98Group 2 trial .............................................. 99Group 3 trial .............................................. 99Complications of treatment ....................... 99Quality of life measures ............................. 99Cost-effectiveness analysis .......................... 100

Willingness to pay ...................................... 100

Modelling ................................................... 101Conclusions ................................................ 102Implications for healthcare ........................ 102Implications for research ........................... 103

Acknowledgements .................................... 105

References .................................................. 107

Appendix 1 Search strategy ...................... 115

Appendix 2 Information sheets ................ 119

Appendix 3A Baseline assessmentquestionnaire .............................................. 133

Appendix 3B Baseline assessmentproforma .................................................... 143

Appendix 3C Standard gamblequestionnaire .............................................. 147

Appendix 3D One-year follow-upquestionnaire .............................................. 149

Appendix 3E One-year assessmentproforma .................................................... 157

Appendix 4 Alternative cost-effectivenessanalyses ....................................................... 161

Appendix 5 Willingness to payquestionnaire .............................................. 163

Health Technology Assessment reports

published to date ....................................... 181

Health Technology AssessmentProgramme ................................................ 193

Contents

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AK above the knee

ANOVA analysis of variance

BK below the knee

BMI body mass index

BNF British National Formulary

CEAC cost-effectiveness acceptabilitycurve

CI confidence interval

DVT deep vein thrombosis

EQ-5D EuroQol quality of lifequestionnaire

FCE finished consultant episode

HHD hand-held Doppler

HRQoL health-related quality of life

ICER incremental cost-effectivenessratio

ITT intention-to-treat

LA local anaesthetic

LSV long saphenous vein

NICE National Institute for Health andClinical Excellence

QALY quality-adjusted life-year

RCT randomised controlled trial

REACTIV Randomised and EconomicAssessment of Conservative andTherapeutic Interventions for

Varicose Veins (study title)

RR relative risk

SD standard deviation

SF-36 Short Form with 36 Items

SF-6D Short Form 6D

SSV short saphenous vein

STD sodium tetradecyl sulphate

SVI Sheffield Vascular Institute

TTO time trade-off

VAS visual analogue scale

VV varicose vein

WTP willingness to pay


vii


List of abbreviations

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), orit has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which casethe abbreviation is defined in the figure legend or at the end of the table.

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Objective

The objective of this study was to establish thecost-effectiveness of surgery and sclerotherapy forthe treatment of varicose veins.

Design

Randomised controlled trials (RCTs) were carriedout for conservative treatment, sclerotherapy andsurgery for varicose veins, supplemented byobservational data collection in those patients whohad exclusion criteria or declined participation inthe RCTs. An economic analysis was carried outalongside the randomised trial. Economicmodelling was undertaken based on the primarydata collection and a literature review (databasesearches undertaken in April 2000 and updated inMarch 2001).

Setting

Primary data collection was from two centres,recruiting from sequential referrals of patients with

varicose veins to vascular surgeons at a large districtgeneral hospital in Exeter and a teaching hospitalin Sheffield over a 2-year period from January 1999.Cost-effectiveness analysis and economic modelling

were carried out using an NHS perspective.

Participants

A total of 1009 patients were recruited, with 34being randomised in Group 1 (minor varicose

veins with no reflux, randomised betweenconservative treatment and sclerotherapy), 77 inGroup 2 (moderate varicose veins with reflux,randomised between surgery and sclerotherapy)and 246 in Group 3 (severe varicose veins withreflux, randomised between conservative treatmentand surgery). The remaining 652 patients formedthe observational part of the study.

Main outcome measuresThe cost-effectiveness analysis was based on NHStreatment costs for the 20023 financial year, and

utilities based on the Short Form 6D (SF-6D)preference-based health measure. For the clinicaltrial, the outcome measures were health-relatedquality of life (HRQoL) [Short Form with 36 Items(SF-36), EuroQol quality of life questionnaire (EQ-5D), visual analogue scale (VAS) and standardgamble], symptomatic relief, anatomical extent(for which a new classification was developed and

validated), patient satisfaction and the incidence

of complications.

Results

Of the RCTs, only the Group 3 trial was largeenough to provide clear results. This showed thatsurgical treatment produced better results thanconservative treatment in terms of HRQoL,symptomatic relief, anatomical extent and patientsatisfaction. The observational study showed no

significant differences in outcomes from theRCTs, with no major complications fromsclerotherapy and a complication rate of 1.7%following surgery. Clinical outcomes of surgeryand sclerotherapy showed significantimprovement in the extent of varicose veins,symptomatic and HRQoL parameters.

Cost-effectiveness analysis based on the Group 3trial showed that the surgery produced anestimated discounted benefit of 0.054 quality-adjusted life-year (QALY) over a 2-year period,

with an additional discounted cost of 387.45,

giving an incremental cost-effectiveness ratio(ICER) of 7175 per QALY. Economic modellingsuggested that surgery produced a still greaterbenefit when considered with a 10-year timehorizon, with an ICER of 1936 per QALY.Injection sclerotherapy produced an incrementalbenefit of approximately 0.044 QALY at a cost of155 when compared with conservative treatment,giving an ICER of 3500 per QALY. When surgery

was compared with sclerotherapy, surgeryproduced greater benefit with a lower ICER(showing extended dominance). These findings

were robust over a range of univariate andmultivariate sensitivity analyses, covering differentassumptions, and estimates of probabilities, costsand outcomes.


ix


Executive summary

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Conclusions

Standard surgical treatment of varicose veins bysaphenofemoral ligation, stripping and multiplephlebectomies is a clinically effective and cost-effective treatment for varicose veins, with anICER well below the threshold normallyconsidered appropriate for the funding oftreatments within the NHS. Injectionsclerotherapy also appears to be cost-effective, butproduces less overall benefit, with a higher ICERthan surgery for patients with superficial venousreflux. In minor varicose veins without reflux,sclerotherapy is likely to provide a small averagebenefit with acceptable cost-effectiveness.

Recommendations for furtherresearch

One of the key issues in calculating cost-effectiveness is the difficulty in evaluating the

potential utility benefit of successful treatment inthis condition. Research is needed into themethodology for producing accurate andacceptable utility evaluations for conditions withrelatively minor effect on HRQoL. The studydemonstrates the difficulty of large RCTs in thisarea. It is suggested that economic modellingcombined with the collection of observational datamay provide a useful approach to the assessmentof the potential of new treatments for thiscondition. In future studies, it is important that a

validated and standardised method ofclassification is used to allow comparisons of theextent of varicose veins, the effects of treatmentand progression of the disease.

Executive summary

x

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The problem

Varicose veins are very common, affecting 2040%adults in the UK.14 They pose a huge burden onthe NHS: Table 1 shows the number of proceduresfrom Department of Health figures.5 In additionto this surgical workload, patients with varicose

veins account for large numbers of outpatientattendances in primary and secondary care.

Further impact results from a demand forprescription of graduated compression hosieryand treatment of varicose veins by compressionsclerotherapy.

