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Systematic review of the safety and

efficacy of foam sclerotherapy for

venous disease of the lower limbs

Xueli Jia, Graham Mowatt, Vivian Ho, Jonathan

Cook, Cynthia Fraser, Jennifer Burr

November 2006

ii

INTERVENTIONAL PROCEDURES PROGRAMME

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

REVIEW BODY REPORT

Title Systematic review of the safety and efficacy of foam sclerotherapy for venous disease of the lower limbs

Produced by Health Services Research Unit

University of Aberdeen

3rd Floor, Health Sciences Building

Foresterhill

Aberdeen AB25 2ZD

The Review Team Xueli Jia, Graham Mowatt, Vivian Ho, Jonathan Cook, Cynthia

Fraser, Jennifer Burr

Correspondence to Xueli Jia

Research Fellow

Health Services Research Unit

University of Aberdeen

3rd Floor, Health Sciences Building

Foresterhill

Aberdeen AB25 2ZD

Tel: (01224) 559801

Fax: (01224) 554580

Email: [email protected]

Date completed November 2006

iii

‘Home unit’ details

The Health Services Research Unit (HSRU) is a multidisciplinary research group of about 50

people based in the University of Aberdeen. The Unit is core-funded by the Chief Scientist

Office of the Scottish Executive Health Department, and has responsibility for the following

general remit:

1. To study or evaluate clinical activities with a view to improving effectiveness and

efficiency in health care;

2. To work for the implementation of proven changes in clinical activities;

3. To encourage and support similar work thoughout Scotland;

4. To train NHS staff in Scotland, and others, in the principles and practice of health

services research in general, and health care evaluation in particular.

The Unit has an established portfolio of health services research focusing on two main

programmes – health care assessment and delivery of care. The Unit is one of the two

research groups that make up the ‘Review Body’ for the National Institute for Health and

Clinical Excellence Interventional Procedures Programme. The other is based at Health

Services Research, University of Sheffield.

Contributions of authors

Xueli Jia drafted the scope, screened the search results, assessed English language studies

and conference abstracts for inclusion, undertook data abstraction and quality assessment of

English language studies, and drafted most sections of the review. Graham Mowatt

commented on the scope of the review, screened French language studies for inclusion,

contacted the authors of included studies for additional information, and commented on the

drafts of the review. Vivian Ho undertook data abstraction of the conference abstracts,

drafted the background section of the review, and contributed to drafting sections

concerning conference abstracts. Jonathan Cook commented on the scope of the review,

drafted the data analysis section of the review, conducted the statistical analysis and

commented on drafts of the review. Cynthia Fraser developed and ran the literature search

strategies, obtained papers and formatted the references. Jennifer Burr commented on the

scope of the review, screened French and German language studies for inclusion,

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determined outcome categories, undertook data abstraction of German language studies,

and commented on drafts of the review.

Conflict of interest

None

Acknowledgements

We thank Kevin Cassar (Consultant Vascular Surgeon, Aberdeen Royal Infirmary) for

providing specialist advice and commenting on the draft of the report and Tania Lourenco

(Research Fellow, HSRU) for screening Portuguese language studies for inclusion and data

abstraction of French language studies. The Health Services Research Unit receives a core

grant from the Scottish Executive Health Department. The views expressed are those of the

authors and not necessarily those of the funding bodies.

Special thanks also go to John Barrett and Dr D Wright for providing additional information

for published studies, Dr. P Coleridge Smith, R. Milleret, and Dr. Kritzinger for providing

unpublished data.

v

TABLE OF CONTENTS

Executive summary xi

List of abbreviations

xxi

1 OBJECTIVE OF THE REVIEW 1

2 BACKGROUND 2

2.1 Description of the underlying health problem 2

2.1.1 Epidemiology 2

2.1.2 Burden of disease 2

2.1.3 Aetiology, pathology and prognosis 2

2.2 Current management and alternative procedures 3

2.3 The interventional procedure under review 4

2.3.1 Description of the interventional procedure 4

2.3.2 Suitable candidates and relevant subgroups 6

2.3.3 Proposed clinical indications/contraindications and putative impact of the procedure

6

2.3.4 Personnel involved and skill/experience required 6

2.3.5 Current use in the UK (including existing guidance) 7

2.3.6 Equipment or devices required 8

3 METHODS FOR REVIEWING SAFETY AND EFFICACY 9

3.1 Search strategy 9

3.2 Inclusion and exclusion criteria 10

3.2.1 Types of studies 10

3.2.2 Types of participants 10

3.2.3 Types of interventions 10

vi

3.2.4 Types of outcomes 11

3.3 Quality assessment strategy 12

3.4 Data extraction strategy 12

3.5 Data analysis 13

3.6 Included studies 13

4 RESULTS 14

4.1 Number and type of included studies 14

4.1.1 English language full text studies 15

4.1.2 English language conference abstracts 17

4.1.3 Non-English language studies 19

4.1.4 Ongoing studies 20

4.1.5 Unpublished studies 21

4.2 Number and type of excluded studies; reasons for exclusion 21

4.3 Quality of available evidence: English language full text studies 21

5 SAFETY RESULTS 26

5.1 Serious adverse events 26

5.1.1 Anaphylaxis 26

5.1.2 Arterial events 26

5.1.3 Retinal artery occlusion 28

5.1.4 Venous thromboembolism 28

5.1.5 Cutaneous necrosis and ulceration 30

5.1.6 Other serious adverse events: intra-arterial injection and grand mal epileptic fit

31

5.2 Adverse events 37

5.2.1 Visual disturbance 37

5.2.2 Central nervous system 39

vii

5.2.3 Other systemic symptoms 39

5.2.4 Local effects: ‘minor’ vein thrombosis 41

5.2.5 Local effects: thrombophlebitis 42

5.2.6 Local effects: skin matting/staining/pigmentation 43

5.2.7 Local effects: local neurological injury 44

5.2.8 Local effects: pain at the site of injection 44

5.2.9 Other adverse events 45

5.3 Studies not reporting adverse events separately and a large study including children

46

5.4 Summary of safety 54

6 EFFICACY RESULTS 59

6.1 Complete occlusion of treated veins 59

6.2 Healing of venous ulcers 62

6.3 Recurrence of venous disease and development of new veins 63

6.4 Quality of life, disappearance of varicosities and changes of CEAP score

69

6.5 Procedure time 69

6.6 Summary of efficacy 72

7 DISCUSSION 74

7.1 Safety: serious adverse events 74

7.1.1 Anaphylaxis 74

7.1.2 Arterial events 74

7.1.3 Pulmonary embolism and deep vein thrombosis 75

7.1.4 Cutaneous necrosis and ulceration 76


76

viii

7.2 Safety: adverse events 76

7.2.1 Visual disturbance 76

7.2.2 Central nervous system disturbance 77

7.2.3 Other systemic symptoms 77

7.2.4 Local effects 77

7.2.5 Other adverse events 77

7.3 Efficacy 78

7.4 Assumptions, limitations, and uncertainties 78

8 CONCLUSIONS

83

9 NEED FOR FURTHER AUDIT OR RESEARCH

84

10 REFERENCE LIST 85

ix

LIST OF APPENDICES

Appendix 1 Search strategies 95

Appendix 2 Checklist of quality assessment of randomised controlled trials of an interventional procedure

100

Appendix 3 Checklist of quality assessment of non-randomised studies evaluating interventional procedures

101

Appendix 4 Reference list of included studies 102

Appendix 5 Characteristics of the included studies: English language full text studies and registry

113

Appendix 6 Characteristics of the included studies: English language conference abstracts

139

Appendix 7 Characteristics of the included studies: non-English language studies

163

Appendix 8 Characteristics of the included studies: unpublished study (case report)

173

Appendix 9 Number and type of excluded studies; reasons for exclusion 174

Appendix 10 Detailed quality assessment results for included English language studies: randomised controlled trials

184

Appendix 11 Detailed quality assessment results for included English language studies: non-randomised comparative studies

185

Appendix 12 Detailed quality assessment results for included English language studies: case series

186

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LIST OF TABLES

Table 1 Classification of chronic lower extremity venous disease 3

Table 2 Number of studies and reports included 13

Table 3 Search results 14

Table 4 Papers selected for full text assessment 14

Table 5 Patient details, indication for foam sclerotherapy and technique used (English language full text studies)

17

Table 6 Patient details, indication for foam sclerotherapy and technique used (English language conference abstracts)

19

Table 7 Summary of the quality assessment of the randomised controlled trials (English language full text studies)

23

Table 8 Summary of the quality assessment of the non-randomised comparative studies (English language full text studies)

24

Table 9 Summary of the quality assessment of the case series (English language full text studies)

25

Table 10 Safety: serious adverse events (comparative studies) 32

Table 11 Safety: serious adverse events (case series) 34

Table 12 Safety: adverse events (comparative studies) 47

Table 13 Safety: adverse events (case series) 50

Table 14 Summary of serious adverse events 57

Table 15 Summary of adverse events 58

Table 16 Efficacy: complete occlusion of veins, recurrence and development of new veins (comparative studies)

64

Table 17 Efficacy: complete occlusion of veins, healing of venous ulcers, recurrence and development of new veins (case series)

66

Table 18 Quality of life and changes of CEAP (RCTs and non-randomised comparative studies)

71

Table 19 Summary of efficacy 73

LIST OF FIGURES

Figure 1 Meta-analysis of foam versus liquid sclerotherapy, and foam sclerotherapy versus surgery, for complete occlusion of treated veins

62

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EXECUTIVE SUMMARY

Background

Venous disease of the lower limbs includes primary and chronic venous insufficiency.

Primary venous insufficiency refers to varicose veins, reticular veins, and telangiectasiae;

chronic venous insufficiency encompasses all of the skin changes of advanced venous

dysfunction including oedema, eczema, pigmentation, lipodermatosclerosis and ulceration.

Current treatment options include compression hosiery, endovenous laser ablation

treatment (EVLT), radiofrequency ablation, open surgery (ligation, stripping and

phlebectomies), and subfascial endoscopic perforator surgery alone or in combination, and

sclerotherapy, which is mostly carried out as an outpatient procedure with no anaesthesia

required. Sclerotherapy techniques in current use include liquid and foam sclerotherapy.

Liquid sclerotherapy involves the injection of sclerosing liquid into affected veins leading to

an inflammatory reaction and consequent venous occlusion. Foam sclerotherapy is a

modification of liquid sclerotherapy but instead of injecting liquid, the liquid is transformed

into foam by forcibly mixing it with air or other type of gas such as O2 and CO2. Foam

sclerotherapy may be a potential treatment for all categories of venous disease. However its

uptake in the UK is not known and, currently, the use of foam sclerotherapy in the UK is ‘off

licence’.

Anaphylaxis, vascular events such as cerebrovascular accident, myocardial infarction,

retinal artery occlusion, and thromboembolism are serious potential complications of foam

sclerotherapy. Known risk factors include allergy to the sclerosant and the existence of a

Patent Foramen Ovale (PFO).

Other important adverse events currently known to be associated with foam sclerotherapy

include transient visual disturbance, cutaneous necrosis or ulceration, and local effects such

as ‘minor’ vein thrombosis, thrombophlebitis, local neurological injury, and skin

pigmentation.

Objective

To systematically review the evidence for the safety and efficacy of foam sclerotherapy for

venous disease of the lower limbs.

xii

Number and quality of included studies

Electronic searches were conducted to identify both published and unpublished studies

evaluating the safety and efficacy of foam sclerotherapy for venous disease. Searches were

not restricted by publication year or language and included abstracts from conference

proceedings. In addition, electronic and hand searching of recent conference proceedings of

prominent phlebology and vascular organisations was undertaken. The tables of contents of

two phlebology journals, not consistently indexed in the major databases, were also

examined for additional reports. Relevant professional and commercial websites were

searched and the reference lists of all included studies were scanned to identify additional

potentially relevant reports. Only one company (Provensis) was identified that produced

sclerosant foam commercially (Varisolve®). This company was contacted for additional

data relating to two unpublished RCTs comparing (i) foam sclerotherapy with surgery and

(ii) foam sclerotherapy with ‘home-made’ foam and liquid sclerotherapy. Authors of other

included studies were contacted where necessary to provide clarification on aspects of their

studies.

From the initial 1138 reports identified by the search strategy, 67 studies (reported in 104

publications) were included, of which 26 were English language full text studies, 24 were

English language conference abstracts, 16 were non-English language full text studies or

conference abstracts, and one was an unpublished study. For studies reported in both full

text and conference abstract form, data from the full text article were included. For studies

with multiple full texts and studies with multiple conference abstracts, data from the most

up-to-date report were included. The diagram below shows the included 67 studies by

study design.

xiii

Eighteen studies in total were comparative studies. Of seven English language full text

randomised controlled trials (RCTs), four compared foam with liquid sclerotherapy, two

compared foam with liquid sclerotherapy and surgery, and one compared foam

sclerotherapy with open surgery. Of two RCTs available as conference abstracts, one

compared foam with liquid sclerotherapy and one compared foam with compression. The

French registry report involved 12,173 treatment sessions (6395 foam, 5434 liquid, 344 both).

The English language full text non-randomised comparative study compared foam with

liquid sclerotherapy. Of five non-randomised comparative studies available as English

language conference abstracts, three compared foam with liquid sclerotherapy, one

compared two types of foam sclerosant (one with added low molecular weight heparin), and

one compared foam sclerotherapy, both of one and more than one treatment session, with

liquid sclerotherapy and open surgery. Both of the two non-English language non-

randomised comparative studies compared foam with liquid sclerotherapy.

Three ongoing comparative studies and two case series were also identified.

In the included studies a total of over 9000 patients were treated with foam sclerotherapy, of

which over 3900 were reported in English language full text studies, over 2900 in English

language conference abstracts and over 2200 in non-English language studies. The

indications for foam sclerotherapy and the technique used with respect to the type and

strength of sclerosant and foam-producing technique were heterogeneous. The most

8 Non-randomised comparative studies: 1 English language full text study 5 English language conference abstracts 2 non-English language full text studies or conference abstracts

9 RCTs: 7 English language full text studies 2 English language conference abstracts

1 registry report: English language full text study

43 case series: 13 English language full text studies 17 English language conference abstracts 13 non-English language full text studies or conference abstracts

6 case reports: 4 English language full text studies 1 non-English language full text study 1 unpublished study

67 included studies

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common indications for foam sclerotherapy were truncal vein (long and/or short saphenous

vein) incompetence or varicosities. In the included studies the most frequently used

sclerosing agent was polidocanol, with a strength ranging from 0.25 to 3%. The most

commonly used foam-producing technique was the Tessari technique, in which two

syringes are connected by a three-way valve and fluid sclerosant is forcibly mixed with air

and frothed into foam by a pumping action.

Only the methodological quality of the English language full text studies was assessed. The

methodological quality of the included RCTs was generally low. In the RCTs the treatment

allocation was adequately concealed in only one of seven trials. Only one study conducted

an intention to treat analysis. In studies comparing foam sclerotherapy with open surgery

blinding of patients is not possible. The non-randomised comparative study gave clear

inclusion or exclusion criteria and clearly described the foam sclerotherapy technique used.

Twelve case series gave clear inclusion or exclusion criteria and all 13 case series clearly

described the foam sclerotherapy techniques used. In general the sample sizes of most

studies were sufficiently large (> 100) to identify rare adverse events. Length of follow-up in

most studies, irrespective of study design, was more than 30 days. No studies reported

methods of follow-up. There was insufficient detail to judge whether the follow-up was by

passive presentation of adverse events or active follow-up. The completeness of follow-up

varied across studies. A few prospective case series reported high dropout rates of over 30%.

Summary of evidence of safety

A substantial amount of evidence was available as conference abstracts and non-English

language reports. Safety and efficacy data were extracted for non-English language studies

and conference abstracts but these types of publication were not quality assessed. Therefore

the evidence from these types of publication should be interpreted with caution, as should

the results of any analyses combining their results with those of full text English language

studies. In general, however, the results reported by conference abstracts and non-English

language studies were similar to those reported by English language full text studies.

Event rates were presented as medians and ranges due to the high degree of heterogeneity

across studies. For ease of interpretation, 22 studies (four on safety, 18 on efficacy) reporting

the number of limbs or veins, but not patients, were not included in the calculation of the

xv

medians and ranges and were reported separately. The results from these 22 studies were

similar to those of the studies reporting patient-level data.

Comparison of the adverse events associated with the treatment of truncal veins versus

‘minor’ veins and primary versus recurrent venous disease was not possible as few studies

treated only ‘minor’ veins or only recurrent venous disease. The effect of patient age on

safety was unclear as no studies presented data by age group. A comparison of the adverse

events associated with different types and strengths of sclerosing agents, volume of foam

and foam-producing techniques was not possible as few studies used a single type and

strength of sclerosing agent. Insufficent data were available to compare different types of

gas based foam. Few studies reported surgeon experience.

Safety outcomes were classified into serious adverse events and adverse events as agreed

with the clinical advisor for this review. Categorising the reported outcomes was

problematic. One reason for this is that the terminology used for some outcomes varied

across the included studies.

Serious adverse events

In the included studies serious adverse events associated with foam sclerotherapy occurred

in 0 to 5.7% of treatments. No anaphylaxis, intra-arterial injections or deaths were reported.

Although no arterial events occurred in a single large case series involving 808 patients, they

did occur at a median rate of 2.1% (range 1.4 to 2.8) in two conference abstracts involving

253 patients. Five English language case series involving 1316 patients reported one patient

suffering a pulmonary embolism. Across all studies, deep vein thrombosis occurred at a

median rate ranging from 0 to 5.7%. Cutaneous necrosis occurred at a median rate of 1.3%

(range 0.3 to 2.6%) in four English language case series involving 781 patients and at a

median rate of 0% (range 0 to 0.2%) in five studies available as conference abstracts or non-

English language studies and involving 766 patients. Cutaneous ulceration was not

reported in the English language studies, although one non-English language study

involving 28 patients reported an event. One case of myocardial infarction occurred 30

minutes following injection and one case of grand mal epileptic fit occurred approximately

40 minutes after treatment (the two events were reported in separate case reports).

xvi

In the comparative studies, the relative risk between foam sclerotherapy and comparator

interventions for all of the serious adverse events reported did not reach statistical

significance. However, the studies were generally too small to detect a difference in rare

outcomes.

Adverse events

The rates of visual disturbance following foam sclerotherapy for varicose veins across all

studies ranged from 0 to 5.9%. No visual disturbance was reported that lasted for longer

than two hours and no long-term or permanent visual impairment was reported. Transient

confusion occurred at a median rate of 0.5% (range 0 to 1.2%). Headache occurred at various

rates across studies, ranging from 0% to 23.0%. Other systemic symptoms, including

coughing, chest tightness/heaviness, panic attack and malaise, and vasovagal ranged from 0

to 2.8%. The French registry reported a rate of 0.2% for coughing and vasovagal events.

In three conference abstracts or non-English language studies involving 579 patients ‘minor’

vein thrombosis occurred at a median (range) rate of 0.9% (0.6 to 4.2%). This is lower than

the rate in two small English language RCTs involving 96 patients (median 8.8%, range 0 to

17.6%) and two English language case series involving 868 patients (median 1.5%, range 1.2

to 1.7%), but higher than the rate of 0.1% reported by the French registry. Thrombophlebitis

occurred at a median (range) rate of 4.4% (0 to 10.3%) in three English language RCTs

involving 125 patients and 3.3% (1.3 to 10.3%) in seven English language case series

involving 1612 patients. This is lower than that reported in ten studies available as

conference abstracts or non-English language studies involving 1235 patients (median 9.2%,

range 0 to 45.8%). The French registry reported a rate of 0.05% for thrombophlebitis.

Long-term (>30 days) skin matting/staining/pigmentation occurred at a median (range)

rate of 31.6% (7.8 to 55.1%) in four English language RCTs involving 517 patients. This rate

is higher than that reported by five English language case series involving 759 patients

(median 2.3%, range 0 to 19.8%) but similar to that in six studies available as conference

abstracts or non-English language studies involving 484 patients (median 19.2%, range 0 to

66.7%).

The occurrence of local neurological injury was less than 1% across all studies. Pain

provoked by injection or persisting in the limbs varied across studies, ranging from 0.6 to

xvii

41.0%. Other adverse events, including allergic reaction, haematoma, extravasation, and

lower back pain, occurred at a median (range) rate of 4.2% (0 to 11.2%) in four English

language RCTs involving 511 patients, and at a rate of less than 1% in other study designs.

In the comparative studies, the relative risks of most adverse events associated with foam

sclerotherapy compared with other treatments did not reach statistical significance.

However, in the French registry the risk of visual disturbance was significantly higher for

the foam compared with the liquid sclerotherapy group and in one RCT the risk of skin

matting/staining/pigmentation was significantly higher for foam sclerotherapy compared

with surgery. Generally, the comparative studies were too small to reliably detect

differences in statistically rare adverse events at the level of the reported rates.

Studies on pathophysiology of foam induced vascular events

One human and one animal study were identified investigating the pathophysiological

mechanisms of vascular events associated with foam sclerotherapy. In the human study,

foam particles were identified in the right heart of all 49 patients 10 to 30 seconds after foam

injection. In four of seven patients in whom a PFO had already been detected, a few high-

density transient signals in the middle cerebral artery were detected. The emboli were

identified within 10 cardiac cycles. In the animal study, larger air-based bubbles were more

likely to obstruct arteriolar vessels and block blood flow than smaller, more uniform sized

physically resolvable gas-based bubbles. Larger numbers of bubbles were more likely to

cause an arterial accident than smaller numbers.

Summary of evidence of efficacy

The follow-up period of the majority of the studies reporting efficacy was less than three

years.

Complete occlusion of treated veins and healing of venous ulcers

The median rate of venous occlusion was 84.4% (range 67.4 to 93.8%) in the English

language RCTs and 84.4% (60.0 to 98.2%) in the English language case series, with rates of

60% or more across all studies. The rates of ulcer healing ranged from 75.4 to 100%.

xviii

In the meta-analysis of RCTs, the relative risk (RR) of three small studies comparing foam

with liquid sclerotherapy for the outcome of complete occlusion of treated veins tended to

favour foam sclerotherapy (RR 1.39, 95% CI 0.91 to 2.11), while the overall effect of two

studies comparing foam sclerotherapy with surgery involving stripping tended to favour

surgery (RR 0.86, 95% CI 0.67 to 1.10). However neither result was statistically significant

and both meta-analyses demonstrated high heterogeneity across studies.

Recurrence of venous disease and development of new veins

The median rates of recurrence or development of new veins varied across studies, ranging

from 3.1 to 27.8%. A rate of 51.2% was reported in the study (RCT) with the longest follow-

up period (ten years).

In both RCTs and non-randomised comparative studies, the risk of recurrence or

development of new veins following foam sclerotherapy was not significantly different to

that of comparator treatments, other than in the RCT with the ten-year follow-up. In this

study the risk of developing new veins was significantly higher for foam sclerotherapy

compared with surgery (ligation: RR 1.4, 95% CI 1.02 to 1.8; ligation combined with liquid

sclerotherapy: RR 1.4, 95% CI 1.1 to 1.9).

Quality of life, disappearance of varicosities and changes of CEAP score

One study involving 272 patients reported that following foam sclerotherapy, patients

required a median of two days to return to normal activity, significantly less than the

median 13 days following surgery. Compared with liquid sclerotherapy or surgery, there

were no statistically significant differences in patient satisfaction, disappearance of

varicosities and change of disease severity as measured by the Aberdeen Vein Questionnaire

and the Clinical, Etiologic, Anatomic, Pathophysiologic (CEAP) score.

Conclusions

Concerning safety, serious adverse events associated with foam sclerotherapy, including

arterial events including stroke and myocardial infarction, grand mal epileptic fit,

pulmonary embolism, and deep vein thrombosis were statistically rare, reported in rates of

xix

less than 6% (range 0 to 5.7%). Cutaneous necrosis and ulceration were reported in rates of

less than 4% (range 0 to 3.6%).

Adverse events such as visual disturbance, transient confusion, other systemic symptoms

(panic attack, malaise, coughing, chest tightness or heaviness, and vasovagal) were reported

in rates of less than 6% (range 0 to 5.9%). Occurrence of headache ranged from 0 to 23.0%.

Local adverse events were more common. ‘Minor’ vein thrombosis ranged from 0 to 17.6%,

thrombophlebitis from 0 to 45.8%, skin matting/staining/pigmentation from 0 to 66.7%, and

pain at the site of injection ranged from 0.6 to 41.0%. Local neurological injury ranged from 0

to 0.7%. Other adverse events including haematoma, local allergic reaction and lower back

pain ranged from 0 to 11.2%.

The risk of adverse events was not significantly different to that of liquid sclerotherapy or

open surgery, except in one study where the rate of visual disturbance was reported as

significantly higher for foam sclerotherapy compared with liquid sclerotherapy, and in

another study where the rate of skin matting/staining/pigmentation was reported as

significantly higher for foam sclerotherapy compared with surgery.

Foam sclerotherapy is a potentially efficacious treatment both for main trunk and minor

vein disease. It is conducted as an outpatient procedure without the requirement for general

anaesthesia and the limited evidence suggests that, compared with surgery, results in an

earlier return to normal activities. This has implications for the NHS in terms of releasing

theatre time for other surgical procedures, and for patients in reduced need for anaesthesia

and a quicker return to normal activities. However, for foam treatment several sessions may

be required.

Foam sclerotherapy appears to be efficacious in occluding incompetent veins, including both

main trunk and minor vein disease, however its longer-term efficacy in terms of recurrence

or new varicosities is less certain. These estimates are based mainly on data from non-

randomised studies with a high dropout rate and no details of methods of follow-up, and as

such may be prone to attrition bias. Only six RCTs reporting venous occlusion were

identified, with a follow-up of mostly less than three years. One RCT reported the

development of new veins requiring treatment at a follow-up period of 10 years.

xx

Need for further audit or research

Some study reports, currently only available as conference abstracts, may be available as full

text papers in the near future. In the five ongoing studies (three comparative and two case

series), one RCT with 450 patients and two-year follow-up comparing foam sclerotherapy

with surgery is currently in progress in the Netherlands. Another RCT with 158 patients and

about two-year follow-up comparing 3% and 1% polidocanol foam is currently in progress

in France. The sample sizes of the other three studies are all less than 200. The five ongoing

studies, all with lengths of follow-up of less than three years, are due to be completed by

2009. Further review incorporating these studies could be informative.

High quality RCTs of foam sclerotherapy compared with surgery and with alternative

minimally invasive treatments, and with a follow-up period of at least three years, are

required to determine the comparative effectiveness of foam sclerotherapy and its optimal

place in clinical practice.

xxi

LIST OF ABBREVIATIONS

CEAP Clinical, Etiologic, Anatomic, Pathophysiologic

CVA Cerebrovascular Accident

CVI Chronic Venous Insufficiency

DVT Deep Vein Thrombosis

EVLT EndoVenous Laser Ablation Treatment

FS Foam Sclerotherapy

GATE Generic Appraisal Tool for Epidemiology

LSV Long Saphenous Vein

PFO Patent Foramen Ovale

POL Polidocanol

ReBIP Review Body for Interventional Procedures

SSV Short Saphenous Vein

STS Sodium tetradecyl sulphate

SFJ Saphenous-Femoral Junction

SPJ Saphenous-Popliteal Junction

TEE Transoesophageal Echocardiogram

TIA Transient Ischaemic Attack

UGFS Ultrasound guided foam sclerotherapy

1

1 OBJECTIVE OF THE REVIEW

To systematically review the evidence for safety and efficacy of foam sclerotherapy for

venous disease of the lower limbs.

2

2 BACKGROUND

2.1 Description of the underlying health problem

2.1.1 Epidemiology

Venous disease, including both primary and chronic venous insufficiency, is a common

problem. Primary venous insufficiency refers to varicose veins and telangiectasiae; chronic

venous insufficiency encompasses all of the skin changes of advanced venous dysfunction

and includes oedema, eczema, pigmentation, lipodermatosclerosis and ulceration.

The prevalence of varicose veins has been estimated as 17% in men and 32% in women aged

35-70 years in England1 and approximately 40% in men and 32% in women aged 18-64 years

in Scotland.2 Approximately 95,000 varicose vein operations were performed in the NHS in

the year 2004/20053 but no data specific to foam sclerotherapy were available.

2.1.2 Burden of disease

The cosmetic appearance of the affected limbs in people with venous insufficiency is a

primary concern for those affected.4 The most common symptoms at presentation were

aching, heaviness, itching, and leg swelling.5

2.1.3 Aetiology, pathology and prognosis

Venous insufficiency which occurs secondary to valve incompetence, weakening of the vein

wall or chronic inflammation, results in a disruption of normal venous blood transport in

the superficial or deep venous systems, the perforating veins or any combination of these.

Incompetence of the deep, superficial and/or perforating veins leads to raised venous

pressure in the lower leg, which can result in varicose veins that appear as dilated, enlarged

or tortuous superficial veins, reticular veins or telangiectatic veins, as well as resulting in the

skin changes associated with chronic venous insufficiency.

The Clinical, Etiologic, Anatomic, Pathophysiologic (CEAP) classification is widely used to

classify stages of venous disease according to clinical signs (C), cause (E), anatomic

3

distribution (A), and pathophysiology (P).6 The clinical classification has seven categories,

(C0 to C6), according to the objective signs of disease listed in the table below.

Table 1 Classification of chronic lower extremity venous disease

Class

0 No visible or palpable signs of venous disease

1 Telangiectases, reticular veins, malleolar flare

2 Varicose veins

3 Oedema without skin changes

4 Skin changes ascribed to venous disease (e.g. pigmentation, venous eczema, lipodermatosclerosis)

5 Skin changes as defined above with healed ulceration

6 Skin changes as defined above with active ulceration

The clinical classification is then refined according to whether symptoms are present or not,

aetiology (congenital, primary or secondary), anatomic site as superficial, deep or

perforating and to objective measures of reflux.

2.2 Current management and alternative procedures

Current treatment options for venous disease include compression hosiery, sclerotherapy

(liquid or foam) with or without ultrasound guidance, endovenous laser ablation treatment

(EVLT), radiofrequency ablation, open surgery (usually sapheno-femoral ligation, stripping

of the long saphenous vein and phlebectomies or sapheno-popliteal ligation, with or without

stripping of the short saphenous vein and phlebectomies), and subfascial endoscopic

perforator surgery alone or in combination.

Liquid sclerotherapy involves injection of a sclerosant (usually Sodium Tetradecyl Sulphate

(STS) or polidocanol) into truncal veins, varicosities, and/or reticular veins, followed by a

period of compression hosiery and/or bandaging. In contrast, foam sclerotherapy involves

mixing the sclerosant with a small amount of air or gas to produce foam, as described in

section 2.3.1, before injection.

4

2.3 The interventional procedure under review

2.3.1 Description of the interventional procedure

Foam sclerotherapy is a variant of sclerotherapy. It differs from liquid sclerotherapy in that

instead of injecting a liquid sclerosant solution into the vein, the sclerosant is transformed

into foam by forcibly mixing it with air or other type of gas. The theory is that the foam

improves the contact with the endothelium of the vein compared to liquid sclerosants with

an improved effect. The foam is characterised by the type and concentration of the

sclerosant agent, type of gas, ratio of liquid to gas, the time between processing and use, and

the bubble size. These characteristics determine the viscosity and stability of the foam.7

The use of sclerosants in the treatment of venous disease was first reported back in 1840,

with absolute alcohol used as the sclerosant.8 Numerous reports with refinements to

sclerosing therapy followed, starting with McAusland in 1939.9 In 1944, Orbach described an

air-block technique in which a small amount of air was injected before the sclerosant to clear

the vessel of blood and allow undiluted contact of the drug with the endothelium.10 In an

animal study,11 it has been shown that foam combines with the solid elements of the vein

walls and thereby destroys its structure very rapidly and the result is irreversible. In 1993

Cabrera-Garrido reported the use of ‘microfoam’ by injecting high doses of foam to fill the

venous lumen at one time.12 A more recent technique by Monfreux described the creation of

foam by having air drawn into a glass syringe filled with sclerosing solution under negative

pressure.13 Currently, the most commonly used technique is the Tessari technique, in which

two syringes are connected by a three-way valve and the fluid sclerosant is forcibly mixed

with air at a ratio of liquid:air of 1:3 or 1:4 and frothed into foam by a pumping action.14

There are various fluid sclerosants available. The common ones in use in the UK include

STS and polidocanol. At present, Fibro-Vein® (0.2 to 3% STS), produced by STD

Pharmaceutical is a licensed local sclerosant indicated for sclerotherapy of varicose veins in

the UK. Polidocanol is a weaker detergent type of sclerosant than STS and higher

concentrations are necessary to produce complete vascular sclerosis for any given diameter

of vein. Currently, the type and concentration of sclerosant for foam sclerotherapy is not

standardised in the UK with STS 3% used for the truncal veins (long and short saphenous),

1% for smaller veins (tributaries) and concentrations of 0.5% or less for reticular veins.

(Personal communication: K Cassar, Consultant Vascular Surgeon, Aberdeen Royal

Infirmary).

5

Foam sclerotherapy is usually conducted as an outpatient procedure with no anaesthesia

required. It involves the insertion of a needle into the affected vein or veins, followed by the

injection of sclerosant foam. An inflammatory reaction is triggered by the sclerosant, with

the intention of producing vein occlusion. Localised compression is often applied over the

main sites of communication between the superficial and deep venous systems (e.g.

sapheno-femoral, sapheno-popliteal junction, perforators) when truncal veins are injected,

with the aim of avoiding entry of sclerosant into the deep veins.

Duplex ultrasound imaging has increasingly been incorporated into the procedure in order

to establish patency and competence of the deep veins, locate the incompetent superficial

vein to be cannulated, guide cannulation, monitor the injection and flow of foam and to

minimise the risk of foam diffusion to the deep venous system. More than one injection may

be given during the same session in an attempt to ensure that all of the target veins have

been completely filled. Ultrasound imaging is also usually used in the follow-up period to

assess the results of treatment and to determine the need for further injections. The

treatment schedule may require more than one treatment session for complete obliteration

of the vein or veins.

Compression is an important part of the treatment to optimise the effect of foam

sclerotherapy. Compression using either compression hosiery or bandages, and varying

from two days to one month, is recommended. Patients are advised to keep as active as

possible, and to avoid dependence of the lower limbs and long periods of immobility.15

Patent applications for two kinds of foam generating devices by BTC International Limited

(UK) have been documented in the USA and Europe, including the UK. Commercial

products (under the above patents) available are Lauromacrogol 400 microfoam (1-3%

polidocanol) and Varisolve (1% polidocanol) with both products based on O2 and CO2

rather than air. Provensis Ltd (UK) is planning a submission, at a time still to be

determined, to the Medicines and Healthcare Products Regulatory Agency (MHRA) to have

Varisolve® licensed in the UK (Personal communication: D Wright, Provensis Ltd, May

2006). Currently, the use of foam sclerotherapy in the UK is ‘off licence’.