The large numbers of patients presenting fortreatment (and the larger numbers with varicose

veins who might potentially do so) have importantimplications for the NHS, specifically:

G Logistic implications for the provision ofservices for assessment and treatment.

G

The costs of these services.G Dilemmas about which patients should haveNHS treatment, with postcode referralpractices (some NHS Trusts restrict referrals topeople with complications such as skin damage,

whereas others treat the larger numbers ofpatients with aching and/or cosmeticcomplaints).

G Waiting list problems, with their politicalramifications. The mean waiting times afterbeing placed on a waiting list for surgery areshown in Table 1. In addition, patients usually

wait for many weeks or months to be seen in

clinic prior to this. Varicose veins are widelyperceived as being of low priority; theirassessment can be time consuming; and surgerycan be lengthy (particularly if veins are

recurrent). All of these factors contribute to longwaiting times for outpatient clinic appointmentsand for treatment in many hospitals.

G Specialisation and training. Assessment ofvaricose veins by surgeons other than vascularspecialists, and by their trainees, may result ininappropriate and/or imperfect treatment. Thishas changed in recent years but may still be anissue in some localities.

G In some patients, varicose veins lead to venousulceration. This is a chronic condition whichplaces major demands on nursing services and

which represents a further massive cost to theNHS.

Aims of the study

The study was known as the REACTIV(Randomised and Economic Assessment ofConservative and Therapeutic Interventions for

Varicose Veins) study. The main aim of theREACTIV study was to investigate the clinical andcost-effectiveness of varicose vein treatments.

The central part of the study took the form ofrandomised controlled trials (RCTs) to comparethe most commonly used methods of managing

varicose veins. The methods considered in thestudy were conservative management, injectionsclerotherapy and surgery. Since these areappropriate to different patient populations, thestudy used three separate RCTs on separategroups of patients. Group 1 was those patients in

whom there were minor varicose veins in theabsence of evidence of reflux in the longsaphenous vein (LSV) or short saphenous vein(SSV). These patients were randomised between


1


Chapter 1

Introduction

TABLE 1 Procedures done for varicose veins in the NHS in England during 20003, including the percentage of patients who werefemale, the number treated as day cases, the number of bed days used and the average waiting time for treatment

Year FCEsa Female (%) Day cases Bed days Waiting time (days)

20001 43,432 66.7 22,890 31,429 21520012 40,697 65.3 21,309 29,062 211

20023 44,196 65.9 24,025 30,109 216

a Finished consultant episodes.

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conservative treatment and sclerotherapy. InGroup 2, patients with moderate varicose veinsand evidence of reflux were randomised betweensurgery and sclerotherapy, and in Group 3 patients

with more extensive varicose veins in the presenceof reflux were randomised between surgery andconservative management.

The study developed a classification for varicoseveins to assist in identifying appropriate patientsfor each group within the study and in assessingprogression or recurrence in the follow-up period.

Economic analysis was carried out alongside theRCTs based on cost and resource use datacollected within the trials and utility estimates

based on health-related quality of life (HRQoL)measures.

Those patients who were excluded or declinedparticipation in the RCTs formed an observationalgroup. Information regarding management,outcomes and follow-up were collected from thisgroup in order to inform economic modelling.

A willingness to pay (WTP) study was carried outto consider aspects of patient preference andeconomic modelling was undertaken to allow

extrapolation of the results and provide furtherinformation in areas that were not adequatelyaddressed through primary data collection.

The structure of the report is described at the endof this chapter.

The clinical effects of varicose veins

Cosmetic embarrassment and concernabout the futureMost people with varicose veins will suffer no

medical harm from them throughout theirlifetime. The commonest complaint is theirunsightliness, and cosmetic motives probablyunderlie many requests for treatment on thegrounds of minor symptoms. In addition, peopleare worried about the spectre of complicationsfrom their varicose veins specifically in thecontext of a family history of ulcers or other legproblems, and also in relation to the risk of deep

vein thrombosis (DVT),6 promoted by recentmedia reports of the dangers of air travel and

venous thromboembolism.

DiscomfortApart from cosmetic embarrassment and concernabout the future, the commonest symptom from

varicose veins is discomfort. This can take a varietyof forms typically described by patients asaching, heaviness or itching. These, and other legpains, are often present in people with varicose

veins as a result of other conditions, includingarthritis and muscular problems,7 but a carefulhistory may help to identify symptoms related to

varicose veins. Discomfort after prolongedstanding, relief by elevation of the leg or by

wearing support hosiery and symptoms over thevaricose veins may be pointers to a venous cause,but this is an area of uncertainty. Ankle swelling asa result of oedema is another complaint whichmay result from varicose veins8 but which hasother common causes.

Patients with all these complaints may be said tohave medically uncomplicated varicose veinsbecause their veins are causing no damage orthreat to their legs: it is in these patients thatthe greatest uncertainty exists about the benefitsand cost-effectiveness of treatment. Themedical complications of varicose veins arethrombophlebitis, bleeding, eczema,lipodermatosclerosis (the latter two oftenconveniently called skin changes), and ulceration.

Superficial thrombophlebitis

This can occur in the absence of varicose veins(when it may be associated with systemic diseasesuch as cancer), but varicose veins are thecommonest underlying cause. Treatment of the

varicose veins may be considered if they arecausing other symptoms or if phlebitis is recurrent(sometimes varicose veins become permanentlyoccluded as a result of phlebitis, and then there isno need to consider definite treatment). Reportsof extension of thrombus into the deep veins913

have raised concerns about this risk, but clinicalDVT is very uncommon and most cases ofsuperficial thrombophlebitis are dealt with in

primary care.

BleedingExternal bleeding is an uncommon consequenceof varicose veins and almost always occurs throughan area of obviously compromised skin overlying a

varicosity in the lower leg. It is alarming and posesa potential threat to life. Bleeding is an indicationfor early referral and treatment of varicose veins,and this is the recommendation of currentguidelines from the National Institute for Healthand Clinical Excellence (NICE).14

Lipodermatosclerosis and ulcerationThe venous hypertension caused by varicose veinsis an important cause of damage to the skin and

Introduction

2

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subcutaneous tissues of the lower leg.15,16 Thisusually starts with eczema or pigmentation andmay then progress through varying severities of

lipodermatosclerosis to ulceration. The chance ofany individual with varicose veins developing skindamage is both uncertain17 and small. Amongthose who do develop skin changes, the risk ofulceration is also unpredictable, but any signs of

venous damage to the skin of the leg is usuallyregarded as an indication to consider preventativemeasures in the form of either compressionhosiery or treatment of the varicose veins.

This spectrum of clinical effects means that theimpact of varicose veins on HRQoL, the benefitfrom different kinds of treatment, and the cost-

effectiveness of interventions may vary greatly.These considerations have led to local restrictionson the referral of patients to secondary care andgeographical inequalities in the provision of

varicose vein treatments, with some districtsdeveloping local guidance to limit referrals of

varicose veins.18,19

Assessment of varicose veins

A fundamental aim of examining varicose veins is

to identify the sites of valvular incompetenceconnecting them with the deep veins. Until themid-1980s it was normal practice for patientssimply to be examined clinically and seldom tohave any special investigations of their veins.

Assessment was by general surgeons, few of whomhad a special interest in the management of

venous disease, and it was often done by trsineeswith limited experience.20 Since then, practice haschanged substantially in a number of respects:

1. Specialisation. Surgeons have becomeincreasingly specialised and varicose veins are

dealt with largely by vascular surgeons, whohave a greater degree of specialist knowledgeand interest in their management.21

2. Training. Trainees can acquire the skills ofhand-held Doppler (HHD) assessment fairlyrapidly,22,23 but there is evidence to suggest thattrainees are likely to miss the presence of refluxmore frequently than fully trained specialists.24

With increasing numbers of consultants invascular surgery, more assessment is done orsupervised by consultants.

3. Hand-held Doppler. HHD has become used

increasingly during the last 15 years, based onevidence that it provides more thorough andaccurate assessment of reflux in the leg

veins2429 than traditional examination,

including traditional manoeuvres such as theTrendelenberg (tourniquet) test. Most surgeons

who use HHD do so as a screening test, toselect patients for more detailed assessment byduplex ultrasound imaging.24,2931 Thecommon criteria for advising duplex aredetection of reflux in the popliteal fossa,3234

recurrent varicose veins35 and atypical veins orother uncertainties about the source of refluxinto the superficial veins after HHDexamination.One study by the Exeter group showed that aselective approach to requesting dupleximaging, based on HHD examination, resultedin requests for duplex (or other additionaltests) in 60 of 283 (21%) patients.31Another

study from Leeds showed that duplex imagingwould have been requested in 39% of 108 limbsafter screening by HHD.29

4. Duplex ultrasound imaging. This has come tobe regarded as the gold standard forassessment of the leg veins, providing bothanatomical and haemodynamic information.Studies on the severity34,36 and distribution3739

of reflux detected by duplex scanning haveshown some correlation with the clinical stateof the limb.Some surgeons advocate duplex imaging for all

patients presenting with varicose veins4044

andthis is probably the counsel of perfection.However, availability of vascular technologiststime and of duplex machines is simply notadequate in many hospitals and there istherefore a reasonable argument for using HHDas a screening test, as described above.24,29,31

This argument depends on knowledge of theaccuracy of the clinicians using HHD indetecting reflux that would require correctionduring treatment of varicose veins.Traditional teaching and logic suggest that themore accurate is the assessment of varicose

veins (by HHD and by duplex imaging), themore thorough and correct the surgery will be,and as a consequence the more durable theresult, but long-term studies have yet tosupport this view.45,46 One problem ofconducting research into the effectiveness ofdifferent methods of assessing and treating

varicose veins is the lack of a reproduciblemethod to describe the extent and size of the

varicosities (this is dealt with in detail inChapter 3).

5. Other special investigations. These include

venography and various forms ofplethysmography. They have only ever beenused in a minority of patients with varicose

veins and have now largely been replaced by


3


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duplex ultrasound imaging.35,4751 They maystill have a place in the investigation of patients

with varicose veins who also have importantdeep venous disease.5254

Treatments for varicose veins

The main forms of treatment for varicose veins areconservative treatment, sclerotherapy and surgery they are described in detail in Chapter 2.

Conservative treatmentConservative treatment refers to a range ofmeasures which may be pursued by people with

varicose veins, either with or without medical

advice. Perhaps the most important is simpleexplanation and reassurance. People with a familyhistory of varicose veins are often frightened thatthey will finish up like their mother, and those

with venous ulcers in their family have specialconcerns. There are widespread misconceptionsthat varicose veins are associated with a likelihoodof DVT, heart disease and amputation. Manypeople are simply worried that their veins will

worsen and cause them harm, so they seekprophylactic treatment.6 These fears and concernsare not well documented but are familiar to

clinicians who regularly see patients with varicoseveins and are the subject of an ongoing study inExeter. They are important reasons why patientspresenting with varicose veins require goodexplanation and reassurance as part of theirmanagement, and this element of conservativetreatment may be all that is required for manypeople.

Compression hosiery can be used for relief ofsymptoms but many patients find this disagreeableand it tends to be used regularly only by those

who have troublesome symptoms.

Advice about elevation55 and exercise is often citedas part of the conservative management of

varicose veins, but evidence of effectiveness islacking and provision of this advice is sporadic.

There are uncertainties about both clinical andcost-effectiveness of conservative measures. Theyare subject to variation in use by doctors and

variable acceptability to patients. In particular,there is no good information about their effect onthe quality of peoples lives.

SclerotherapySclerotherapy (compression sclerotherapy orinjection treatment) offers a relatively simple form

of outpatient treatment which can obliteratevaricose veins for a variable length of time.Sclerotherapy became popular in the 1960s5658

and dedicated sclerotherapy clinics wereestablished in many hospitals. Since that time, thepopularity of sclerotherapy has declined based onevidence of poor long-term effectiveness. Despiteits poor long-term results, many patients obtain asatisfactory short-term outcome, sclerotherapy isrepeatable and many patients do not returnrequesting further treatment. Sclerotherapy is nowgenerally considered to be most appropriate for

varicose veins below the knee (BK) [wherecompression is easier to apply than above the knee(AK)] in the absence of saphenous vein reflux.This usually means veins which are not causing

severe symptoms or medical complications.

There is almost no published information aboutthe effect of sclerotherapy on HRQoL, itsacceptability to patients compared with surgery orits cost-effectiveness. A study by Campbell andcolleagues showed that patients preferred theincreased chance of a good long-term result fromsurgery, taking into account the inconvenience andlikely discomfort from operation compared withsclerotherapy.59

SurgerySurgery for varicose veins is regarded as thedefinitive treatment for patients withincompetence in the long or short saphenoustrunks.5961 The results are longer lasting thanthose of sclerotherapy,6264 but surgical treatmentinvolves a day-case or inpatient operation, generalanaesthesia (usually), often a period ofrecuperation and time off work and the possibilityof complications. Recurrence is not uncommonand about 20% patients presenting to hospital

with symptomatic varicose veins have hadoperations before.25 Recurrence rates ranging

from 20 to 80% have been reported between 5 and20 years after surgery.65

The advantages of surgery over other treatmentsin terms of cost-effectiveness have not been thesubject of detailed study. In particular, evidence onthe results of surgery compared with othertreatments is from the era before ultrasoundexamination of varicose veins and clinicalassessment is known to be frequently flawed.