6

2.3.2 Suitable candidates and relevant subgroups

Foam sclerotherapy is suitable for the treatment of any type of superficial venous

incompetence. Currently, young and fit people tend to be selected for conventional or

endoluminal treatment. People who are not fit for surgery and those with chronic venous

insufficiency secondary to superficial venous incompetence are suitable candidates for foam

sclerotherapy.

2.3.3 Proposed clinical indications/contraindications and putative impact of the procedure

Foam sclerotherapy is potentially indicated for all categories of superficial venous disease

from telangiectases and reticular veins, to larger calibre varicose veins, and for chronic

venous insufficiency secondary to superficial venous incompetence. The most generally

accepted contraindications for foam sclerotherapy are similar to those for conventional

liquid sclerotherapy, such as allergy to the sclerosant, a history of acute superficial or deep

vein thrombosis, or hypercoagulopathies.

Potential adverse events associated with sclerotherapy (liquid and foam) include allergy,

thrombophlebitis, pigmentation, nerve damage, cutaneous necrosis, ulceration and matting.

There are concerns that the sclerosant can potentially enter the deep veins and induce

venous thromboembolism. There are additional concerns that, particularly in people with a

Patent Foramen Ovale (PFO), the sclerosant may enter the arterial circulation and induce an

ischaemic stroke or retinal artery occlusion. The use of foam may increase this risk.

Transient visual disturbances are reported following sclerotherapy. The mechanism is

uncertain but is felt to be vasospastic, and similarly the risk may be higher in foam

compared with liquid sclerotherapy.

2.3.4 Personnel involved and skill/experience required

Vascular surgeons mainly undertake foam sclerotherapy in the UK, although general

surgeons, radiologists, dermatologists, nurse practitioners, and general practitioners may

perform the procedure. Detailed data are not available on the type of practitioners

undertaking foam sclerotherapy in the UK. Knowledge of the surgical anatomy and

experience in foam-producing and injection techniques are required. Access to and skill in

7

ultrasound imaging is desirable particularly when the long or short saphenous veins require

cannulation.

2.3.5 Current use in the UK (including existing guidance)

Foam sclerotherapy has begun to be widely used in Europe, the USA, Australia and some

other countries since the early 1990s. However no data were identified on current levels of

use in the UK. There are no established guidelines in the UK for foam sclerotherapy

concerning indications for treatment, use of off-licence foam sclerosants, foam-producing

technique, type and strength of fluid sclerosant, and the experience required by the

practitioner to undertake the procedure. Established guidance is available in Australia for

the treatment of lower limb venous diseases by sclerotherapy, developed by the Australian

College of Phlebology (ACP).16

Under these guidelines:

• Polidocanol or STS can be used as a liquid or foam, but foam is considered ‘off label’ use;

• A foam dilution range of between two parts liquid/three parts air to one part

liquid/four parts air is recommended;

• The maximum volume of 3% STS injected as foam should not exceed 4 ml liquid per day;

• The maximum volume of 5% polidocanol injected as a 1:3 air-diluted foam is 16 ml per

day; and

• The total volume of foam injected in one day should not exceed 20ml regardless of the

liquid: air dilution used for STS or polidocanol.

The German Society of Phlebology has issued guidance7,15 on the concentration and volume

of foam for sclerotherapy, based on a consensus meeting of European experts on foam

sclerotherapy in 2003. In Germany the only sclerosant authorised for sclerotherapy is

polidocanol (aethoxysklerol) at concentrations of 0.25, 0.5, and from 1-4%. Similar to the UK

and Australia, transforming the approved liquid into foam is considered ‘off label’ use.

These guidelines recommend:

• When sclerosing large veins, a total amount of foam 6 to 8 ml using the Tessari or

double-syringe technique, or 4 ml with the Monfreux technique per session should not

8

be exceeded, and not more than 3 ml using the Tessari or double-syringe technique for

the treatment of small saphenous veins;

• If foam is used for the treatment of small intracutaneous varicose veins (reticular,

telangiectasia), only up to 0.5 ml of fluid foam should be used. Viscous foams are not

suitable; and

• A more viscous foam should be used for treating larger varicose veins.

2.3.6 Equipment or devices required

Two syringes and a three-way tap are required to produce foam from sclerosant using the

Tessari technique. Intravenous cannulae of varying length and sizes are required to allow

cannulation of the veins. Sclerosant (usually STS or polidocanol) is required for injection.

Ultrasound equipment is required for guidance of cannulation of truncal veins and

monitoring movement of injected foam as well as to identify the major junctions between the

superficial and deep veins and allow compression at the correct site. Compression hosiery

and bandages are required immediately post treatment.

9

3 METHODS FOR REVIEWING SAFETY AND EFFICACY

3.1 Search strategy

Electronic searches were conducted to identify both published and unpublished studies

evaluating the safety and efficacy of foam sclerotherapy for venous disease. Searches were

not restricted by publication year or language and included abstracts from conference

proceedings. The main databases searched were Medline (1966 – May Week 2 2006),

Embase (1980 – Week 20 2006), Medline in-process (23rd May 2006), Biosis (1969 – 19th May

2006), Science Citation Index (1981 – 20th May 2006), ISI proceedings (1990-23rd June 2006),

Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2006), Conference

Papers Index (2000- June 2006), Cochrane Database of Systematic Reviews (The Cochrane

Library, Issue 2, 2006), Database of Abstracts of Reviews of Effectiveness (April 2006), HTA

Database (April 2006), National Research Register (Issue 2, 2006), Clinical Trials (June 2006)

and Current Controlled Trials (June 2006). A list of the databases searched and full details of

the searches are documented in Appendix 1.

In addition, electronic and hand searching of recent conference proceedings of prominent

phlebology and vascular organisations (details in Appendix 1) was undertaken. The table of

contents of two phlebology journals (Phlebologie (1970-2005) and Australasian Journal of

Phlebology (1999-2004)), not consistently indexed in the major databases, were also

examined for additional reports. Relevant professional and commercial websites were

searched and the reference lists of all included studies were scanned to identify additional

potentially relevant reports. Only one company (Provensis) was identified that produced

sclerosant foam commercially (Varisolve®). This company was contacted for additional

data relating to two unpublished RCTs comparing (i) foam sclerotherapy with surgery and

(ii) foam sclerotherapy with ‘home-made’ foam and liquid sclerotherapy. Authors of other

included studies were contacted where necessary to provide clarification on aspects of their

studies.

10

3.2 Inclusion and exclusion criteria

3.2.1 Types of studies

Types of studies considered were randomised controlled trials (RCTs); non-randomised

comparative studies; case series, case reports, and population-based registry reports that

prospectively collected audit data on foam sclerotherapy for all categories of venous disease.

We excluded earlier reports of studies reproduced in later publications, where the results

related to the same outcomes.

The review was conducted in accordance with the methods agreed by NICE for the

systematic reviews conducted by the Review Body for Interventional Procedures (ReBIP).

Non-English language reports were restricted to French, German, Italian, Spanish, Dutch,

and Portuguese.

3.2.2 Types of participants

The participants considered were adults (≥16 years old) undergoing foam sclerotherapy for

the treatment of venous disease of the lower limbs.

3.2.3 Types of interventions

The interventions considered were foam sclerotherapy, alone or combined with other

treatment, for venous disease. There were no restrictions on foam-producing techniques, or

type, strength or volume of the sclerosant agent.

For RCTs and non-randomised comparative studies, there was no restriction on the

comparator. A comparison of foam-producing techniques, or type, strength or volume of

the sclerosant agent was outwith the scope of this review.

We included studies that reported the use of foam sclerotherapy, whether or not they

reported the use of ultrasound guidance to identify treated veins, monitor foam injection or

foam flow.

11

We excluded treatment of cutaneous venous malformations.

3.2.4 Types of outcomes

Safety

We classified safety outcomes into serious adverse events and adverse events as agreed with

the clinical advisor for this review.

Serious adverse events included:

• Anaphylaxis;

• Arterial events;

• Venous thromboembolism;

• Cutaneous necrosis and ulceration; and

• Other serious adverse events such as epileptic fits.

Adverse events included:

• Visual disturbance such as scotoma;

• Central nervous system disturbance such as confusion, migraine and other type of

headache;

• Other systemic symptoms such as coughing, chest tightness, and vasovagal,;

• Local effects such as ‘minor’ vein thrombosis, thrombophlebitis, skin

matting/staining/pigmentation, local neurological injury, pain provoked on injection

and pain persisting in limbs; and

• Other adverse events such as allergic reaction (local or systemic) and haematoma.

Efficacy

Efficacy outcomes included:

• Complete occlusion of treated veins;

• Healing of venous ulceration;

• Recurrence of varicose veins and development of new veins;

• Quality of life such as time to return to normal activity, patient satisfaction, symptom

relief, and change of disease severity measured by CEAP score (in this category, only

comparative studies were considered); and

12

• Other outcomes such as procedure time (only comparative studies were considered).

Where data were available we examined immediate (≤24 hours), short-term (≤30 days) and

longer-term (>30 days) adverse events, and short-term (≤30 days) and longer-term (>30

days) efficacy. Where data on longer-term outcomes were reported for several time points

later than 30 days we used the data given for the longest follow-up period.

3.3 Quality assessment strategy

Two reviewers independently assessed the quality of the studies, using one of two separate

checklists depending on study design. Any disagreements were resolved by consensus or

arbitration by a third party. A 14-question checklist was used to assess the quality of RCTs

(see Appendix 2). A 17-question checklist was used to assess the quality of non-randomised

comparative studies (see Appendix 3), with the same checklist minus four questions used to

assess the quality of case series. The checklist for RCTs was adapted from Verhagen and

colleagues17 and the checklist for non-randomised studies and case series was adapted from

several sources, including the NHS Centre for Reviews and Dissemination’s guidance for

those carrying out or commissioning reviews,18 Verhagen and colleagues,17 Downs and

Black19 and the Generic Appraisal Tool for Epidemiology (GATE). Both checklists were

developed through the Review Body for Interventional Procedures (ReBIP).

The methodological quality of the French registry report was commented on in the text

rather than formally assessed.

3.4 Data extraction strategy

One reviewer screened the titles (and abstracts where available) of all papers identified by

the search strategy. Full text copies of all reports deemed to be potentially relevant were

obtained and one reviewer assessed English, Italian and Dutch language reports for

inclusion. Any areas of uncertainty were resolved by consultation with a second reviewer.

Another two reviewers assessed French and German language reports for inclusion, and

another researcher assessed Portuguese language reports for inclusion.

13

We developed and piloted a data extraction form. Two reviewers independently extracted

details of study design, methods, participants, interventions and outcomes for English

language reports. One reviewer extracted data for conference abstracts. Another two

reviewers extracted limited data for German and French language reports.

3.5 Data analysis

The results were presented for numbers of patients if data were provided; otherwise the

results refer to the numbers of limbs, veins, or treatment sessions (explicit in the relevant

tables). Relative risks and 95% confidence intervals (CIs) were calculated for comparative

studies. To summarise the results, median event rates (and ranges) were tabulated by study

design. For ease of interpretation, studies reporting the number of limbs or veins but not at

the patient level (22 studies out of 67) were not included in calculating the summary

measures.

Meta-analysis of RCTs using Cochrane Collaboration Review Manager (RevMan 4.2.8 or

later) software was conducted to compare the efficacy (complete occlusion of veins) of foam

sclerotherapy versus liquid sclerotherapy and foam sclerotherapy versus surgery. We

assessed heterogeneity between studies from the I-squared test. We used a random effects

model to derive summary estimates with 95% confidence intervals of relative risk, where

there was substantial heterogeneity.

3.6 Included studies

The numbers of studies and reports included are shown in Table 2.

Table 2 Number of studies and reports included

English language full text studies

English language conference abstracts

Non-English language studies

Unpublished studies Study design

Studies Reports Studies Reports Studies Reports Studies Reports

RCTs 7 17 2 2 0 0 0 0 Registry 1 4 0 0 0 0 0 0 Non-randomised comparative studies

1 1 5 5 2 2 0 0

Case series 13 25 17 24 13 18 0 0 Case reports 4 4 0 0 1 3 1 1

Total 26 51 24 31 16 21 1 1

14

4 RESULTS

4.1 Number and type of included studies

The searches identified 1138 reports after deduplication. The titles and abstracts (where

available) of all papers were screened and 295 (228 full text papers; 63 abstracts) were

selected for full text assessment (Table 3). In addition, four papers were unpublished. Table

4 details the numbers of papers that were included and excluded. Appendix 4 gives the

references for all included studies.

Table 3 Search results Database Searched Number selected

Medline/Embase/Medline In-Process multi file search

(after deduplication in Ovid)

SCI

Biosis

CENTRAL

CDSR

DARE

HTA database

NRR

CCT

Clinical Trials

ISI Conference Proceedings

ZETOC Conferences

Conference Papers Index

Conference Proceedings

Journal search

Web search

Unpublished papers

184

1

13

5

2

1

5

3

0

0

0

0

6

57

12

2

4

Total selected 295

Table 4 Papers selected for full text assessment

Assessment Number of papers

Included in review 106

Retained for background information 17

Excluded – did not meet inclusion criteria 156

Unobtainable papers 11

Ongoing studies 5

Total 295

15

4.1.1 English language full text studies

Twenty-six studies reported in 51 full text papers, conference abstracts, personal

communication or media release met the inclusion criteria for the review. There were seven

RCTs,20-36 one French registry report,37-40 one non-randomised comparative study,41 13 case

series,42-66 and four case reports.67-70

In the RCT by Alos and colleagues,20 patients acted as their own controls, with one vein

treated by foam and another vein, either of the same limb or the other limb, treated by liquid

sclerotherapy (within-patient study). The report by Wright and colleagues36 consisted of

two independent RCTs: (a) foam (available as commercial product) sclerotherapy versus

surgery, and (b) foam (available as commercial product, same as (a)) versus ‘home-made’

foam or liquid sclerotherapy.

Twelve studies were reported in more than one paper. Authors were contacted where

necessary to confirm the duplication of reports. There were four reports of the study by

Barrett and colleagues42-45 with the primary reference being Barrett 2004;44 two reports of the

study by Belcaro and colleagues21,22 with the primary reference being Belcaro 2003;21 four

reports of the study by Bergan and colleagues46-48,65 with the primary reference being Bergan

2006;46 four reports of the study by Bountouroglou and colleagues23-26 with the primary

reference being Bountouroglou 2006;26 four reports49-52 of the study by Cabrera and

colleagues with the primary reference being Cabrera 2001;51 two reports of the study by

Cavezzi and colleagues55,56 with the primary reference being Cavezzi 2002;56 two reports of

the study by Coleridge Smith and colleagues57,58 with the primary reference being Coleridge

Smith 2006 in press;58 four reports of the study by Guex and colleagues37-40 with the primary

reference being Guex 2005;39 four reports of the study by Hamel-Desnos and colleagues27-29,33

with the primary reference being Hamel-Desnos 2003;29 two reports of the study by Kakkos

and colleagues61,62 with the primary reference being Kakkos 2006;62 two reports of the study

by Kern and colleagues31,32 with the primary reference being Kern 2004;31 and three reports

of two studies by Wright and colleagues30,35,36 with the primary reference for both studies

being Wright 2006 in press.36

Excluding the French registry report, 25 studies enrolled 3935 patients treated with foam

sclerotherapy while one study44 reported only the number of limbs (n=116) treated but gave

no indication of the number of patients enrolled (see Table 5 for demographic details and

16

indication for treatment for the 25 included studies). The studies took place during the

period 1993 – 2005. Five studies took place in Italy, four each in Spain and the USA, three in

the UK (all in England), two in the Netherlands, and one each in Australia, Egypt, France,

Ireland, Japan, New Zealand and Switzerland. One study36 was a multi-centre study (the

locations of the centres were not reported). The median length of follow-up across studies

was six months (range 2 weeks to 10 years). Nineteen studies provided details of the gender

of 1968 patients, 79.2% of whom were female. In studies providing details of patient age, all

patients were over 16 years old (range 17 to 91 years).

The most common indications for foam sclerotherapy recorded were saphenous vein

incompetence and/or saphenous vein varicosities (see Table 5). The most frequently used

sclerosant for foam was polidocanol (1838 patients, 46.7%). In those studies reporting foam-

producing technique, the most frequently used technique was the Tessari technique (70.0%).

All studies used ultrasound guidance for identifying veins, monitoring foam injection or

foam flow. Nine studies20,36,41,58,62,68-70 provided details of the number of treatment sessions of

730 patients, 92.6%of whom received one treatment session. Another 11

studies26,44,46,51,53,54,56,59,62,64,66 provided details of the mean of treatment sessions. The means

ranged from 1.1 sessions to 3.6 sessions. One study59 reported smaller veins (reticular veins

and telangiectasias) separately and the mean was 5 sessions.

The French registry report39 included data on 12,173 treatment sessions with foam sclerosant

alone, liquid sclerosant alone or both at each session. The type of veins injected included

reticular and spider veins, long saphenous vein trunk or junction, short saphenous vein

trunk or junction, main tributaries, small varices of non saphenous veins, perforating veins,

and postsurgical recurrences. Ultrasound guidance was used in 36% of sessions treated by

foam sclerosant alone and in 0.9% of sessions treated by liquid sclerosant alone. No

information was reported on the age or gender of patients, the type, strength or dose of

sclerosant solution, or the foam-producing technique used.

Appendix 5 provides details of the characteristics of the included English language studies.