New endovascular treatments for

varicose veinsThese include new alternatives to surgicalstripping of the long saphenous vein (ablation ofthe vein by radiofrequency6668 or laser69,70 and

Introduction

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injection of sclerosant foam.7173 They havebecome subjects of debate since the inception ofthe present project and have not yet disseminated

widely in the NHS. The new techniques forablating the long saphenous vein (radiofrequencyor laser) are unlikely to have any importantdifferences in outcome from stripping: they aresimply different ways of ablating the longsaphenous vein at operation, but controversysurrounds their expense and durability.7476

One other new method recently promoted for useduring surgery for varicose veins is transilluminatedpowered phlebectomy, which is an alternative tohook phlebectomy (avulsion) of varicose veins. Thismethod has its advocates, and it may have

advantages for extensive varicosities, but a recentstudy failed to support its claimed benefits.77

None of these treatments was readily available inthe NHS at the time when this study wasundertaken. They will not be considered further.

Other treatments

For the sake of completeness, it is perhaps worthrecording some other treatments which have been

used for symptomatic treatment of varicose veins,but which have not entered mainstream practice.Reported drugs used for treatment includedihydroergotamine,78 flunarizine,79 rutosides80

and horse chestnut seed oil.81 Hydrotherapy withsulphurous water has recently been reported toimprove varicose vein symptoms.82

Important uncertainties

G How can we be sure which symptoms are beingcaused by varicose veins?

G What is the effect of varicose veins on HRQoL?G Which patients will develop medical

complications from their varicose veins?

G How should patients be selected for treatmentof varicose veins?

G How can assessment of varicose veins bestandardised for research purposes?

G What conservative measures are effective incontrolling symptoms of varicose veins? What istheir cost-effectiveness?

G What is the place of sclerotherapy?G What are the effects of conservative treatment,

sclerotherapy and surgery on symptoms andHRQoL in well-defined groups of patients?How durable are their effects?

G How does the cost-effectiveness of thesedifferent treatments compare?

Structure of the report

With a view to addressing uncertainties in theevidence described above, this report presents the

work undertaken as follows:

Chapter 2 Review of the existing evidence onG prevalence and epidemiology of

varicose veinsG treatments for varicose veins

(systematic review).Chapter 3 Description of a new method for

classification of the extent andseverity of varicose veins.

Chapter 4 Description of clinical trials,including methodology and clinicalresults.

Chapter 5 Economic analysis of themanagement of varicose veins,including the economic analysisrelating to the clinical trial and a

WTP study.Chapter 6 Economic modelling of the

management of varicose veins.Chapter 7 Discussion and suggested

implications of the findings of thevarious studies for clinical practiceand for future research.


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Prevalence and epidemiology ofvaricose veins

Determining the prevalence of varicose veins isdifficult. Many studies have been published, butthey vary in definitions of varicose veins, methodsof diagnosis and response rates to questionnaires.They have been undertaken in different countries,on different ethnic groups and on populations of

different age ranges and gender distributions. Thetime when the study was done may haveinfluenced findings and in this chapter onlystudies published after 1970 have been included.

Tables 2, 3 and 4 show the findings of studiespublished since 1970, arbitrarily divided betweenthose from westernised societies1,3,8392 (Table 2),European countries only1,3,84,87,88,91 (Table 3) and

various different ethnic groups9397 (Table 4).Overall, they demonstrate a wide range ofobserved prevalences. The European data are

most relevant to this report and Table 3 showsthese, from studies which specified varicose veins(rather than reticular veins, thread veins, etc.).

Five of the six studies reported prevalences of24.632.2% in women.1,84,87,88,91 The range inmen was wider, but three of five studies whichreported male prevalence had results in the range14.519.3%.1,87,88 The findings of a recent largestudy from the USA, examining an age-stratified,ethnically mixed population, reported prevalences

which fell within these ranges (27.7% in womenand 15% in men),92 as did a similar large study

done in the USA in 1973 (25.9% for women and12.9% for men).83

Taking into account all this diverse information, itis reasonable to conclude that the prevalence of

visible varicose veins in Europe and the USAis approximately 2530% for adult women andapproximately 15% for men.

Factors affecting prevalenceGender

All the studies described above which examined

gender differences found a higher prevalence inwomen than men. Just one study reported malepredominance, the Edinburgh Vein Study, which is


7


Chapter 2

Review of existing evidence

TABLE 2 Prevalence of varicose veins in studies reported since 1970 from westernised societies

First author and No. of Country Sample population Age Prevalence Prevalenceyear subjects (years) in men (%) in women (%)

Coon, 197383 6389 USA Random >10 12.9 25.9

Guberan, 197384 610 Switzerland Store employees 1570 29

Widmer, 197885 4529 Switzerland Factory workers 2574 56 (included 55

reticular veinsand threadveins)

Abramson, 198186 4802 Israel Random >15 10.4 29.5

Novo, 198887 1122 Sicily Randomised 2059 19.2 46.2

Leipnitz, 198988 2821 Germany Random 4565 14.5 29

Hirai, 199089 541 Japan Patients and staff >15 45

Franks, 19921 (calculated 1338 England Random 3570 17 31from original report byEvans et al., 19994)

Komsuoglu, 199490 850 Turkey All local population >60 34.5 38.3

Sisto, 199591 8000 Finland Cluster sample from >30 6.8 24.6

population registerEvans, 19983 1566 Scotland Random? 1864 39.7 32.2

Criqui, 200392 2211 USA University employees 4079 15 27.7

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influential because it is a recent and major UK-basedpopulation study.4 The cosmetic aspect of varicose

veins is generally more important to women, andall studies which have reported treatment ratesdescribe higher rates for women.86,91,98

AgeThe prevalence of varicose veins increases withage, as demonstrated in several studies.4,83,85,86,89,97

Even among children an increased prevalence hasbeen observed between the ages of 10 and12 years (no varicosities observed) and 1416 years(observed in 3.7%).99 In the Edinburgh Vein Study,overall prevalence increased significantly from11.5% in the age range 1824 years to 55.7% inthe age range 5564 years.4

Ethnicity

Studies in developing countries have generallyshown a lower prevalence of varicose veins thanthose from Europe (see Table 2, but note themarked difference in prevalence between railway

workers in northern and southern India,93 those inthe south having a prevalence similar to that inEurope). There are, however, no good data onpossible variations in prevalence in different racialgroups in the UK.

Other factorsIt is not the aim of this section to analyse thepossible aetiology of varicose veins in detail.However, a variety of factors have been associated

with their development, and a brief description ofthese seems relevant to consideration of theirprevalence.