17

Table 5 Patient details, indication for foam sclerotherapy and technique used (English language full text studies)

Studies (n=25)

Patients 3935 Sex Male 410 (10.4%) Female 1558 (39.6%) Not recorded 1967 (50.0%) Age group

≥ 16 years 2616 (66.5%) Not recorded 1319 (33.5%) Indication for foam sclerotherapy ‘Major’ vein (SFJ/LSV, SPJ/SSV) incompetence and/or varicosities 2735 (69.5%) ‘Minor’ vein venous disease 131 (3.3%) Both major veins and minor veins 676 (17.2%) Venous ulcers 83 (2.1%) Not recorded 310 (7.9%) Foam sclerotherapy technique Used STS as sclerosing solutions 668 (17.0%) Used POL as sclerosing solutions 1838 (46.7%) Used either STS or POL (not reported separately) 1369 (34.8%) Used ethanolamine oleate 60 (1.5%) Tessari technique for producing foam 1848 (50.0%) Monfreux technique for producing foam 406 (10.3%) Other techniques for producing foam 367 (9.3%) Not recorded 1314 (33.4%) Used ultrasound guidance to identify treated veins, monitor foam injection or foam flow 3935 (100%) One treatment session required 676 (92.6%) ≥ 2 treatment sessions required 54 (7.4%)

Notes: 1. Another study by Barrett and colleagues44 reported number of limbs (n 116) but not number of patients. The

details of the study were not listed in the table as it was not possible to calculate the number of patients. 2. ‘Minor’ venous disease includes reticular vein, telangiectasia, tributaries vein varicosities and perforator

vein incompetence. 3. Treatment sessions required: the data given in the table are from nine studies20,36,41,58,62,68-70 that provided

details of the number of treatment sessions. Another 11 studies26,44,46,51,53,54,56,59,62,64,66 reported mean treatment sessions, with the means ranging from 1.1 to 3.6 sessions. One study59 reported smaller veins (reticular veins and telangiectasias) separately, with a mean of 5 treatment sessions.

4.1.2 English language conference abstracts

Twenty-four studies reporting 30 conference abstracts and one unpublished abstract met the

inclusion criteria for the review. There were two RCTs,71,72 five non-randomised

comparative studies,73-77 and 17 case series.(P Coleridge Smith, Middlesex Hospital Vascular

Laboratory, London, 2006)78-100

18

There were four reports of the study by Gonzalez and colleagues85-88 with the primary

reference being Gonzalez 2005.88 and three reports by Forlee and colleagues82,83,89 with the

primary reference being a conference abstract.83 There were two reports of the study by

Tessari97,97,98,98 with the primary reference being Tessari 2004.98 Coleridge Smith provided

additional information for a study reported in a conference abstract81 through personal

communication.(P Coleridge Smith, Middlesex Hospital Vascular Laboratory, London, 2006)

Twenty-one studies enrolled 2921 patients (see Table 6 for demographic details and

indication for foam sclerotherapy for the 21 studies) while another three studies did not give

an indication of the precise number of patients treated but reported the number of limbs

treated80,99 (nearly 380 in total) or did not report the number of patients enrolled or the

number of limbs treated.77

Five studies reported patient recruitment/treatment dates. These five studies took place

during the period 1996 – 2004. Nineteen studies reported the study location, with four

studies each taking place in France, Italy and the UK, two each in Canada, Chile and the

USA, and one in Israel. All studies reported follow-up except one non-randomised

comparative study73 and four case series,78,81,92,98 with a median length of follow-up across

studies of one year (range two weeks to five years). Five studies provided details of the

gender of 1475 patients, 72.3% of whom were female. In studies providing details of the age

of patients, all patients were over 16 years old (range 32 to 86 years). The most frequently

used sclerosant for foam was polidocanol (1805 patients, 61.8%). In those studies reporting

foam-producing technique the most frequently used technique was the Tessari technique

(90.0%). Use of ultrasound guidance was mentioned in 12 studies mainly for the monitoring

of the foam injection. No English language conference abstracts provided details of the

number of treatment sessions. Four studies71,73,80,100 provided details of the mean number of

treatment sessions, which ranged from 1.1 to 2.3 sessions. One study96 treated recurrent

veins after surgery and reported a mean of five treatment sessions.

The indications for foam sclerotherapy, most frequently used sclerosant and foam-

producing technique are comparable to that of the English language full text studies.

Appendix 6 provides details of the characteristics of the included English language

conference abstracts.

19

Table 6 Patient details, indication for foam sclerotherapy and technique used (English language conference abstracts)

Studies (n=21)

Patients 2921 Sex Male 408 (14.0%) Female 1067 (36.5%) Not recorded 1446 (49.5%) Age group ≥ 16 years 1656 (56.7%)

Not recorded 1265 (43.3%) Indication for foam sclerotherapy ‘Major’ vein (SFJ/LSV, SPJ/SSV) incompetence and/or varicosities 2073 (71.0%) ‘Minor’ vein venous disease 312 (10.7%) Recurrent venous disease after prevous treatment 373 (12.8) Venous ulcers 20 (0.7%) Not recorded 143 (4.9%) Foam sclerotherapy technique Used STS as sclerosing solutions 714 (24.4%) Used POL as sclerosing solutions 1805 (61.8%) Used either STS or POL (not reported separately) 352 (12.1%) Not reported 50 (1.7%) Tessari technique for producing foam 1349 (46.2%) Monfreux technique for producing foam 0 Other techniques for producing foam 150 (5.1%) Not recorded 1422 (48.7%) Used ultrasound guidance to identify treated veins, monitor foam injection or foam flow 1558 (53.3%) Use of ultrasound guidance not recorded 1363 (46.7%)

Notes: 1. One non-randomised comparative study by Grondin77 did not report number of patients or limbs. One case series by Cavezzi80 reported number of limbs (nearly 100) but not number of patients. One case series by Vin99 reported number of limbs (280) but not number of patients. The details of the study were not listed in the table as it is not possible to calculate the number of patients.

2. ‘Minor’ vein venous disease includes reticular vein, telangaectasia, tributaries vein varicosities and perforator vein incompetence.

3. No studies provided details of the number of treatment sessions. Four studies71,73,80,100 provided details of the mean of treatment sessions. The means ranged from 1.1 sessions to 2.3 sessions. One study96 treated recurrent veins after surgery and reported a mean of 5 sessions.

4.1.3 Non-English language studies

Sixteen studies were reported as non-English language studies (in 21 full text studies or

conference abstracts). There were two non-randomised comparative studies,(R Milleret,

Clinique St Jean, Montpellier, 2006)101,102 13 case series103-119 and one case report.120-122

There were three reports of the study by Benigni and colleagues120-122 with the primary

reference being Benigni 2005;121 two reports of the study by Hamel-Desnos and

20

colleagues107,108 with the primary reference being Hamel-Desnos 2005;108 two reports by

Henriet and colleagues109,110 with the primary reference being Henriet 1999;110 and two

published112,113 and one unpublished report (R Milleret, Clinique St Jean, Montpellier, 2006)

of the study by Milleret and colleagues with the primary reference being Milleret 2004.112

Three studies were German language103,117,119 and twelve were French language reports.

Appendix 7 provides details of the characteristics of the included non-English language full

text studies.

4.1.4 Ongoing studies

Five ongoing studies were identified. One RCT108 in France (n=158) is comparing foam of

polidocanol 3% versus 1% for treating long saphenous vein disease and although it was due

to be completed by Feburary 2006 no results are as yet available. Another RCT123 in the

Netherlands is comparing foam sclerotherapy with surgery, with 450 patients with primary

truncal varicosities of the long saphenous vein, sapheno-femoral junction incompetence and

reflux for at least 20 cm of the long saphenous vein and with a normal deep vein system

recruited. The follow-up period is 18 to 24 months and the study is expected to be

completed in 2009.

One comparative study (unclear whether RCT) (J Earnshaw, Consultant Surgeon,

Gloucestershire Royal Hospital) in Gloucester is investigating whether foam sclerotherapy

of saphenous trunk veins can speed up the healing of chronic venous leg ulcers, with 150

patients with leg ulcers recruited. No details of the control group were provided. The study

is expected to be completed by 2007. One case series in Birmingham (K Darvall,

Birmingham Heartlands Hospital) is studying the effect of foam sclerotherapy on health

related quality of life, with 100 patients recruited but no details of the inclusion criteria

provided. This study was completed in April 2006 but no published data are as yet

available. Another case series (G Geroulakas, Ealing Hospital NHS Trust) in London is

assessing whether foam sclerotherapy can improve the efficiency of varicose vein surgery.

No other details were provided. This study is expected to be completed by December 2006.

21

4.1.5 Unpublished studies

Unpublished data from one case report involving three patients were received from

personal communication (P.Kritzinger, York Vein & Laser Clinic, Newmarket, Ontario,

2006). Appendix 8 provides details of this report.

4.2 Number and type of excluded studies; reasons for exclusion

A list of potentially relevant studies identified by the search strategy, for which full text

papers were obtained, but which subsequently failed to meet the inclusion criteria given in

Section 3.2 and hence were excluded, is given in Appendix 9.

4.3 Quality of available evidence: English language full text studies

Only the methodological quality of the English language full text studies was assessed. The

results of the quality assessment of (1) RCTs, (2) non-randomised comparative studies and

(3) case series are summarised in Tables 7, 8 and 9 respectively. In the RCTs the treatment

allocation was adequately concealed in only one of seven trials. The non-randomised

comparative study41 gave clear inclusion or exclusion criteria and clearly described the foam

sclerotherapy technique used. Twelve case series gave clear inclusion or exclusion criteria

and all 13 case series clearly described the foam sclerotherapy techniques used. Length of

follow-up in most studies, irrespective of study design, was more than 30 days, considered

an adequate period of time to assess the occurrence of adverse events and occlusion of

treated veins. No studies reported methods of follow-up and details of how outcomes were

ascertained. The completeness of follow-up varied across studies. A few prospective case

series reported high dropout rates of over 30%.

Appendices 10 to 12 provide details of the quality assessment of the included RCTs, non-

randomised comparative studies and case series respectively.

In the French registry report,39 22 physicians specialising in phlebology from 22 phlebology

clinics in France volunteered to report their daily activities and problems related to

sclerotherapy injections. The French registry report provided data on 12,173 treatment

sessions of venous (foam or liquid) sclerotherapy. The median (standard deviation)

registration period across clinics was 8 (3.1) weeks. Patients were followed up for up to one

22

month after the registration period ended. No information on the methods of follow-up and

completeness of follow-up was provided. Information was provided on adverse events. No

information on those lost to follow-up was provided.

23

Table 7 Summary of quality assessment of the randomised controlled trials (English language full text studies)

Criteria Yes No Unclear

1. Was the assignment to the treatment groups really random?

720,21,26,29,31,34,36 0 0

2. Was the treatment allocation concealed?

121 126 520,29,31,34,36

3. Were the groups similar at baseline in terms of prognostic factors?

320,21,31 134 321,29,36

4. Were the eligibility criteria specified? 720,21,26,29,31,34,36 0 0

5. Was the intervention (and comparison) clearly defined?

620,21,26,29,31,34 136 0

6. Were the groups treated in the same way apart from the intervention received?

320,29,34 0 421,26,31,36

7. Was there a follow-up period > 30 days? 7 20,21,26,29,31,34,36 0 0

8. Was the outcome assessor blinded to the treatment allocation?

320,31,34 0 421,26,29,36

9. Was the care provider blinded? 0 0 720,21,26,29,31,34,36

10. Were the patients blinded? 220,31 221,26 329,34,36

11. Were the point estimates and measures of variability presented for the primary outcome measures?

620,21,26,29,31,36 134 0

12. Was the withdrawal/drop-out rate likely to cause bias?

0 520,21,26,31,36 229,34

13. Did the analyses include an intention-to-treat analysis?

321,29,34 320,26,31 136

14. Was the operation undertaken by somebody experienced in performing the procedure?

0 0 720,21,26,29,31,34,36

24

Table 8 Summary of quality assessment of the non-randomised comparative studies (English language full text studies)


1. Were participants a representative sample selected from a relevant patient population?

141 0 0

2. Were the inclusion/exclusion criteria of participants clearly described?

141 0 0

3. Were participants entering the study at a similar point in their disease progression?

0 141 0

4. Was selection of patients consecutive? 0 0 141

5. Was data collection undertaken prospectively? 0 0 141

6. Were the groups comparable on demographic characteristics and clinical features?

141 0 0

7. Was the intervention (and comparison) clearly defined? 141 0 0

8. Was the intervention undertaken by someone experienced at performing the procedure?

0 0 141

9. Were the staff, place, and facilities where the patients were treated appropriate for performing the procedure? (E.g. access to back-up facilities)

141 0 0

10. Were all the important outcomes considered? 141 0 0

11. Were objective (valid and reliable) outcome measure/s used? 141 0 0

12. Was the assessment of main outcomes blind? 0 0 141

13. Was follow-up long enough to detect important effects on outcomes of interest?

141 0 0

14. Was information provided on non-respondents, dropouts? 0 141 0

15. Were participants lost to follow-up likely to introduce bias? (e.g. high drop-out rate; differential drop-out; no description of those lost)

0 0 141

16. Was length of follow-up similar between comparison groups 141 0 0

17. Were all the important prognostic factors identified? 0 141 0

18. Were the analyses adjusted for confounding factors? 0 141 0

25

Table 9 Summary of quality assessment of the case series (English language full text studies)



1344,46,51,53,54,56,58-60,62-64,66 0 0


1244,46,51,53,54,56,58-60,62-64 166 0


0 544,46,60,64,66

851,53,54,56,58,59,62,63

4. Was selection of patients consecutive?

551,53,54,63,64 0 8 44,46,56,58-60,62,66

5. Was data collection undertaken prospectively?

456,58,63,64 544,46,51,53,59 454,60,62,66

7. Was the intervention clearly defined?

1344,46,51,53,54,56,58-60,62-64,66

0 0


158 0 1244,46,51,53,54,56,59,60,62-64,66

9. Were the staff, place, and facilities where the patients were treated appropriate for performing the procedure? (e.g. access to back-up facilities)

353,58,64 0 1044,46,51,54,56,59,60,62,63,66

10. Were all the important outcomes considered?

1344,46,51,53,54,56,58-60,62-64,66 0 0

11. Were objective (valid and reliable) outcome measure/s used?

1344,46,51,53,54,56,58-60,62-64,66 0 0

13. Was follow-up long enough (>30 days) to detect important effects on outcomes of interest?

1244,46,51,53,54,56,58-60,63,64,66 162 0

14. Was information provided on non-respondents, dropouts?

0 1344,46,51,53,54,56,58-60,62-64,66 0

15. Were participants lost to follow-up likely to introduce bias? (e.g. high drop-out rate; no description of those lost)

0 164 1244,46,51,53,54,56,58-60,62,63,66

17. Were all the important prognostic factors identified?

746,51,53,58,60,62,63 544,54,56,64,66 159

26

5 SAFETY RESULTS

We classified safety outcomes into serious adverse events and adverse events.

5.1 Serious adverse events

Serious adverse events included: anaphylaxis, vascular events, cutaneous necrosis and

ulceration, and other serious adverse events such as intra-arterial injection and epileptic fits.

The occurrence of serious adverse events by type of event, along with relative risk data, is

shown in Table 10 for comparative studies, while Table 11 shows serious adverse events for

case series.

5.1.1 Anaphylaxis

Among the English language studies, the French registry39 and two case series58,64 reported

data on anaphylaxis, stating that no events occurred. The French registry39 reported 6395

treatment sessions with foam and 5434 with liquid sclerotherapy. The two case series

involved a total of 822 patients and used polidocanol or STS as the sclerosing agent,58 or

STS.64 No conference abstracts or non-English language studies reported anaphylaxis.

5.1.2 Arterial events

We included outcomes reported as stroke, cerebrovascular accident, myocardial infarction,

transient ischaemic attack, and transient ‘embolic’ events in this category.

Cerebrovascular accident (CVA)

One case of stroke was reported in a case series involving 89 patients78,83 and was also

detailed in a case report.82 A 61 year old man with type I diabetes mellitus, hypertension,

hypercholesterolaemia and asthma underwent foam sclerotherapy to the long saphenous

vein (CEAP IV). Shortly after the injection of 20ml 0.5% polidocanol made foam he

developed a right hemiparesis and a mild expressive aphasia (7/42 on the National Institute

of Health Stroke Severity Scale). Ten minutes later, the power in the right upper limb

improved from 1/5 to 4/5 and speech returned to normal. Two weeks later, the power in

the right upper limb returned to normal. The fine motor coordination remained mildly

impaired. The long saphenous vein was occluded. The patient was reported as having fully

recovered.78,83

27

A carotid duplex scan, performed immediately, showed normal arteries with rapidly

moving echogenic particles within the left carotid lumen. This was similar to the duplex

appearance of foam in the LSV. A magnetic resonance image of the brain was normal. The

electrocardiogram showed sinus rhythm, and 24-hour Holter ECG monitoring did not reveal

any paroxysmal arrhythmias. His transoesophageal echocardiogram (TEE) revealed an 18

mm PFO with an associated atrial septal aneurysm. A right-to-left shunt was demonstrated

with a colour flow duplex scan and the bubble test on the TEE. Grade II atheroma of the

distal arch of the aorta was demonstrated.

Myocardial infarction

Myocardial infarction (MI) was reported in an unpublished report (P. Kritzinger, York Vein

& Laser Clinic, Newmarket Ontario, 2006). A 70 year old, otherwise healthy woman

underwent foam sclerotherapy to the incompetent left long saphenous vein. About thirty

minutes after the injection of 8 ml 1% STS made foam she developed central chest tightness

with radiation to her left arm and jaw.

The patient was given oxygen and aspirin immediately and four doses of nitroglycerin spray

but this failed to relieve pain. Subsequent investigations confirmed a myocardial infarction

(creatine kinase of 800 IU). An echocardiogram (type of echocardiogram not specified)

showed no right-to-left shunt. The patient had had three previous injections of 0.5% or 1%

STS foam 8ml, 6ml and 5ml and had reported scotomas following a previous treatment. No

other details of the case were reported.

Other arterial events reported

Among the English language studies, one case series involving 808 patients58 reported data

on cerebrovascular events, with no cases occurring in the six-month follow-up period.

Among the conference abstracts, one non-randomised comparative study77 reported that

0.2% of all patients (absolute numbers not reported) experienced a transient ischaemic attack

in the foam sclerotherapy group while no one experienced this event in the control group

(liquid sclerotherapy, absolute numbers not reported). No further details describing the

transient ischaemic attacks were provided. The authors stated that they used CO2 based

foam to reduce the likelihood of air embolism-related symptoms such as chest pain and

transient ischaemic attacks. One case series78 reported five (2.8%) of 181 patients experienced

transient ‘embolic’ events, with no further details provided.

28

5.1.3 Retinal artery occlusion

No studies reported this outcome.

5.1.4 Venous thromboembolism

Pulmonary embolism

Among the English language studies, two RCTs (reported in one paper36) involving 656

patients and five case series46,51,53,54,60 involving 1316 patients reported data on pulmonary

embolism. No events occurred in the RCTs in either the intervention or control groups. In

four of the case series no events occurred, while Bergan and colleagues,46 reported one

(0.3%) of 290 patients suffering a pulmonary embolism four months after treatment. The

type of venous disease for which the patient was being treated was unclear. The treated

veins were varicose veins, chronic vein insufficiency with ulcers or chronic vein

insufficiency with ulcers failing to heal after compression treatment.

In the conference abstracts, one non-randomised comparative study77 (number of patients

not stated) reported that 0.01% of patients treated by foam sclerotherapy suffered a

pulmonary embolism compared with 0.03% treated by liquid sclerotherapy. The venous

disease treated was saphenous vein incompetence. No further details of the events were

provided.

Three non-English language case series106,112,119 (two case series, 977 patients; one case series,

167 veins) reported data on venous thromboembolism, with no events occurring.

Deep vein thrombosis (DVT)

We included outcomes reported as thrombosis of the femoral vein, popliteal vein, tibial vein,

and ‘calf deep vein’ thrombosis and non specifically as DVT.

In the English language full text studies, four RCTs26,31,36 (two RCTs were reported in one

paper36) and eleven case series46,51,53,54,56,58-60,62,64 two series were reported in one paper59)

reported data on deep vein thrombosis.

29

In two RCTs involving a total of 80 patients in the intervention arm no events occurred.26,31

In the two RCTs by Wright and colleagues36, one RCT compared Varisolve (1%

polidocanol made foam) (n=259) with ‘home made’ foam or liquid sclerotherapy (n=125),

while the other RCT compared Varisolve (n=178) with surgery (stripping) (n=94). Eleven

(2.5%) of 537 patients treated by Varisolve suffered a DVT, of which nine were

asymptomatic (detected by ultrasound examination). In the control groups, one (0.8%) of

125 patients treated with ‘home made’ foam or liquid sclerotherapy experienced a DVT,

while none of the 94 patients who underwent surgery (stripping) experienced an event.

In the English language case series, out of a total of 2828 patients treated, 11 cases of DVT

were reported with a median rate of 0.4% (range 0 to 1.0). Two DVTs reported by Frullini

and colleagues59 were located at the popliteal vein; the Monfreux foam-producing technique

had been used for one patient and the Tessari technique for the other. Venous disease

treated in this series included large, medium or minor varicose veins including telangiectatic

veins. The other studies reporting DVT did not state the location of the affected veins.

In the conference abstracts, two non-randomised comparative studies74,77 and six case

series79,83 81,88,92,99 reported data on DVT. All the case series used polidocanol.

In the non-randomised comparative study by Gobin and colleagues74 one (0.4%) of 229

patients treated with 1% polidocanol foam (Varisolve ®) experienced a DVT compared with

one (0.9%) of 113 in the liquid sclerotherapy group (relative risk 0.5; 95% CI 0 to 7.8). In the

non-randomised comparative study by Grondin and colleagues,77 (number of patients not

reported) 0.12% patients treated by foam sclerotherapy suffered deep vein thrombosis

compared with 0.07% in the liquid sclerotherapy group.

Among the six case series (four case series, 302 patients; two case series, 366 limbs), six cases

of DVT were reported, with two in the study by Bhowmick and colleagues (n=35),79 one

each in the study by Coleridge Smith and colleagues (n=24),81 by Forlee and colleagues

(n=86 limbs),83 Gonzales and colleagues (n=143)88 and by Vin and colleagues (n=280 limbs).99

No DVT occurred in the study by Morrison and colleagues (n=100).92 In the case series by

Bhowmick and colleagues,79 the DVT was located in the distal calf deep vein. The venous

diseases treated in this series were varicose veins using 1% polidocanol foam (Varisolve).

In the case series by Coleridge Smith and colleagues,81 the DVT was located at the popliteal

30

vein, occurring in the fourth week, after gastroenteritis and following air travel. The venous

diseases treated in this series were symptomatic primary or recurrent varicose veins,

sapheno-femoral junction/long saphenous vein or sapheno-popliteal junction/short

saphenous vein reflux. In the case series by Forlee and colleagues,83 the DVT was located in

a calf deep vein. The venous disease treated was varicose veins. No other studies reported

the location of thrombosis.

In the non-English language studies, four case series104,108,112,119 reported data on DVT. All

used polidocanol. Out of a total of 1135 patients, ten cases of DVT were reported with the

incidence in all the studies being less than 2%.

5.1.5 Cutaneous necrosis and ulceration

Necrosis

In the English language studies, one RCT29 involving 45 patients, the French registry,39 and

four case series46,59,60,62 involving 781 patients reported data on necrosis. No cases of necrosis

occurred in the RCT or French registry report in either the foam or liquid sclerotherapy

groups. Eight cases occurred in the case series. The venous disease treated was chronic

venous insufficiency with ulcer,46 or symptomatic recurrent veins.62 All follow-up periods

were more than 30 days except for the study by Kakkos and colleagues62 (three weeks). No

details of recovery were reported for cutaneous necrosis.


not reported) and two case series involving 483 patients93,100 reported occurrence of

cutaneous necrosis. In the non-randomised comparative study by Grondin and colleagues,77

0.01% of patients treated with foam sclerotherapy suffered cutaneous necrosis compared

with 0.03% of patients treated by liquid sclerotherapy. One case (0.2%) of necrosis occurred

in the case series by Nitecki and colleagues93 involving 423 patients. Weiss and colleagues100

reported that no cutanous necrosis occurred in 43 patients treated for telangiectasias and

reticular veins.

In the non-English language studies, one non-randomised comparative study involving 40

patients101 and two case series105,119 involving 263 patients reported data on cutaneous

necrosis, with no cases occurring.

31

Cutaneous ulceration

In the English language studies, two RCTs26,31 and one case series64 reported data on

cutaneous ulceration. No case occurred following foam sclerotherapy in the longer-term

(>30 days) follow-up period, but one case occurred following surgery (ligation combined

with stripping and avulsion).26 No conference abstracts reported cutaneous ulceration. One

non-English language case series117 reported that one (3.6%) of 28 patients developed

cutaneous ulceration.


In the French registry report39 no cases of intra-arterial injection occurred using either foam

or liquid sclerotherapy.

A grand mal epileptic fit was reported in the case report by Kritzinger (P. Kritzinger, York

Vein & Laser Clinic, Newmarket Ontario, 2006). A 70 year old man was injected with 5ml

of 1% STS foam to a large lateral thigh perforator vein. Forty minutes later, he experienced

scintillating scotomas, followed by confusion, stupor, and then a grand mal seizure.

Subsequent investigations found no evidence of MI, cardiovascular accident, septal defects

(right-to-left shunt), DVT, pulmonary embolism or sepsis. The patient remained in intensive

care for three days and was discharged on day five, with no further follow-up reported. It is

unclear whether he had a history of epilepsy.

No other serious adverse events were reported in the conference abstracts or non-English

language studies.

32

Table 10 Safety: serious adverse events of foam sclerotherapy for venous disease at lower limbs (comparative studies)

Foam Comparator Relative risk Study

Length of follow-up

Comparator No. % No. % 95% CI

Anaphylaxis English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 0/6395 sessions 0 0/5434 sessions 0 - Arterial events Conference abstracts, non-randomised comparative studies

Grondin 2003a77 5y Liquid sclerotherapy NR 0.2 NR 0 - Venous thromboembolism: pulmonary embolism English language full text studies, RCT Wright in press a36 1y Foam or liquid sclerotherapy (1% POL) 0/259 0 0/125 0 - Wright in press b36 1y Surgery (high ligation, stripping, avulsion phlebectomy) 0/178 0 0/94 0 - Conference abstracts, non-randomised comparative studies Grondin 2003b76 5y Liquid sclerotherapy N/R 0.01 N/R 0.03 - Venous thromboembolism: deep vein thrombosis English language full text studies, RCT Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 0/29 0 0/23 0 - Kern 200431 Liquid sclerotherapy (0.25% POL) 0/51 0 0/45 0 - Liquid sclerotherapy (100% Chromated glycerine) 0/51 0 0/51 0 - Wright in press a36 1y Foam or liquid sclerotherapy (1% POL) 2/259 0.8 1/125 0.8 1.0 (0.1, 10.5) Wright in press b36 1y Surgery (high ligation, stripping, avulsion phlebectomy) 9/178 5.1 0/94 0 10.1 (0.6, 171.4) English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 1/6395 sessions 0.02 0/5434 sessions 0 2.6 (0.1, 62.6) Conference abstracts, non-randomised comparative studies

Gobin 200374 N/R Liquid sclerotherapy 1/229 0.3 1/113 0.9 0.5 (0, 7.8) Grondin 2003b76 5y Liquid sclerotherapy N/R 0.12 N/R 0.07 - Cutaneous: necrosis English language full text studies, RCT Hamel-Desnos 200329 1y Liquid sclerotherapy (3% POL) 0/45 0 0/43 0 - English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 0/6395 sessions 0 0/5434 sessions 0 - Conference abstracts, non-randomised comparative studies Grondin 2003b76 5y Liquid sclerotherapy N/R 0.01 N/R 0.03 - Non-English language full text studies, non-randomised comparative studies Benigni 1999101 75 days Liquid sclerotherapy 0/20 0 0/20 0 -

33

Table 10 Safety: serious adverse events of foam sclerotherapy for venous disease at lower limbs (comparative studies) CONT

Study Length of follow-up

Comparator Foam Comparator Relative

risk

Cutaneous: ulceration English language full text studies, RCT Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 0/29 0 1/23 4.3 0.3 (0, 6.3) Kern 200431 Liquid sclerotherapy (0.25% POL) 0/51 0 0/45 0 - Liquid sclerotherapy (100% Chromated glycerine) 0/51 0 0/51 0 - Other serious adverse events: intra-arterial injection English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 0/6395 sessions 0 0/5434 sessions 0 - Note: 1. Foam sclerotherapy in the RCT by Bountouroglou and colleagues26 was combined with ligation.

34

Table 11 Safety: serious adverse events of foam sclerotherapy for venous disease at lower limbs (case series)

Study id Length of follow-up Sclerosant Immediate (≤ 24h) Short-term (≤ 30d) Longer-term (> 30d)

n/N % n/N % n/N %

Anaphylaxis English language full text studies Coleridge Smith in press58 6m 1% POL, 1% STS or 3% STS 0/808 0 Padbury 200464 6m STS 0/14 0 Arterial events English language full text studies Coleridge Smith in press58 6m 1% POL, 1% STS or 3% STS 0/808 0 Conference abstracts Forlee 200683 Mean 6m 0.5-3% POL 1/72 1.4 Baker 200678 N/R POL 5/181 2.8 Venous thromboembolism: pulmonary embolism English language full text studies Bergan 200646 60d 1-3% POL 1/290 0.3 Cabrera 200453 > 6m 0.27-1% POL 0/116 0 Cabrera 200151 Mean 2.5y for venous

ulcers; 4-6y for 415 LSV; N/R for 265 SV

POL (0.65-3% Lauromacrogol 400 microfoam) 0/752 0

Cavezzi 199954 1m 1-3% STS or 1-4% POL 0/98 0 Hamada 200660 1y Ethanolamine oleate 0/60 0 Non-English language studies Frullini 2000106 N/R 3-4% POL or STS 1-3% 0/167 veins 0 Milleret 2004112 1m STS 1-3% 0/764 0 Wildenhues 2005119 2y POL (1% or 3% ) 0/213 0

35

Table 11 Safety: serious adverse events of foam sclerotherapy for venous disease at lower limbs (case series) CONT


n/N % n/N % n/N %

Venous thromboembolism: deep vein thrombosis English language full text studies Bergan 200646 60d 1-3% POL 2/290 0.7 Cabrera 200453 > 6m 0.27-1% POL 0/116 0 Cabrera 200151 4-6y POL (0.65-3% Lauromacrogol 400 microfoam) 0/752 0 Cavezzi 200256 1m STS 2/194 1.0 Cavezzi 199954 12-43w 1-3% STS, 1-4% POL 1/98 1.0 Coleridge Smith in press58 6m 1% POL, 1% STS or 3% STS 3/808 0.4 Frullini 2002 a59 20-180d POL or STS 1/257 0.4 Frullini 2002 b59 20-180d POL or STS 2/196 1.0 Padbury 200464 6m STS 0/14 0 Hamada 200660 1y Ethanolamine oleate 0/60 0 Kakkos 200662 3w 3% STS 0/38 0 Conference abstracts Forlee 200683 6m 0.5-3% POL 1/86 limbs Bhowmick 200179 3m POL (Varisolve®) 2/35 5.7 Coleridge Smith 200381 1y 1% POL (Varisolve) 1/24 4.2 Gonzales Zeh 200588 2y 3% POL 1/143 0.7 Vin 200599 1y 3% POL 1/280 limbs 0.4 Morrison 200392 N/R 1% POL 0/100 0 Non-English language studies Creton 2005104 Mean 10m N/R 2/130 1.5 Hamel-Desnos 2005108 6m POL (1% or 3%) 1/158 0.6 Milleret 2004112 3m STS 1-3% 5/764 0.7 Wildenhues 2005119 2y POL (1% or 3% ) 2/213 0.9

36

Table 11 Safety: serious adverse events of foam sclerotherapy for venous disease at lower limbs (case series) CONT


n/N % n/N % n/N %

Cutaneous: necrosis English language full text studies Bergan 200646 60d 1-3% POL 1/290 0.3 Frullini 2002 a59 20-180d POL or STS 4/257 1.6 Frullini 2002 b59 20-180d POL or STS 2/196 1.0 Kakkos 200662 3w 3% STS 1/38 2.6 Conference abstracts Nitecki 200593 Mean 10m 3% POL 1/423 0.2 Weiss 2002100 6m 0.1%, 0.2% STS 0/60 0 Non-English language studies Ferrara 2005105 3m POL (0.2% 0/50 0 Wildenhues 2005119 2y POL (1% or 3% ) 0/213 0 Cutaneous: ulceration English language full text studies Padbury 200464 6 months STS 0/14 0 Non-English language studies Stücker 2005117 N/R POL (2%) 1/28 3.6 Others Non-English language studies Schadeck 2004114 Mean 14.7m POL (3% Lauromacrogol 400 microfoam) 0/108 0 Note: 1. Wildenhues 2005119 reported 2 cases of DVTs in patients with coagulopathies. 2. Stucker 2005117 reported a case of superficial erosion of 4mm at injection site healed after one week, follow-up time not reported. 3. Schadeck 2004114 reported that no cases of intra-arterial injection occurred.

37

5.2 Adverse events

Adverse events included: visual disturbance such as scotoma; central nervous system

disturbance such as confusion, migraine and other type of headache; other systemic

symptoms such as vasovagal, coughing, chest tightness; local effects such as ‘minor’ vein

thrombosis, thrombophlebitis, skin matting/staining/pigmentation, local neurological

injury, and pain provoked on injection and pain persisting in limbs; and other adverse

events such as allergic reaction (local or systemic) and haematoma.

For English language studies, occurrence of these types of events, along with relative risk

data, is shown in Table 12 for comparative studies, while Table 13 shows this category of

events for case series.

5.2.1 Visual disturbance

Visual disturbance includes blurred vision, migraine with aura or scotoma.

In the English language studies, two RCTs20,31 involving 171 patients, the French registry39

involving 12,173 treatment sessions, nine case series46,51,53,54,56,58-60,66 involving 2848 patients,

and one case report70 provided data on visual disturbance. The incidence of visual

disturbance occurring in these studies ranged from 0 to 5.9%. The sclerosing agents used

were polidocanol, STS or ethanolamine oleate. In the French registry,39 the relative risk (95%

CI) of visual disturbance with foam sclerotherapy, compared with liquid sclerotherapy, was

16.1 (2.2 to 120.6).

A few English language studies reported timing or duration of visual disturbance. Weaver

and colleagues70 reported in a case report that the visual disturbance occurred immediately

after injection. Two studies53,70 reported the duration of the visual disturbance, with a range

from 2 to 30 minutes, while the three cases of visual disturbance reported by Kern and

colleagues31 all lasted less than two hours. Fourteen cases of visual disturbance reported by

Coleridge Smith and colleagues58 were managed by resting supine and resolved in most

cases within 30 minutes. Frullini and colleagues59 reported four cases as transient visual

disturbances. No longer-term reduction or impairment in vision was reported by any study.