1. Body mass and height. Some studies haveshown an association between obesity and

varicose veins for women,85,86,100 but this is nota consistent finding.84,88,89 No such association

has been demonstrated for men.2

A recentreport from the Edinburgh Vein Study hasshown an association with increasing height forboth sexes.100


8

TABLE 3 Prevalence of varicose veins in studies of European population samples


Guberan, 197384 610 Switzerland Store employees 1570 29

Novo, 198887 1122 Sicily Random 2059 19.3 46.2

Leipnitz, 198988 2821 Germany Random 4565 14.5 29

Franks, 19921 (figures 1338 England Random 3570 17 31calculated from originalreport by Evans et al.,19994)

Sisto, 199591 8000 Finland Cluster sample from >30 6.8 24.6population register

Evans, 19983 1566 Scotland Random 1864 39.7 32.2

TABLE 4 Selected studies which investigated prevalence in different ethnic groups


Malhotra, 197293 354 North India Railway workers 1865 6.8 323 South India Railway workers 1865 25.1

Beaglehole, 197594 377 Cook Island Pukapakans 1564 2.1 4.0417 Cook Island Rarotongans 1564 15.6 14.9721 New Zealand Maoris 1564 33.4 43.7356 New Zealand Europeans 19.6 37.8786 Tokleau Island 2.9 0.8

Stanhope, 197595

728 New Guinea Rural villagers 2070 5 0.1Richardson, 197796 1259 Tanzania Clinic patients 4.8 4.1

Maffei, 198697 1755 Brazil Clinic patients >15 37.9 50.9

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2. Pregnancy. Pregnancy appears to increase therisk but any association between numbers ofpregnancies and increasing prevalence of

varicose veins is controversial.2 Nevertheless,many women blame pregnancy for thedevelopment of their varicose veins.

3. Family history. There is a widely held belief ofa familial tendency to varicose veins, butpeople with varicose veins are likely to know offamily members also affected by this commoncondition, so biasing any questionnaire surveytowards a positive association.2 The Edinburgh

Vein Study has recently added to the reports offamilial susceptibility.100

4. Occupation and lifestyle factors. There havebeen reports of increased prevalence among

those with occupations which involve prolongedstanding,86,101,102 but these are not conclusive,and the Edinburgh Vein Study failed to showany consistent relationship with lifestylefactors.100 It is perhaps worth noting that thefrequently cited association between the

wearing of tight corsets and varicose veins isnot supported by convincing evidence.2,84,86,101

Key pointsG Varicose veins affect 2530% of adult women

and about 15% of men in western society.G

Their prevalence increases with increasing age.G They are probably more common in women

who have been pregnant or who are obese, andthere may be a familial susceptibility.

Treatment of varicose veins

IntroductionThe published evidence for the treatment of

varicose veins is currently poor. A systematicreview of injection sclerotherapy has beenpublished in the Cochrane Library,103 but no other

published systematic reviews were available.

In order to evaluate the evidence for treatmentsfor varicose veins, systematic literature reviews

were undertaken. All prospective RCTs oftreatments for varicose veins were sought. Trialsincluding patients undergoing treatment for thecomplications of varicose veins (venous ulcerationand chronic venous insufficiency) and recurrent

varicose veins were excluded. These have beenpublished in the Cochrane Library104,105 and fulldetails of the search strategies, methodology and

results are available in these publications.Figure 1shows a breakdown flow diagram of the articlesidentified for the Cochrane reviews based on theQUOROM statement.106

The review process was split into three areas:

G surgery versus sclerotherapyG stripping of the LSV

G use of a tourniquet.In addition, other data were identified fromexisting reviews or other papers relating to thecomparison of sclerotherapy and conservativetreatment and a range of other treatments.

The search strategy for the review is given inAppendix 1 and the full details will be found inthe Cochrane Library. A summary of the results ofthe review is presented below separately for eachof the main areas covered.

Surgery versus sclerotherapySeven randomised controlled trials were describedin a total of 10 separate papers.6264,107113

Of the seven studies, only five were directlycomparable as they used similar interventions forthe surgery and sclerotherapy, namely those byBeresford and colleagues,109 Doran andcolleagues,110 Einarsson and colleagues,64 Hobbs62

and Jakobsen.63 The two remaining studiescompared a new technique for endovascularsclerotherapy against general anaesthetic surgery

or local anaesthetic surgery and sclerotherapy, byBelcaro and colleagues,113 and general anaestheticsurgery with local anaesthetic surgery andsclerotherapy, by Rutgers and Kitslaar.111

However, amongst the five comparablestudies,6264,109,110 there was a wide variation interms of the outcome measures used in the studies.Consequently, there were insufficient data toperform a meta-analysis. Only one trial, byEinarsson and colleagues,64 included an objectivequantitative measure with which to value theoutcome (foot volumetry). The other trials relied on

subjective assessment of the results of theinterventions. This was probably a result of the

widely accepted problem that there are few validatedand reproducible outcome measures that can assessthe extent or severity of varicose veins. Objectivemeasures such as duplex and foot volumetry couldbe used but these were not universally employedacross the studies. Duplex scanning, however, wasnot widely available until the 1990s.

The subjective measures used to assess extent andtype of varicose veins also were not uniform. Each

study made its own classification system and inmany cases this system had not been piloted or

validated. Direct comparisons between studieswere consequently difficult. The second main area


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of difficulty is the amount of statistical informationprovided in the trials. Very few provided data thatincluded means, standard deviations (SDs) orconfidence intervals (CIs) and some did not even

includep-values to support their results.

The overall quality of the studies was variable. Themain criticism of the studies was that although all

seven trials stated that they were randomised,only two, by Einarsson and colleagues64 andHobbs,62 clearly stated their method ofrandomisation in which the generation of the

random sequence and the allocation of theinterventions were adequate. This was a majorfailing, significantly affecting the quality andestimation of treatment effects.114


10

Potentially relevant articlesidentified from search strategy

(n = 2036)

Potential RCTs (n = 136)

Surgery vs sclerotherapy(n = 63)

Non-RCT(n = 39)

RCTs (n = 24)

Did not meet inclusioncriteria (n = 14)

Duplicate publication(n = 3)

RCTs with usableinformation (n = 7)





RCTs (n = 10) RCTs (n = 23) RCTs (n = 5)



RCTs (n = 25) RCTs (n = 5)

Non-RCT(n = 28)

Non-RCT(n = 15)

Stripping of LSV(n = 53)

Tourniquet(n = 20)

Duplicates and non-RCTfrom abstract (n = 1899)

FIGURE 1 Breakdown of included studies based on QUOROM statement

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The numbers of patients studied varied between150 and 516 (mean 261); however, none of thetrials had ana priori sample size calculation. There

were also some discrepancies in the numbers ofpatients in some of the trials that reported earlyand late results. In Hobbss study,62 the first results

were published before the trial had finishedrecruiting, which may have been a potential sourceof bias. In Chant and colleagues trial,108,109 theinitial numbers seen and considered forrandomisation were different (339 vs 249), eventhough the number who were actually randomised

was consistent between the two studies. Length offollow-up for the trials was generally good, with arange of 210 years (mean 4.86 years).

Many of the measures used were subjective andmay not be reproducible or comparable betweenstudies. Only one study108,109 made any commenton the blinding of their outcome assessor. In somecases blinding of the observers may not have beenpossible, but in those cases where it was, many ofthe studies did not clearly state whether they usedblinding or not, which again introduces potentialbias. Results from statistical methods employed

were not clearly documented in a fashion thatallowed an accurate assessment of power orprecision. All precluded a formal meta-analysis.

Even documentation on complication rates, whichshould have been recorded for all of these trials,was not always provided or given in a standardform. The majority of complications were minor;however, the major ones such as a pulmonaryembolism are potentially life threatening. This is asignificant risk of treatment for a condition thatdoes not threaten life or limb.

This review highlights many of the problems facedby researchers evaluating treatments for varicose

veins. Although the population with varicose veinsis large and easily accessible, follow-up can be

difficult. In addition, there is a challenge of howto measure change in the state of the varicosities.Subjective measures are always open to bias andno single classification system has been uniformlyadopted. Objective measures such as duplexscanning and foot volumetry can be used, butthese have not been universally employed in thesetrials and their relationship with clinical benefit isuncertain.

A general trend to better results after surgery thansclerotherapy was seen in all the trials, but was

only consistent when the follow-up period was 3 years. Of the five comparable trials, threeshowed that sclerotherapy was more effective inthe first year. These outcomes rapidly deteriorated

so that by 5 years, surgery was the most effectiveintervention. For the majority of patients withsignificant varicose veins, surgery appeared toprovide a more long-term benefit thansclerotherapy in terms of recurrence.

When costs were included in the comparison,sclerotherapy had a clear initial advantage,although the data on which costs were based werefrom the 1960s. Sclerotherapy also appeared toprovide benefit in terms of patients not requiringhospital admission or as much time off work.These results were not surprising, but what wasnot addressed was the true cost-effectiveness ofthese treatments. In particular, the possible needfor repeated treatment by sclerotherapy was not

considered. A formal economic cost-effectivenessanalysis would be required to address thisadequately.

Many of the trials evaluating sclerotherapy wererelatively old and there have been severaladvances that have made surgical treatment safer,less expensive and more effective. These includeday-case surgery, stripping to the knee (as opposedto not stripping or stripping to the ankle) and theuse of tourniquets. None of the cost data tookaccount of day-case surgery, which has the

potential to reduce the costs associated with surgery.

Stripping of the LSVFive papers115119 and two publishedabstracts120,121 describe three RCTs comparingstripping of the LSV to the knee with notstripping the vein.. Three papers report separatetrials comparing stripping to the ankle with notstripping the LSV.122124

Two trials were identified which considered aspectsof stripping technique. Corbett and Harries125

compared plastic and metal strippers and found

no significant difference in outcome in terms oftechnical operative success. Khan andcolleagues126 carried out a pseudo-randomisedtrial which compared stripping to the knee withsequential avulsions and found some difference inpain and bruising at 1 week in favour of sequentialavulsion, but no longer term differences.

Three papers report separate trials dealing withthe direction of stripping the full length of theLSV.127129 Seven papers report six trialscomparing invagination stripping with standard

stripping of the LSV.130136

Only one study, byHolme and colleagues,137,138was found thatcompared stripping of the LSV to the knee withstripping to the ankle.


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The overall quality of the studies included in thereviews was variable. Very few studies specificallystated their method of randomisation of patients.This is a major failing and significantly affects thequality of the studies on critical appraisal. Thenumbers of participants involved in the majorityof studies was small and only one study containeda power calculation to estimate sample size.135,136

Most studies stated their inclusion criteria but thereporting of exclusion criteria was less commonand was not always explicit.

The majority of studies described their methods ofcarrying out the intervention well, although thishad been edited in some of the shorterpublications. In many cases blinding of patients

was described but very few clinicians providing thetreatment were blinded, as this was usuallyunavoidable.

The reporting of the results was again variable andwas generally better with studies published morerecently. The numbers lost to follow-up were notalways described. Few papers stated the methodsused to improve their losses to follow-up orreasons for exclusion. An explicit statement ofanalysis being on an intention-to-treat (ITT) basistended to be associated with the more recently

published studies.

Outcome measures were generally reported well,but in some cases their validity could bequestioned. In addition, the outcome measuresused were not reproducible or comparablebetween studies. An example of this could be seen

where subjective measures of pain or satisfactionwere used. The most common method of assessingthese was by visual analogue scale (VAS) or ascoring system. These were created specificallyfor each study and had not been piloted or

validated.

Measurement of complications was open tocriticism. Some, such as numbness in thesaphenous nerve region, may have existed prior tosurgery. Only a minority of the studies stated thatthey checked for this before hand.

Much controversy exists about the need forstripping the LSV, the level to which it should bestripped, in which direction and with whattechnique. Fears about stripping include the riskof deep vein damage, increased trauma to the

tissues and damage to the saphenous nerve, setagainst the potential benefit in reducingrecurrence rates. The increasing use of coronaryartery bypass grafting raises additional issues

about the potential advantages of preserving theLSV for use as a bypass conduit.

The studies included in this systematic review wereof variable quality, and the reporting of importantaspects related to trial quality could have beenmuch improved. Studies that were published morerecently tended to be better and this may berelated to an increased awareness of qualityresulting from initiatives such as the CONSORTstatement.139An important problem was thediversity of the outcome measures used and thisprecluded any meta-analysis. The lack of clearlydefined outcome measures is a continuingproblem in assessing outcomes of varicose veinsurgery.

However, there are some conclusions that can bedrawn. Stripping the LSV appears to produce abetter result, both clinically and functionally. Thisadvantage was seen at 2 years but at 5 years therecurrence rates were similar. Duplex examinationsuggested that neovascularisation was the mostcommon cause of recurrent saphenofemoral

junction (SFJ) reflux, and that this was generallybecause of new connections between the area ofthe SFJ and an intact refluxing LSV. In patients

who had the LSV stripped the re-operation rate

was found to be significantly reduced.

Stripping the LSV to the ankle was not associatedwith any differences in terms of patientsperception and, more importantly, the incidenceof saphenous nerve injuries was significantlyincreased compared with stripping to the kneelevel. When the strip was extended to the anklethe direction of the strip seemed to be importantin terms of nerve injury, being higher whenstripping was done upwards (ankle to groin).

When comparing invagination perforate-invaginate

(PIN) stripping and conventional stripping with anolive, there appeared to be no difference betweenthe two techniques. In addition, the technicalfailure rate of the invagination PIN stripper was aconcern. No differences were shown for strippersmade of different materials.

When examining stripping versus perforatorligation, thus preserving the LSV for future use asan arterial conduit, three studies showed nosignificant differences but these trials were not ofthe highest quality.

There is no randomised trial currently availablethat considers the cost-effectiveness of strippingthe LSV in varicose vein surgery.


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Use of tourniquetTourniquets have been used as means toexsanguinate limbs when there is a risk ofsignificant blood loss, such as in orthopaedicsurgery.140 However, there are potential problemsin using tourniquets on the lower limbs such asthrombosis141 and nerve damage.142 The natureof varicose vein surgery is such that the potentialfor blood loss could be significant and this has ledto some authors advocating the use oftourniquets.143145

There are a number of potential tourniquets inwidespread use, including the Rhys-Davies cuff146

and Lofquist cuff.147 The Rhys-Davies cuff wasdeveloped as a means for exsanguination of limbs

during orthopaedic operations.146 The Lofquistcuff,147 also known by its manufacturers name theBoazal cuff, is a pneumatic tourniquet originallyinvented by Dr Johan Lfqvist.