38

A total of four cases of scotoma were reported by four English language case series51,54,56,66

involving 1121 patients. Tessari and colleagues66 reported the scotoma as transient. No

study reported the outcome of longer-term impairment in vision.

A total of three cases of visual disturbance were followed by headache or migraine and were

reported by one English language case series46 and one case report70. The patient in the case

report experienced two episodes of migraine, following the first treatment with polidocanol

foam 18 ml and the second treatment with polidocanol liquid 9 ml, with the experience

reported as being typical of her migraine attacks. One-to-two hours before the third

treatment using 9 ml polidocanol liquid, non-steroid anti-inflammatory tablets were given,

and only momentary blurring of vision was experienced following treatment.70

In the conference abstracts, one non-randomised comparative study74 involving 342 patients

and one case series92 involving 100 patients reported visual disturbance. In the non-

randomised comparative study,74 two (0.9%) of 229 patients in the foam group compared

with one (0.9%) of 113 patients in the liquid group experienced visual disturbance. The

number of patients experiencing visual disturbance was not reported in the case series by

Morrison and colleagues92 but the authors stated that visual disturbance was the most

commonly occurring side effect and rarely lasted more than four hours, and resolved more

quickly with ambulation and water ingestion.

In the non-English language studies, one non-randomised comparative study102 involving

508 patients, two case series106,114 (108 patients; 167 veins) and one case report121 involving

five patients reported data on visual disturbance. In the non-randomised comparative

study, five (2.0%) of 254 patients experienced visual disturbance in the foam group

compared with none of 254 in the liquid sclerotherapy group. Two visual disturbances

occurred during the treatment of 167 veins in the case series by Frullini.106 The study by

Schadeck and colleagues114 reported that none of the 108 patients experienced visual

disturbance. In the case reports by Benigni and colleagues,121 visual disturbance occurred in

five patients shortly after foam injection (range 3 to 10 minutes). One patient developed a

headache that lasted two hours. Another patient with a history of migraine experienced a

headache that lasted four hours. This patient reported that the experience was similar to a

previous migraine attack.

39

5.2.2 Central nervous system

This category included transient confusion and headache.

Transient confusion

In the English language studies, three case series54,59,60 involving 611 patients reported four

(0.7%) cases of transient confusion. Two cases occurred in the same patient during different

treatment sessions.59 No studies in the conference abstracts reported transient confusion. In

the non-English language studies, Frullini and colleagues106 reported one (0.6%) episode of

transient confusion during the treatment of 167 veins.

Headache

In the English language studies, the RCTs by Wright and colleagues36 reported a rate of 5.4%

(14/259) in the foam group of one RCT and 23.0% (41/178) in the foam group of the other

RCT. The mean rate is therefore 12.6%. The rates were similar to those associated with the

comparators (surgery; ‘home made’ foam or liquid sclerotherapy). The French registry39

reported that there were no cases of headache alone in either group of patients treated with

foam or liquid sclerotherapy. The case series by Bergan and colleagues,46 involving 290

patients, reported the occurrence of two (0.7%) cases of true migraine.

In the conference abstracts, one non-randomised comparative study by Gobin and

colleagues74 reported headache in patients treated with long saphenous vein/short

saphenous vein incompetence, with moderate-to-severe varicosities. Seven (3.1%) of 229

patients in the foam sclerotherapy group experienced headache compared with seven (6.2%)

of 113 patients in the liquid sclerotherapy group, giving a relative risk of 0.5 (0.2 to 1.4). No

further details of the episodes were provided.

No non-English language studies reported headache.

5.2.3 Other systemic symptoms

This category of symptoms included panic attack, malaise, cough, chest tightness or

heaviness, and vasovagal.

40

In the English language studies, five case series involving 1091 patients46,53,56,59,62 reported

data on systemic symptoms. In the French registry report there were four (0.1%) cases of

coughing out of 6395 treatment sessions by foam sclerotherapy, with none in the 5434

treatment sessions by liquid sclerotherapy.39

Bergan and colleagues46 reported eight (2.8%) cases of systemic symptoms out of 290

patients treated in their case series (four of dry cough and two each of panic attack and chest

tightness). No information was provided on when these episodes began or their duration.

In the case series by Cabrera and colleagues,53 two (1.7%) out of a total of 116 patients

experienced dry cough that lasted for less than one minute. In another case series involving

752 patients Cabrera and colleagues51 reported that coughing lasting less than 15 minutes

occurred but gave no indication of the number of patients affected. The case series by

Cavezzi and colleagues56 and Frullini and colleagues,59 involving a total of 647 patients, each

reported one case of malaise.

The unpublished case reports by Kritzinger (P Kritzinger, York Vein & Laser Clinic,

Newmarket Ontario, 2006) recorded one case of chest tightness (this was a separate case

from the case of MI).


not reported) and one case series92 involving 100 patients reported data on chest discomfort

and dry cough. No patients had dyspnoea/chest pain after treatment in the non-

randomised comparative study.77 Morrison and colleagues92 reported that dry cough and

chest discomfort were the most commonly occurring side effects but did not state the

number of patients experiencing these events. This study, using 1% polidocanol foam to

treat all sizes of venous insufficiency, reported that systemic symptoms were short-lived (1-4

hours).92

A non-English language case series by Sica and colleagues116 reported that one (0.7%) of 148

patients experienced transient chest tightness.

Vasovagal

In the English language studies, one within-patient RCT involving 75 patients20 and the

French registry39 reported vasovagal events alone. In the RCT no vasovagal events occurred.

In the French registry report, six (0.1%) cases of vasovagal events occurred out of 6395 foam

41

sclerotherapy treatment sessions compared with four (0.1%) out of 5434 liquid sclerotherapy

treatment sessions,39 relative risk (95% CI) 1.3 (0.4 to 4.5). The French registry also reported

that no cases of ‘nausea and vomiting alone’ occurred in either group. No conference

abstracts or non-English language studies reported vasovagal.

5.2.4 Local effects: ‘minor’ vein thrombosis

This category included outcomes reported as thrombosis in reticular vein, microthrombi,

superficial vein thrombosis, thrombosis in gastrocnemius vein or soleal vein, and venous

extension.

In the English language studies, two RCTs29,31 and two case series58,60 reported data on

‘minor’ vein thrombosis.

Hamel-Desnos and colleagues29 reported that no ‘venous thrombosis’ occurred in 88 patients

treated by either polidocanol foam sclerotherapy or liquid sclerotherapy. Nine (17.6%) of 51

patients treated by foam sclerotherapy in the RCT by Kern and colleagues31 developed

microthrombosis compared with five (11.1%) of 45 cases in the group treated by polidocanol

liquid and eight (15.7%) of 51 in the group treated by 100% chromated glycerine.

The French registry39 reported five muscular vein microthrombi from the foam

sclerotherapy treatment sessions compared with none for liquid sclerotherapy.

Ten (1.2%) of 808 patients in the case series reported by Coleridge Smith and colleagues58

developed gastrocnemius or posterior tibial vein thrombosis (data not reported separately).

One (1.7%) of 60 patients in the case series by Hamada and colleagues60 developed soleal

vein thrombosis.

No studies reported the timing of occurrence of ‘minor’ vein thrombosis; it was assumed

that these events occurred in the longer-term (>30 days).

In the conference abstracts, one case series by Coleridge Smith and colleagues81 (n=24)

reported thrombosis located at the gastrocnemius vein. Three non-English language case

series103,106,119 reported occurrence of ‘minor’ vein thrombosis, all with rates of less than 1%.

42

5.2.5 Local effects: thrombophlebitis

In the English language studies, we included cases reported as cutaneous inflammation,29

local inflammation,20 thrombophlebitis,26,31,53,58,62 segmental phlebitis of a collateral vein,66

phlebitis,60 varicophlebitis,59 superficial thrombophlebitis54 and lymphoedema worsening.59

Four RCTs and nine case series reported data on thrombophlebitis. The RCT by Alos and

colleagues20 reported both short-term (≤ 30 days) and longer-term (>30 days) data. The case

series by Cabrera and colleagues51 mentioned occurrence of inflammation but provided no

data.

In the RCT by Alos and colleagues,20 fewer patients had thrombophlebitis at one year

follow-up than at 30 day follow-up. Bountouroglou and colleagues26 reported that three

cases of thrombophlebitis associated with foam sclerotherapy were self-limiting. Cabrera

and colleagues51 reported that inflammation was always resolved with anti-inflammatory

drugs or adequate bandaging. Cabrera and colleagues did not regard superficial phlebitis as

an adverse event.

Longer-term (>30 days) thrombophlebitis ranged from 1.3% to 10.3% in the case series.

There was no significant difference in the incidence of thrombophlebitis for foam

sclerotherapy compared with surgery26 or liquid sclerotherapy.20,29,31

In the French registry, three instances of thrombophlebitis occurred in the foam

sclerotherapy group compared with one in the liquid sclerotherapy group, with the

difference not statistically significant (relative risk 6.0; 95% CI, 0.3 to 115.1).

The following outcomes reported by conference abstracts were included in this section:

venous inflammation, inflammation and pain, varicophlebitis, phlebitis, superficial

thrombophlebitis, discomfort resembling superficial thrombophlebitis and oedema. Two

non-randomised comparative studies74,77 and six case series79,81,83,94,95,99 reported

thrombophlebitis. The occurrences of thrombophlebitis were 20% or over in three case

series.79,81,94 No further details of the events were provided by the studies.

Seven non-English language case series103,106,108,111,114,117,119 involving over 809 patients

reported the occurrence of thrombophlebitis, with rates ranging from 0 to 14.6%.

43

5.2.6 Local effects: skin matting/staining/pigmentation

In the English language studies, four RCTs20,26,31,36 and six case series53,58-60,62,64 reported data

on these outcomes. All reported longer-term (>30 days) data except Kakkos and colleagues62

who reported a follow-up of 21 days.

The RCT by Alos and colleagues20 also reported short-term (≤30 days) data (in the

polidocanol foam sclerotherapy group 39 (52.7%) of 74 patients experienced local effects

compared with 11 (14.9%) of 74 in the liquid sclerotherapy group), with fewer patients

reporting skin matting/staining/pigmentation at one year (foam, 21 (33.3%) of 63 patients

versus liquid, 4 (6.3%) of 63 patients). This study was a within-patient RCT, with two veins

from the same leg or different legs randomly assigned to receive foam or liquid

sclerotherapy. Cabrera and colleagues53 reported that the pigmentation in 90% of 23 patients

resolved spontaneously after six months.

There was no statistically significant difference in skin matting/staining/pigmentation

between foam sclerotherapy and open surgery in the RCT by Bountouroglou and

colleagues26 (relative risk 8.8; 95% CI 0.5 to 151.4) but in the RCT by Wright and colleagues36

(relative risk 1.33; 95% CI 1.01 to 1.75) foam sclerotherapy was associated with a higher risk

that was just statistically significant. There was no significant difference between foam and

liquid sclerotherapy in both the RCT by Kern and colleagues31 (relative risk to polidocanol

liquid 1.2, 95% CI 0.3 to 5.0; relative risk to chromated glycerine 9.0, 95% CI 0.5 to 163.0) and

in the RCT by Wright and colleagues 36 (relative risk 1.0; 95% CI 0.8 to 1.3).

The longer-term rate in the case series ranged from 0% to 19.8%.

In the conference abstracts, one non-randomised comparative study73 and five case

series81,83,94,95,100 reported data on skin matting/staining/pigmentation. Patients in the non-

randomised comparative study and case series by Schadeck and colleagues95 and Weiss and

colleagues100 were treated for reticular and telangiectatic veins. Ten (19.2%) of 52 patients

treated by foam sclerotherapy in the non-randomised comparative study developed skin

matting compared with 23 (30.3%) of 76 patients in the liquid sclerotherapy group (relative

risk 0.6; 95% CI 0.3 to 1.2). In the case series, the occurrence of skin

matting/staining/pigmentation ranged from 11% to 50%.

44

In the non-English language studies, one non-randomised comparative study101 involving 40

patients and three case series106,112,114 involving 108 patients reported data on skin

matting/staining/pigmentation. Frullini and colleagues106 reported that six patients

developed skin matting/staining/pigmentation during the treatment of 167 veins. Milleret

and colleagues112 reported that 12% of patients still had pigmentation one year after

treatment, decreasing to 3% at three years. However no data were provided giving the

number of patients affected.112

5.2.7 Local effects: local neurological injury

In the English language studies, one RCT26 and six case series46,51,53,58,60,64 reported data on

local neurological injury, parasthesias or neurasthenia.

Three cases of neurological injury were reported in the French registry,39 one associated with

foam sclerotherapy and the other two associated with liquid sclerotherapy. No details were

reported of the location of the nerve or severity.

Two cases of parasthesias were reported in the case series by Bergan and colleagues.46 No

further details of the cases were provided.

No conference abstracts or non-English language studies reported local neurological injury.

5.2.8 Local effects: pain at the site of injection

In the English language studies, two RCTs20,36 and one case series64 reported data on pain

provoked by injection or long-term pain at the sclerosis region. In the RCTs the patients

were injected with polidocanol and experienced no pain. However in the case series 23% of

23 patients injected with STS experienced pain. In the study by Wright and colleagues20,36

there was no significant difference in the level of pain between foam sclerotherapy and

surgery seven days after treatment.

Another RCT by Kern and colleagues31 used a 0-100 analogue scale to measure pain at the

site of injection two months after treatment (score: foam sclerotherapy 20.69 (95% CI, 14.61

45

to 26.77) versus 0.25% polidocanol liquid sclerotherapy 20.1 (95% CI, 13.44 to 26.77) versus

100% chromated glycerine liquid sclerotherapy 35.05 (95% CI, 29.21 to 40.89)).

In the conference abstracts, two non-randomised comparative studies73,74 involving 470

patients and one case series involving 41 patients91 reported pain at the site of injection. In

the non-randomised comparative study by Gobin and colleagues,74 70 (30.6%) patients

experienced pain provoked by foam injection (type of sclerosant not reported) compared

with 28 (24.8%) patients in the liquid sclerotherapy group. In the non-randomised

comparative study by Chung and colleagues,73 four (7.7%) patients experienced pain

provoked by STS or ethanolamine foam sclerotherapy compared with 10 (13%) in the liquid

sclerotherapy group. In the case series by McCollum and colleagues,91 14 (35%) patients

experienced pain provoked by injection of 1% polidocanol (Varisolve) foam and took

nonsteroidal anti-inflammatory drugs to relieve pain.

Two non-English language case series103,108 involving 500 patients reported data on

persisting pain at the lower limbs. In one case series one (0.63%) of 158 patients had

persisting pain two weeks after polidocanol foam sclerotherapy, while in the other 24 (7%)

of 342 patients still had pain one month after polidocanol foam sclerotherapy.

5.2.9 Other adverse events

We included outcomes reported as haematoma, allergic reaction (local or systemic),

extravasation, and local back pain in this section.

In the English language studies, three RCTs26,29,36 and two case series56,60 reported data on

these outcomes. One case (1.3%) of haematoma was reported associated with foam

sclerotherapy in the RCT by Hamel-Desnos and colleagues.29 One case (0.5%) of allergic

reaction to STS foam was reported in the case series by Cavezzi and colleagues,56 with no

further details provided (unclear whether local or systemic).

In the conference abstracts, two non-randomised comparative studies73,77 reported allergic

reaction or extravasation although neither reported the number of patients affected. In the

non-randomised comparative study by Grondin and colleagues,77 0.3% of patients who

underwent foam sclerotherapy experienced allergy compared with 0.7% in the liquid

sclerotherapy group, with no further details provided (unclear whether local or systemic). In

46

another non-randomised comparative study by Chung and colleagues,73 extravasations

occurred more frequently in the foam sclerotherapy compared with the liquid sclerotherapy

group, although numbers of patients were not reported.

In the non-English language studies, one non-randomised comparative study102 involving

508 patients and two case series106,108 reported data on other adverse events. No allergic

reaction following foam sclerotherapy occurred in the case series by Frullini and

colleagues.106 One (0.6%) of 158 patients in the case series by Hamel-Desnos and

colleagues108 experienced lower back pain.

5.3 Studies not reporting adverse events separately and a large study including children

In the English language studies, no adverse events occurred in the non-randomised

comparative study by Yamaki and colleagues41 and the case series by McDonagh and

colleagues,63 involving a total of 239 patients. In the conference abstracts, the RCT by

Martimbeau71 reported that the rate of adverse events associated with foam sclerotherapy

was 0.2% compared with 2.4% associated with liquid sclerotherapy but did not further

specify the adverse events. The case series by Sierra and colleagues,96 available as a

conference abstract, reported that no serious adverse events occurred and that ‘minor’

sequelae were quickly resolved.

Another French language study110 reported the safety of foam sclerotherapy in 10,263

patients recruited during November 1995 to September 1998. This study included both

adults and children (mean patient age 51 years, range 8 to 93 years). The foam used was

0.5% polidocanol foam made by the Monfreux foam-producing technique, with over 70,000

injections. Nine cases of visual disturbance occurred, all happening immediately after

treatment; seven migraines occurred, mostly in younger patients; two patients experienced

metal taste; and one case each of skin ulceration, thrombophlebitis, oedema, sworming,

difficulty in speech, headache, and vomiting occurred.