Twenty papers were identified from the searchstrategy that were potential RCTs evaluatingtourniquets in surgery for varicose veins. One wasa study identified from the National ResearchRegister,147which was subsequently published andincluded in the review,145 10 were non-randomisedcohort studies,144,147155 two were review

articles,156,157

one was a description of surgicaltechnique,158 one was a postal questionnaire,159

one was a duplicate publication145 and one was aletter commenting on the use of tourniquets.143

Three trials were identified dealing with the use ofa tourniquet for varicose vein surgery.145,160,161

These trials randomised 176 patients and 211limbs to either using a tourniquet during the

varicose vein operation or not using a tourniquet.All showed a significant but small (about 100 ml)reduction in blood loss when a tourniquet wasused, without reports of significant complications.

The methodological quality of the includedstudies was relatively poor. The studies had smallsample sizes and there were noa priori sample sizecalculations performed for any of the studies. Themethods of randomisation were also poorlyreported and the blinding to allocation wasunclear. One trial, by Corbett and Jayakumar,160

reported that randomisation was on the basis oftoss of a coin by the anaesthetist and another, bySykes and colleagues,145 that sealed envelopes

were used. However, details were missing on how

the randomisation sequence was generated. Thefinal trial, by Thompson and colleagues,161 simplyreported in the abstract that it was a randomisedstudy and provided no other details.

All the trials examined the effect of using atourniquet in terms of total blood loss. However,there were variations in defining total blood lossand how it was measured, with only Corbett and

Jayakumar160 reporting how the blood loss wasestimated. This lack of detail in the other twotrials could mean that there were significant

variations in how total blood loss was estimated.Furthermore, Corbett and Jayakumar160 andThompson and colleagues161 reported mean bloodloss and Sykes and colleagues145 reported medianblood loss.

All the trials included operative time as anoutcome measure, but there were variations in howthis was measured. Corbett and Jayakumar160

defined the operative time from the start of theavulsions until the start of dressing the wounds.However, Thompson and colleagues161 defined itas the time from entering theatre to completion ofthe dressings. No details were provided in theother trial. None of the trials determined therelative cost-effectiveness of the use of atourniquet.

The available evidence on the evaluation of theuse of tourniquets in varicose vein operations islimited to three RCTs. These trials were all of poor

quality and had deficiencies in trial design, samplesize and measurement of outcomes. None of thetrials had sufficient power and sample size todetermine the differences between use or non-useof a tourniquet during varicose vein surgery. Also,they were not of sufficient size to determine theincidence of potential relatively rare complicationssuch as nerve damage or arterial injury (especiallyin older patients). This is a consideration whenrecommending the use of tourniquets. As largenumbers of varicose vein operations areundertaken, there is the potential for a significantnumber of additional complications not reported

in these trials to be caused by using a tourniquet.There were also variations in how outcomes weremeasured, with two trials reporting means and theother medians.

Despite these limitations, all three trials agreedthat the amount of blood loss can be significantlyreduced when using a tourniquet with nosignificant increase in operating time, reportedadverse events or subjective outcome. The meanand median total blood loss was relatively small inboth groups and not necessarily clinically

significant. However, without a tourniquet therewas a wider range of total blood loss and those inthe upper limits potentially lost enough blood torequire a blood transfusion. A further


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consideration is that any potential for reduction ofexposure to blood for healthcare staff should beconsidered in the light of the possibilities ofblood-borne diseases such as HIV and hepatitis C.

A reduction in blood loss could result in areduction of post-operative bruising, but this wasincluded as an outcome measure in only one trial,by Sykes and colleagues.145Although it reported asignificant reduction in the area of bruising withthe use of a tourniquet, the trial had a relativelysmall sample size of 25 patients in each arm.

None of the trials explored the cost-effectivenessof the use or non-use of a tourniquet. The trialsdid not find any increase in the largest potential

cost, which was length of operation. Also, therewere no discussions of the costs of the tourniquets,other equipment or any additional potential costssuch as staffing or training.

Sclerotherapy versus conservativetreatmentHigh-quality evidence was already availableregarding sclerotherapy versus conservativetreatments in the form of a CochraneCollaboration systematic review undertaken by Tisiand Beverley.103

Their review aimed to examine all RCTs comparinginjection sclerotherapy and conservative treatments(graduated compression stockings and/orobservation). They also examined differences insclerosants and techniques for sclerotherapy.However, they included sclerotherapy for thread

veins in addition to varicose veins.

The search strategy and methods for the reviewfollowed standard Cochrane Collaborationmethodology and can be found in their reviewarticle. The methods were comparable to those

used in reviews undertaken by ourselves.

A total of 28 studies were identified for inclusionin their review. Of these, 16 were excluded as theydid not meet the inclusion criteria or were non-randomised studies. The remaining 12 studies

were included in the review. These studiesexamined six different aspects:

1. sclerotherapy with sodium tetradecyl sulphate(STD) versus alternate sclerosants

2. local anaesthetic (LA) versus no LA

3. use of Moleform versus Sorbo pads at injectionsites after sclerotherapy

4. use of elastic compression versus conventionalbandaging after sclerotherapy

5. short-term versus standard bandaging aftersclerotherapy

6. sclerotherapy versus graduated compressionstockings.

The last comparison was of most interest in termsof the evidence for different treatments of varicose

veins.

No RCTs were found that compared sclerotherapywith simple observation. One trial was found thatcompared sclerotherapy with graduatedstockings.162 The trial was conducted in 1973 andshowed advantage in terms of symptoms andcosmetic appearance for sclerotherapy [relativerisk (RR) 1.61, 95% CI 1.19 to 2.18].

The review concluded that there was no evidenceto support the claims of Fegan56 regarding thetype and duration of compression followingsclerotherapy. Tissi and Beverley found nodifferences between various types and duration ofcompression on the incidence of superficialthrombophlebitis, obliteration of varicose veins orrecurrence rate. In addition, they found nodifference between the strength of STD used.

Tisi and Beverley103 showed in their review that theavailable evidence on the effectiveness of

sclerotherapy in the treatment of varicose veins waslimited and of poor quality. There was a particularlack of evidence comparing sclerotherapy withcompression stockings, with only one trial foundthat examined pregnant women.

Other treatmentsEighteen potential studies were identifiedevaluating the effectiveness of other treatments for

varicose veins. However, five were non-randomisedstudies and five evaluated compression andchronic venous insufficiency with or without the

presence of varicose veins. Six studies described ineight papers were included. No trials wereidentified that compared surgery with observationor sclerotherapy with observation.

Hence six trials were identified that examinedother non-surgical interventions for varicose

veins.163168 Four of these examineddrugs.163165,168 one a homeopathic preparation166

and one hydrotherapy.167,169,170

Two of the drug studies165,168 assessed oxerutins(a group of chemicals derived from a naturally

occurring bioflavonoid called rutin). Both studiesfound no statistically significant differencesbetween those randomised to oxerutins and thoserandomised to placebo.