47

Table 12 Safety: adverse events of foam sclerotherapy for venous disease of the lower limbs (comparative studies)

Foam sclerotherapy Comparator Adverse

events Study

Length of follow-up

Comparator No. % No. %

Relative risk 95% CI

Visual disturbance English language full text studies, RCTs Alos 200620 1y Liquid sclerotherapy (1-2.5% POL) 0/75 0 0/75 0 - Kern 200431 5w Liquid sclerotherapy (0.25% POL) 3/51 5.9 0/45 0 6.2 (0.3, 116.7) Liquid sclerotherapy (100% Chromated glycerine) 3/51 5.9 0/51 0 7.0 (0.4, 132.2) English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 19/6395 sessions 0.3 1/5434 sessions 0.02 16.1 (2.2, 120.6) Conference abstracts, non-randomised comparative studies Gobin 200374 N/R Liquid sclerotherapy 2/229 0.9 2/113 1.8 0.5 (0.1, 3.5) Non-English language studies, non-randomised comparative studies Demagny 2002102 6m Liquid sclerotherapy 5/254 2.0 0/254 0 11.0 (0.6, 197.9) Central nervous system disburbance: headache English language full text studies, RCTs Wright in press a36 1y Foam or liquid sclerotherapy 14/259 5.4 7/125 5.6 1.0 (0.4, 2.3) Wright in press b36 1y Surgery (high ligation, stripping, avulsion) 41/178 23.0 20/94 21.3 1.1 (0.7, 1.7) English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 0/6395 sessions 0 0/5434 sessions 0 - Conference abstracts, non-randomised comparative studies Gobin 200374 N/R Liquid sclerotherapy 7/229 3.1 7/113 6.2 0.5 (0.2, 1.4) Other systemic symptoms: panic attack, malaise, cough, chest tightness or heaviness, and vasovagal English language full text studies, RCTs Alos 200620 1y Liquid sclerotherapy (1-2.5% POL) 0/75 0 0/75 0 - English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 10/6395 sessions 0.2 4/5434 sessions 0.1 2.1 (0.7, 6.8) Confernce abstracts, non-randomised comparative studies Grondin 2003b76 5y Liquid sclerotherapy N/R 0 N/R 0 - Local effects: ‘minor’ vein thrombosis English language full text studies, RCTs Hamel-Desnos 200329 1y Liquid sclerotherapy (3% POL) 0/45 0 0/43 0 - Kern 200431 5w Liquid sclerotherapy (3% POL) 9/51 17.6 5/45 11.1 1.6 (0.6, 4.4) Liquid sclerotherapy (100% Chromated glycerine) 9/51 17.6 8/51 15.7 1.1 (0.5, 2.7) English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 5/6395 sessions 0.1 0/5434 sessions 0 9.4 (0.5, 169.0)

48

Table 12 Safety: adverse events of foam sclerotherapy for venous disease of the lower limbs (comparative studies) CONT


events Study

Length of follow-up



Local effects: thrombophlebitis English language full text studies, RCTs Alos 200620 1y Liquid sclerotherapy (1-2.5% POL) 1/71 1.4 0/71 0 - Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 3/29 10.3 0/23 0 5.6 (0.3, 103.2) Hamel-Desnos 200329 1y Liquid sclerotherapy (3% POL) 2/45 4.4 3/43 7.0 0.6 (0.1, 3.6) Kern 200431 5w Liquid sclerotherapy (0.25% POL) 0/51 0 0/45 0 - Liquid sclerotherapy (100% Chromated glycerine) 0/51 0 0/51 0 - English language full text studies, registry Guex 2005 39 1m Liquid sclerotherapy 3/6395 sessions 0.05 0/5434 sessions 0 6.0 (0.3, 115.1) Conference abstracts, non-randomised comparative studies Gobin 200374 N/R Liquid sclerotherapy 1/229 0.4 0/113 0 1.5 (0.1, 36.2) Grondin 2003b76 5y Liquid sclerotherapy N/R 11.0 N/R 4.34 - Local effects: skin matting/staining/pigmentation English language full text studies, RCTs Alos 200620 1y Liquid sclerotherapy (1-2.5% POL) 21/63 33.3 4/63 6.3 - Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 5/29 17.2 0/23 0 8.8 (0.5, 151.4) Kern 200431 Liquid sclerotherapy (0.25% POL) 4/51 7.8 3/45 6.7 1.2 (0.3, 5.0) Liquid sclerotherapy (100% Chromated glycerine) 4/51 7.8 0/51 0 9.0 (0.5, 163.0) Wright in press a36 1y Foam or liquid sclerotherapy 119/259 45.9 57/125 45.6 1.0 (0.8, 1.3) Wright in press b36 1y Surgery (ligation+stripping+avulsion) 98/178 55.1 39/94 41.5 1.33 (1.01, 1.75) Conference abstracts, non-randomised comparative studies Chung 200373 N/R Liquid sclerotherapy 10/52 19.2 23/76 30.3 0.6 (0.3, 1.2) Grondin 2003b76 5y Liquid sclerotherapy N/R 5 N/R 0.42 - Non-English language studies, non-randomised comparative studies Benigni 1999101 75 days Liquid sclerotherapy 7/20 35.0 1/20 5.0 7.00 (0.95, 51.80) Local effects: local neurological injury English language full text studies, RCTs Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 0/29 0 2/23 8.7 0.2 (0, 3.2) English language full text studies, registry Guex 200539 1m Liquid sclerotherapy 1/6395 sessions 0.02 2/5434 sessions 0.04 0.4 (0, 4.7)

49

Table 12 Safety: adverse events of foam sclerotherapy for venous disease of the lower limbs (comparative studies) CONT


events Study

Length of follow-up



Local effects: pain at the site of injection English language full text studies, RCTs Alos 200620 1y Liquid sclerotherapy (1-2.5% POL) 6/71 8.5 1/71 1.4 - Wright in press a36 1y Foam or liquid sclerotherapy 77/259 29.7 3/125 2.4 1.20 (0.8, 1.7) Wright in press b36 1y Surgery (ligation+stripping+avulsion) 73/178 41.0 39/94 41.5 1.0 (0.7, 1.3) Conference abstracts, non-randomised comparative studies Gobin 200374 N/R Liquid sclerotherapy 70/229 30.6 28/113 24.8 1.2 (0.9, 1.8) Chung 200373 N/R Liquid sclerotherapy 4/52 7.7 10/76 13.2 0.6 (0.2, 1.8) Other adverse events: allergic reaction, haematoma, extravasation, and lower back pain English language full text studies, RCTs Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) 0/29 0 2/28 7.1 0.2 (0.01, 3.9) Hamel-Desnos 200329 1y Liquid sclerotherapy (3% POL) 1/45 2.2 0/43 0 2.9 (0.1, 68.6) Wright in press a36 1y Foam or liquid sclerotherapy 29/259 11.2 9/125 7.2 1.6 (0.8, 3.2) Wright in press b36 1y Surgery (ligation+stripping+avulsion) 11/178 6.2 1/94 1.1 5.8 (0.8, 44.3) Conference abstracts, non-randomised comparative studies Grondin 2003b76 5y Liquid sclerotherapy N/R 0.3 N/R 0.7 - Non-English language studies, non-randomised comparative studies Demagny 2002102 6m Liquid sclerotherapy 0/254 0 1/254 0.4 0.3 (0, 8.1) Notes: 1. The included non-randomised comparative study by Yamaki and colleagues41 did not report safety results. 2. The English language full text RCT reported by Alos and colleagues20 was a within-patient study, two veins in the same leg or different legs were randomly assigned to receive foam or liquid

sclerotherapy, therefore relative risk was not calculated. 3. The foam sclerotherapy reported in the English language full text RCT by Bountouroglou26 was combined with saphenofemarol junction ligation. 4. The non-randomised comparative study by Gobin74 was in a conference abstract: 26 of 229 in foam group and 19 of 113 in comparator group were recurrent veins, data not reported separately. 5. Visual disturbance: The French registry by Guex and colleagues39: the number of patients were not reported but treatment sessions were; 16 visual disturbances occurred in the foam sclerotherapy group in which eight

were transient visual disturbance alone, eight were associated with headache, nausea, vasovagal fainting; four visual disturbances occurred in the sclerosing liquid group, all transient visual disturbances alone.

6. Thrombophlebitis: The non-randomised comparative study by Grondin76 in a conference abstract did not report the number of patients but stated that there was an increased rate of thrombosis in the foam sclerotherapy

group compared with the liquid sclerotherapy group; 7. Other adverse events: Demagny102 reported a case of allergic reaction which regressed spontaneously in the comparator group; The non-randomised comparative study by Chung and colleagues73 in a conference abstract did not report the number of patients but stated that extravasation happened more frequently with foam

sclerotherapy than with liquid sclerotherapy, but did not report the number of patients who developed extravasation.

50

Table 13 Safety: adverse events of foam sclerotherapy for venous disease of the lower limbs (case series)

Sclerosant Immediate (≤ 24h) Short-term (≤ 30d) Longer-term (> 30d)

Study id Length of follow-up n/N % n/N % n/N %

Visual disturbance English language full text studies Bergan 200646 60d 1-3% POL 5/290 1.7 Cabrera 200453 > 6m 0.27-1% POL 2/116 1.7 Cabrera 200151 4-6Y POL (0.65-3% Lauromacrogol 400 microfoam) 7/752 0.9 Cavezzi 200256 1m STS 1/194 0.5 Cavezzi 199954 12-43w 1-3% STS, 1-4% POL, 1/98 1.0 Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 14/808 1.7

Frullini 2002a59 20-180d POL or STS 3/257 1.2 Frullini 2002b59 20-180d POL or STS 1/196 0.5 Hamada 200660 1y Ethanolamine oleate 0/60 0 Tessari 200166 1m 1.1-3% STS 2/77 2.6 Non-English language studies Frullini 2000106 N/R 3-4% POL or STS 1-3% 2/167 veins 1.2 Schadeck 2004114 Mean 14.7m POL (3% Lauromacrogol 400) 0/108 0 Central nervous system disturbance: transient confusion English language full text studies Cavezzi 199954 12-43w 1-3% STS, 1-4% POL 1/98 1.0 Frullini 2002a59 20-180d POL or STS 3/257 1.2 Frullini 2002b59 20-180d POL or STS 0/196 0 Hamada 200660 1y Ethanolamine oleate 0/60 0 Non-English language studies Frullini 2000106 N/R 3-4% POL or STS 1-3% 1/167 veins 0.6 Central nervous system disturbance: headache English language full text studies Bergan 200646 60d 2/290 0.7

51

Table 13 Safety: adverse events of foam sclerotherapy for venous disease of the lower limbs (case series) CONT


Study id Length of follow-up n/N % n/N % n/N %

Other systemic symptoms panic attack, malaise, cough, chest tightness or heaviness, and vasovagal English language full text studies Bergan 200646 60d 1-3% POL 8/290 2.8 Cabrera 200453 > 6m 0.27-1% POL 2/116 1.7 Cavezzi 200256 1m STS 1/194 0.5 Frullini 2002a59 20-180d POL or STS 0/257 0 Frullini 2002b59 20-180d POL or STS 1/196 0.5 Kakkos 200662 3w 3% STS 0/38 0 Non-English language studies Sica 2005116 1y STS (1% STS) 1/148 0.7 Local effects: ‘minor’ vein thrombosis English language full text studies Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 10/808 1.2 Hamada 200660 1y Ethanolamine oleate 1/60 1.7 Conference abstracts Coleridge Smith 200381 1y 1% POL (Varisolve) 1/24 4.2 Non-English language studies Breu 2004103 6w POL 2/342 0.6 Frullini 2000106 N/R 3-4% POL or STS 1-3% 1/167 veins 0.6 Wildenhues 2005119 2y POL (1% or 3%) 2/213 0.9 Local effects: thrombophlebitis English language full text studies Cabrera 200453 > 6m 0.27-1% POL 12/116 10.3 Cavezzi 199954 12-43w 1-3% STS, 1-4% POL 3/98 3.1 Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 40/808 5.0 Frullini 2002a59 20-180d POL or STS 5/257 1.9 Frullini 2002b59 20-180d POL or STS 8/196 4.1 Hamada 200660 1y Ethanolamine oleate 2/60 3.3 Kakkos 200662 3w 3% STS 6/73 sessions 8.2 Tessari 200166 1m 1.1-3% STS 1/77 1.3

52



Study id Length of follow-up n/N % n/N % n/N

Conference abstracts Coleridge Smith 200381 1y 1% POL (Varisolve®) 11/24 45.8 Bhowmick 200179 3m POL (Varisolve®) 7/35 20.0 Forlee 200683 Mean 6m 0.5-3% POL 11/86 limbs 12.8 Vin 200599 1y 3% POL 9/280 limbs 3.2 Schadeck 200195 Mean 14.7m 3% STS or 0.2-0.5% POL 14/118 11.9 Sadoun 200394 2y N/R 5/20 25.0 Non-English language studies Breu 2004103 6w POL 18/342 5.3 Frullini 2000106 N/R 3-4% POL or STS 1-3% 5/167 veins 3.0 Hamel-Desnos 2005108 2y POL (1% or 3%) - 14.6 Lucchi 2003111 6m 3% STS or 8% or 12% polyiodine iodine 14/118 11.9 Schadeck 2004114 Mean 14.7m POL (3% Lauromacrogol 400) 7/108 6.5 Stücker 2005117 N/R POL (2% 1/28 3.6 Wildenhues 2005119 2y POL (1% or 3%) 0/213 0 Local effects: matting/skin staining/pigmentation English language full text studies Cabrera 200453 > 6m 0.27-1% POL 23/116 19.8 Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 11/115 limbs 9.6 Frullini 2002a59 20-180d POL or STS 6/257 2.3 Frullini 2002b59 20-180d POL or STS 0/196 0 Hamada 200660 1y Ethanolamine oleate 0/60 0 Kakkos 200662 3w 3% STS 3/45 limbs 6.6 Padbury 200464 6m STS 2/15 13.3 Conference abstracts Coleridge Smith 200381 1y 1% POL (Varisolve®) 16/24 66.7 Forlee 200683 Mean 6m 0.5-3% POL 33/86 legs 38.4 Schadeck 200195 N/R 3% STS or 0.2-0.5% POL Retic. 14/100

Telang. 11/100 14.0 11.0

Weiss 2002100 6m 0.1%, 0.2% STS 11/60 18.3 Sadoun 200394 2y N/R 10/20 50.0

53



Study id Length of follow-up n/N % n/N % n/N

Non-English language studies Frullini 2000106 N/R 3-4% POL or STS 1-3% 6/167 veins 3.6 Milleret 2004112 1m STS 1%-3% NR 3.0 Schadeck 2004114 Mean 14.7m POL (3% Lauromacrogol 400) 0/108 0 Local effects: local neurological injury English language full text studies Bergan 200646 60d 1-3% POL 2/290 0.7 Cabrera 200453 > 6m 0.27-1% POL 0/116 0 Cabrera 200151 4-6y 0.65-3% Lauromacrogol 400 microfoam 0/752 0 Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 0/808 0 Hamada 200660 1y Ethanolamine oleate 0/60 0 Padbury 200464 6m STS 0/14 0 Local effects: pain provoked by injection English language full text studies Padbury 200464 6m STS 3/14 21.4 Conference abstracts McCollum 200191 3m POL (Varisolve®) 14/41 34.1 Non-English language studies Breu 2004103 6w POL 24/342 7.0 Hamel- Desnos 2005108 2y POL (1% or 3%) 1/158 0.6 Other less serious adverse events: allergic reaction, haemotoma, extravasation, and lower backpain English language full text studies Cavezzi 200256 1m STS 1/194 0.5 Hamada 200660 1y Ethanolamine oleate 0/60 0 Non-English language studies Frullini 2000106 N/R 3-4% POL or STS 1-3% 0/167 veins 0 Hamel-Desnos 2005108 2y POL (1% or 3%) 1/158 0.6 Note:

1. Visual disturbance: Morrison and colleagues92 did not report the number of patients experiencing visual disturbance or systemic symptoms but stated they were the most commonly occurring adverse events in the study using 1% polidocanol foam.

2. Systemic symptoms: Sica116 reported chest discomfort as ‘transitory thoracic constriction’. 3. Thrombophlebitis: Cavezzi and colleagues80 reported that less than 3% of nearly 100 limbs developed thrombophlebitis but did not report the actual number; Vin and colleagues99 reported that 3.3% of

patients developed thrombophlebitis but did not report the number of patients treated. 4. Matting/skin staining/pigmentation: Sadoun and colleagues94 reported that skin pigmentation resolved in 90% after 6 months; Milleret 112 reported that 12% of patients had pigmentation one year later

and 3% of patients had pigmentation three years after treatment. 5. Others: Frullini106 reported occurrence of allergy; Hamel- Desnos108 reported occurrence of lower back pain.

54

5.4 Summary of safety

Thirteen English language full text studies26,29,31,36,46,51,53,54,56,58,59,62,64 involving 3353 patients, 12

English language conference abstracts73,74,77,77,78,81,83,88,92,93,99,100 involving over 1353 patients,

eight non-English language studies101,105,106,108,113,114,117,119 involving over 1341 patients and an

unpublished case report (P. Kritzinger, York Vein & Laser Clinic, Newmarket Ontario, 2006)

reported serious adverse events.

Table 14 summarises the serious adverse events associated with foam sclerotherapy (four

studies reporting the number of limbs or veins but not patients were not included in the

table for ease of interpretation). No cases of anaphylaxis or intra-arterial injection were

reported. No arterial events occurred in the English language full text studies but occurred

at a median rate of 2.1% (range 1.4 to 2.8%) in two conference abstracts involving 253

patients. One pulmonary embolism was reported in one of five English language case series

involving a total of 1316 patients. Across all studies, DVT occurred at a median rate of less

than 1% (range 0 to 5.7%). Cutaneous necrosis occurred at a median rate of 1.0% (range 0 to

2.6%) in four English language case series involving 781 patients and 0% (range 0 to 0.2%) in

five studies available as conference abstracts or non-English language studies involving 766

patients. Cutaneous ulceration did not occur in English language studies but occurred in

one (3.6%) of 28 patients in a non-English language study. One case of MI and one case of

grand mal epileptic fit were reported in separate case reports (P. Kritzinger, York Vein &

Laser Clinic, Newmarket Ontario, 2006).