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The other two drug studies randomised betweenheptaminol adenosine phosphate (a cardiacstimulant and vasodilator) and placebo163 andbetween calcium dobesilate (a vasoprotectant andcapillary dilator) and placebo.164 Schmidt andcolleagues163 showed significant improvement in

venous outflow measured by plethysmography butdid not measure any clinical outcomes.

Androulakis164 also reported significantimprovements for patients on the drug treatment,measured by plethysmography, which correlated

with subjective improvements. However, therewere a significant number of withdrawals and theanalysis was not ITT.

Ernst and colleagues166 randomised patients

between a homeopathic preparation (Poikiven)and placebo. They reported significantimprovements in objective measures(plethysmography and leg circumference) butthere were significant differences between thegroups at baseline and the analysis was not ITT.

The final trial167,169,170 randomised betweenhydrotherapy and no hydrotherapy. The studyreported significant reductions in leg volumes andankle/calf circumference for the hydrotherapygroup.

No clear evidence has been found that alternativetherapies offer a more beneficial form of treatmentin terms of symptom relief. None of thesetreatments removed the cosmetic element of

varicose veins, a factor that is often important topatients and a driving force behind them seekingtreatment. The evidence presented about the drugtherapies concerns small numbers of patients andraises doubts about drug tolerability and efficacy.Many of the changes in the objective symptoms areonly small and it is unclear how these can beinterpreted in terms of clinical improvement. There

are no trials which duplicate the interventions and

therefore can substantiate or disagree with theirfindings. Conventional treatments have been thesubject of multiple clinical trials and the evidencecurrently appears to be that the alternativetherapies cannot offer a convincing replacement forthe conventional therapies.

There is no evidence regarding costs for thesetreatments as they are purely experimental drugsat the moment and are not routinely being usedanywhere. No costs for hydrotherapy werereported.

Key pointsG Published studies of varicose vein treatments

are hampered by the lack of a widely accepted

classification of the extent of varicose veins andconsistent definitions of recurrence.

G Trials comparing surgery with sclerotherapysuggest that the outcomes of sclerotherapydeteriorate over the first few years and all trials

with follow-up of 3 years are consistent inshowing benefit for surgical treatment.

G Evidence regarding stripping of the LSVsuggests that this technique reduces recurrencerates, at least in the early years. There is noevidence to suggest a benefit for stripping tothe ankle and this produces a greater rate of

saphenous nerve injury, especially when thedirection of stripping is from ankle to groin. Nobenefit was found for alternative stripperdevices or for invagination stripping.

G The use of a surgical tourniquet during surgeryresults in lower operative blood loss without anyreported increase in complications.

G Evidence for the effectiveness of sclerotherapyand for benefits of individual techniques orsclerosants was inadequate to draw firmconclusions.

G There is inadequate evidence to support the useof drug or alternative therapies in the

management of varicose veins.


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Background

As described above, previous research relating tovaricose veins has suffered from a lack of agenerally agreed and workable classificationsystem to stratify recruited patients and judge theextent of the condition and outcomes oftreatment. One of the initial tasks for the trialparticipants was to identify an anatomical

classification of varicose veins that could beapplied consistently by trial participants, wouldprovide a system of classification with a direct andpragmatic bearing on treatment and wasapplicable to a clinical setting.

To this end, a project was set up to develop apragmatic classification of uncomplicated varicose

veins using a modified nominal group processapproach.171

MethodsDevelopment was through an iterative process in

which a group of interested participants within thetrial met to reach consensus on the content andform of the classification. The process wentthough a number of stages:

G The group met and agreed a set of criteria thatshould be fulfilled by an ideal classification.

G A literature search was carried out to identifyexisting systems of classification for varicose

veins and copies of appropriate papers were

obtained and circulated to participants in thegroup.

G The group met and considered existingclassifications against the proposed criteria.

G Group members put forward suggestions and aconsensus was reached regarding a provisionalclassification.

G A pilot study was carried out in which newreferrals with varicose veins were independentlyexamined and classified by members of thegroup.

G The results of this study were summarised to

the trial participants with a list of the items thatcaused discrepancy in the classification and aconsensus was reached about necessaryamendments.

Results

The criteria agreed by the group are listed inTable 5.

Literature reviewThe literature review identified 10 classificationsystems based on anatomical features of varicose

veins. Of these, there were two that had been

widely used in other studies.

The Basle system85,172was felt to be unsatisfactoryfor a number of reasons:

G The grading system was based on degree andextent of tortuousity and prominence, which

was not thought to be open to objectiveevaluation.

G The system used a variety of terms that wereunfamiliar to most current clinical staff.

G It made no reference to any use of Doppler

examination or assessment of reflux.G It was felt that the system could not be widelyapplied without special expertise.

G There were no clear links with options forclinical management.


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Chapter 3

Classification of varicose veins

TABLE 5 Characteristics of proposed criteria for the

classification of varicose veins

G The process should be simple, easily understood andlearnt by staff at all levels

G It should be suitable for use in an outpatient clinicwithout special equipment or additional resourcerequirements

G There should be an acceptable level of inter- or intra-observer variation

G It could take into account frequently used methods ofassessment, including inspection, physical andHHD examination, but should not require the resultsof additional special investigations

G It should have a direct and pragmatic bearing ontreatment. Hence factors which have a significantimpact on the suitability for surgery or sclerotherapyshould be taken into consideration

G It should be easily applicable to both scientific studies

and routine clinical practiceG Varicose veins should be distinguished from thread

veins

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The CEAP classification173 is a comprehensivesystem, which attempts to describe the wholespectrum of venous problems. The anatomicalpart of the classification does not take into accountthe size or extent of varicosities and it was felt thatthe system was complex and difficult to learn.

Of the other classifications reviewed, all were feltto be unsatisfactory as they required specialinvestigations,174177 related specifically torecurrent varicose veins178 or provided nomeasures of the extent of varicosities or of adistinction between those AK or BK.89,179

Proposed classification systemA consensus was reached on the following items

that were felt to be relevant to the classification.

G Distinction between thread veins and varicoseveins, the former being excluded from theclassification.

G Site (upper thigh, lower thigh, BK), size andextent of varicose veins as these have a bearingon the suitability for sclerotherapy and durationof surgery.

G The presence of groin, LSV or popliteal fossareflux based on an HHD examination.

G Medical complications, including ulceration andskin changes.

G Recurrent varicose veins in which a redosaphenofemoral or saphenopopliteal ligation

would be required.

Pilot studyEleven patients referred to a vascular outpatientclinic with a diagnosis of varicose veins wereexamined by between three and seven members of

staff (four consultant vascular surgeons, a clinicalassistant and two vascular surgical trainees). Eachpatient was assessed independently by severalparticipants using a prepared proforma andgrouped according to the worst leg.

Classification of varicose veins

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TABLE 6 Criteria for allocation of patients to varicose vein categories

Definitions

Varicose veins (VVs). Tortuous veins that bulge or protrude.

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