In the comparative studies, the risks of all of the serious adverse events associated with foam

sclerotherapy were not significantly different from those associated with comparator

interventions (see relative risk in Table 10).

Fifteen English language full text studies20,26,29,31,46,51,53,54,56,58,59,62,64,66,70 involving 3075 patients,

14 conference abstracts73,74,76,77,79-81,83,91,92,94,95,99,100 involving over 1066 patients, 12 non-English

language studies101-103,106,108,111,113,114,116,117,119,121 involving over 2154 patients, and an

unpublished case report (P. Kritzinger, York Vein & Laser Clinic, Newmarket Ontario, 2006)

reported adverse events.

Table 15 summarises the data on adverse events associated with foam sclerotherapy (studies

reporting data by number of limbs or veins but not patients were not included in this table

55

for ease of interpretation). Visual disturbance occurred at a median rate of less than 2%

(range 0 to 5.9%). No visual disturbance was reported lasting more than two hours. No

longer-term or permanent impairment was reported. Transient confusion occurred at a

median rate of 0.5% (range 0 to 1.2%) in three English language case series involving 611

patients. Headache occurred at various rates across studies with a range of 0 to 23.0%.

Other systemic symptoms, including coughing, chest tightness/heaviness, panic attack and

malaise, and vasovagal occurred at a median rate of 0.5% (range 0 to 2.8%) in six English

language case series involving 1091 patients.

‘Minor’ vein thrombosis occurred at a median rate of 0.9% (range 0.6 to 4.3%) in three

studies available as conference abstracts or non-English language studies involving 579

patients. This is lower than the rate in two English language RCTs involving 96 patients

(median 8.8%, range 0 to 17.6%) and two English language case series involving 868 patients

(median 1.5%, range 1.2 to 1.7%).

Thrombophlebitis occurred at a median rate of 4.4% (range 0 to 10.3%) and 3.3% (range 1.3

to 10.3%) in three English language RCTs involving 125 patients and seven English language

case series involving 1612 patients respectively. This is lower than that reported in ten

studies available as conference abstracts or non-English language studies involving 1235

patients (median 9.2%, range 0 to 45.8%).

Longer-term (>30 days) skin matting/staining/pigmentation occurred at a median rate of

31.6% (range 7.8 to 55.1%) in four English language RCTs involving 517 patients. This rate is

higher than that in five English language case series involving 759 patients (median 2.3%,

range 0 to 19.8%) and also higher than that in six studies available as conference abstracts or

non-English language studies involving 484 patients (median 19.2%, range 0 to 66.7%).

The occurrence of local neurological injury was less than 1% across all studies. Pain

provoked by injection or persisting in the limbs varied across studies with a range of 0.6% to

41.0%. Other adverse events, including local allergic reaction, haematoma and lower back

pain, occurred in a median of 4.2% (range 0 to 11.2%) in four English language RCTs

involving 511 patients and at a rate of less than 1% in other study designs.

In the comparative studies, the risks of adverse events associated with foam sclerotherapy

were not significantly different from those associated with comparator interventions, other

56

than for visual disturbance, which was significantly higher for foam compared with liquid

sclerotherapy in the French registry, and the risk of skin matting/staining/pigmentation,

which was significantly higher for foam sclerotherapy compared with surgery in the RCT by

Wright and colleagues36 (see relative risks in Table 12).

A comparison of the adverse events associated with different types and strengths of

sclerosing agents, and volume of foam and foam-producing techniques was not possible as

few studies used a single type and strength of sclerosing agent.

57

Table 14 Summary of serious adverse events of foam sclerotherapy for venous disease

Adverse events No. of studies n/N Median rate (%)

(range)

Anaphylaxis Registry 139 0/6396 0 Case series (English language full text studies) 258,64 0/822 0 Arterial events Case series (English language full text studies) 158 0/808 0 Case series (conference abstracts) 278,83 6/253 2.1 (1.4, 2.8) Venous thromboembolism: pulmonary embolism RCT (English language full text studies) 236 0/437 0 Case series (English languagefull text studies) 5 46,51,53,54,60 1/1316 0 (0, 0.3) Case series (non-English language studies) 2106,119 0/977 0 Venous thromboembolism: deep vein thrombosis RCT (English language full text studies) 426,31,36 11/517 0.4 (0, 5.1) Registry (English language full text studies) 139 1/6395 0.02 Case series (English language full text studies) 1146,51,53,54,56,58-60,62,64 11/2828 0.4 (0, 1.0)

Studies in conference abstracts and non-English language

1058,74,79,81,88,92,99,104,108,112,113,119 16/2076 0.7 (0, 5.7)

Cutaneous: necrosis RCT (English language full text studies) 129 0/45 0 Registry (English language full text studies) 139 0/6395 0 Case series (English language full text studies) 446,59,60,62 8/781 1.3 (0.3, 2.6) Studies in conference abstracts and non-English language 593,100,101,105,119 1/766 0 (0, 0.2) Cutaneous: ulceration RCT (English language full text studies) 226,31 0/80 0 Case series (English language full text studies) 164 0/14 0 Studies in conference abstracts and non-English language 1117 1/28 3.6 Others: intra-arterial injection Registry 139 0/6395 0 Studies in conference abstracts and non-English language 1114 0/108 0

Note: 1. One case each of myocardial infarction and grand mal epileptic fit were reported by Kritizinger. 2. Guex 200539: adverse events were presented by number of treatment sessions rather than by

number of patients. 3. The report by Wright and colleagues36 consisted of two studies (RCTs); the report by Frullini59

consisted of two studies (case series). 4. Studies not reporting results at the patient level: Non-English language case series by Frullini 200079,81,106 n=167 veins, reported no pulmonary

embolism, details available in Table 11.

58

Table 15 Summary of adverse events of foam sclerotherapy for venous disease

Adverse events No. of studies n/N Median rate (%)

(range)

Visual disturbance RCT (English language studies) 131 3/51 5.9 Registry 139 19/6395 0.3 Case series (English language studies) 1046,51,53,54,56,58-60,66 36/2848 1.1 (0, 2.6) Studies in conference abstracts and non-English language 374,102,114 7/591 0.9 (0, 2.0) Central nervous system disturbance: transient confusion Case series (English language studies) 454,59,60 4/611 0.5 (0, 1.2) Central nervous system disturbance: headache RCT (English language studies) 236 55/437 14.2 (5.4, 23.0) Registry 139 0/6395 0 Case series (English language studies) 146 2/290 0.7 Studies in conference abstracts and non-English language 174 7/229 3.1 Other systemic symptoms: coughing, chest tightness/heaviness, panic attack and malaise, and vasovagal Registry 139 10/6395 0.2 Case series (English language studies) 646,53,56,59,62 12/1091 0.5 (0, 2.8) Local effect: ‘minor’ vein thrombosis RCT (English language studies) 229,31 9/96 8.8 (0, 17.6) Registry 139 5/6395 0.1 Case series (English language studies) 258,60 11/868 1.5 (1.2, 1.7) Studies in conference abstracts and non-English language 381,103,119 5/579 0.9 (0.6, 4.2) Local effect: thrombophlebitis RCT (English language studies) 326,29,31 5/125 4.4 (0, 10.3) Registry 139 3/6395 0.05 Case series (English language studies) 753,54,58-60,66 71/1612 3.3 (1.3, 10.3) Studies in conference abstracts and non-English language 1074,79,81,94,95,103,111,114,117,119 81/1235 9.2 (0, 45.8) Local effect: local neurological injury RCT (English language studies) 126 0/29 0 Registry 139 1/6395 0.02 Case series (English language studies) 646,51,53,58,60,64 2/2040 0 (0, 0.7) Local effect: matting/skin staining/pigmentation RCT (English language studies) 426,31,36 226/517 31.6 (7.8, 55.1) Case series (English language studies) 553,58-60,64 42/759 2.3 (0, 19.8) Studies in conference abstracts and non-English language 673,81,94,95,100,101,114 74/484 19.2 (0, 66.7) Local effect: pain at the site of injection RCT (English language studies) 236 150/437 35.7 (29.7, 41.0) Case series (English language studies) 164 3/14 21.4 Studies in conference abstracts and non-English language 573,74,91,103,108 113/822 7.7 (0.6, 34.1) Others RCT (English language studies) 4 26,29,36 41/511 4.2 (0, 11.2) Case series (English language studies) 255,60 1/254 0.3 (0, 0.5) Studies in conference abstracts and non-English language 2102,108 1/412 0.3 (0, 0.6)

Notes:

1. Case reports: six cases of visual disturbance and one case of chest heaviness were reported by Benigni and colleagues,121 Weaver and colleagues70 and the unpublished case reports by Kritzinger.

2. The RCT by Alos and colleagues20 is a within-patient study, therefore was not listed in the table. 3. Guex39: results were presented by number of treatment sessions. 4. The report by Wright and colleagues36 consisted of two studies (RCTs); the report by Frullini59

consisted of two studies (case series). 5. Studies not reporting results at the patient level (details available in Table 13): (1) English language full text case series by Kakkos 200662 n=73 sessions/45 limbs, reported 8.2%

thrombophlebitis and 6.6% skin matting/staining/pigmentation; (2) Conference abstract case series by Forlee 200682 n=86 limbs, reported 1/86 limbs ‘minor’ vein

thrombosis, 11/86 limbs thrombophlebitis, and 33/86 limbs skin matting; (3) Conference abstract case series by Vin 200599 n=280 limbs, reported 9/280 limbs

thrombophlebitis; (4) Non-English language case series by Frullini 2000106 n=167 veins, reported 0.6% ‘minor’ vein

thrombosis, 5/167 veins thrombophlebitis, 3.6% skin matting, and 0% allergic reaction.

59

6 EFFICACY RESULTS

The following five aspects of efficacy are covered in this section: 1. complete occlusion of

treated veins; 2. healing of venous ulceration; 3. recurrence of venous disease (all types) and

development of new veins; 4. quality of life, disappearance of varicosities and changes of

CEAP score (only comparative studies considered); 5. procedure time (only comparative

studies considered).

Table 16 shows for English language comparative studies the efficacy data, with relative

risks, of foam sclerotherapy for venous disease of the lower limbs while Table 17 shows

efficacy data for English language case series.

6.1 Complete occlusion of treated veins

We included results reported as ‘complete occlusion of treated veins’. ‘Successful treatment’

and ‘elimination of reflux’ were included if the study did not present data on ‘complete

occlusion of treated veins’.


In the English language studies, three RCTs,20,26,36 one non-randomised comparative study,41

eight case series44,46,51,58,60,62-64 and two case reports67,68 reported data on complete occlusion of

treated veins, assessed by ultrasound imaging. One RCT20 also reported data on short-term

(≤ 30 days) occlusion of veins. One case series62 reported data only on short-term (≤ 30 days)

occlusion of veins. Another case series66 reported that nearly 100% of treated veins were

completely occluded but did not give the number of patients.

Another two RCTs did not report occlusion of veins but ‘treatment failure needing new

interventions’21 and elimination of reflux29 Another two case series did not report occlusion

of veins but ‘obliteration of the vessels or antegrade flow’56 or ‘stable sclerofibrosis or re-

canalisation without reflux’.54 One case report69 also reported ‘elimination of reflux’ instead

of occlusion of veins.

The venous occlusion rates with foam sclerotherapy in RCTs were all more than 80%. The

occlusion rate with foam sclerotherapy was significantly higher than comparators in the

RCT by Belcaro and colleagues.21 In this RCT, the venous occlusion rate was calculated by (1

60

minus the rate of treatment failure requiring new treatment). Foam sclerotherapy had a

significantly higer occlusion rate than stab avulsion (relative risk 1.3; 95% CI 1.2 to 1.5)

(Table 16). Foam sclerotherapy had a significantly higher venous occlusion rate than liquid

sclerotherapy in the RCT by Hamel Desnos and colleagues29 (relative risk 2.1 ; 95% CI 1.5 to

3.2), in the RCT by Wright and colleagues36 (relative risk 1.1 ; 95% CI 1.0 to 1.1), and in the

non-randomised comparative study by Yamaki and colleagues41 (relative risk 3.9; 95% CI 1.9

to 7.8). However, in the other RCT by Wright and colleagues,36 foam sclerotherapy had a

significantly lower venous occlusion rate than surgery (ligation, stripping and avulsion)

(relative risk 0.8 ; 95% CI 0.7 to 0.9).

The rates in the case series ranged from 60% to 98% (Table 17). The case reports stated that

all treated veins were occluded.

Two RCTs31,34 and three case series53,59,66 did not report data on occlusion of veins. The

French registry did not report data on the efficacy of foam sclerotherapy.

Conference abstracts

In the conference abstracts, one RCT,71 three non-randomised comparative studies74,76,87 and

11 case series78-81,83,90,91,95,96,98,99 reported data on complete occlusion of veins using foam

sclerotherapy.

Another non-randomised comparative study77 did not report occlusion of veins but rather

success rate (no measurements provided). Another three case series did not report occlusion

of veins but success rate (no measurements provided),108 successful treatment judged by

ultrasound and patient satisfaction (no criteria provided),93 and reflux rate.88 Another case

series by Frullini84 reported the occlusion rate with STS foam and polidocanol foam

sclerotherapy separately but did not report the number of patients separately (patients in

total: n= 21).

The occlusion rates in the RCT71 and non-randomised comparative studies74,76,87 were all

more than 80% except for occlusion of the long saphenous vein in the RCT by Martimbeau

and colleagues71 (11 of 25, 44%). In this study,71 the occlusion rate with foam sclerotherapy

was significantly higher than that of liquid sclerotherapy in treating long saphenous veins

(relative risk 3.7, 95% CI 1.2 to 11.6) and short saphenous veins (relative risk 1.8, 95% CI 1.1

61

to 2.7) (Table 16). The rates of venous occlusion in the case series ranged from 50% to 98.2%

(Table 17).


In the non-English language studies, five case series103,114,116,118,119 reported data on complete

occlusion of veins using foam sclerotherapy. Another non-randomised comparative study102

and two case series106,108 did not report occlusion of veins but rather success rate (no

measurement provided). Another case series111 only reported ‘elimination of reflux’. The

venous occlusion rates in the non-English language studies were all 75% or over (Table 16,

17).

Meta-analysis of RCTs

Two English language RCTs21,29 and one RCT available as a conference abstract71 were

included in a meta-analysis comparing venous occlusion of foam versus liquid

sclerotherapy. Heterogeneity across the three studies was very high (I-square 93.4%). Foam

sclerotherapy was more efficacious in achieving venous occlusion compared with liquid

sclerotherapy, although the difference was not statistically significant (relative risk 1.3, 95%

CI 0.9 to 2.1). Two English language RCTs26,36 compared venous occlusion of foam

sclerotherapy versus surgery involving stripping. Surgery was more efficacious than foam

sclerotherapy in achieving venous occlusion, but again the difference was not statistically

significant (relative risk 0.9, 95% CI 0.7 to 1.1).

62

Figure 1 Meta-analysis of foam versus liquid sclerotherapy, and foam sclerotherapy versus surgery, for complete occlusion of treated veins

Review: Foam sclerotherapy for venous disease

Comparison: 01 Foam versus liquid sclerotherapy

Outcome: 01 Complete occlusion of veins

Study Foam Liquid RR (random) Weight RR (random)

or sub-category n/N n/N 95% CI % 95% CI Order

01 Full papers

Hamel-Desnos 2003 38/45 17/43 28.24 2.14 [1.45, 3.16] 0

Belcaro 2003 119/129 111/123 36.93 1.02 [0.95, 1.10] 0

Subtotal (95% CI) 174 166 65.17 1.45 [0.58, 3.62]

Total events: 157 (Foam), 128 (Liquid)

Test for heterogeneity: Chi² = 21.05, df = 1 (P < 0.00001), I² = 95.2%

Test for overall effect: Z = 0.80 (P = 0.42)

02 Conference abstract

Martimbeau 2003 81/100 60/100 34.83 1.35 [1.12, 1.63] 0

Subtotal (95% CI) 100 100 34.83 1.35 [1.12, 1.63]


Test for heterogeneity: not applicable


Total (95% CI) 274 266 100.00 1.39 [0.91, 2.11]


Test for heterogeneity: Chi² = 30.48, df = 2 (P < 0.00001), I² = 93.4%


0.1 0.2 0.5 1 2 5 10

Favours liquid Favours foam

Review: Foam sclerotherapy for venous disease

Comparison: 02 Foam versus surgery (with stripping)

Outcome: 01 Complete occlusion of veins

Study Foam Surgery RR (random) Weight RR (random)

or sub-category n/N n/N 95% CI % 95% CI Order

Bountouroglou 2006 23/29 18/23 37.57 1.01 [0.76, 1.35] 0

Wright in press b 120/178 81/94 62.43 0.78 [0.69, 0.89] 0

Total (95% CI) 207 117 100.00 0.86 [0.67, 1.10]

Total events: 143 (Foam), 99 (Surgery)

Test for heterogeneity: Chi² = 2.63, df = 1 (P = 0.11), I² = 61.9%


0.1 0.2 0.5 1 2 5 10

Favours surgery Favours foam

6.2 Healing of venous ulcers

In the English language studies, three case series46,51,53 involving 216 patients and two case

reports67,68 involving three patients reported data on healing of venous ulcers. All studies

used polidocanol foam. The rate of longer-term (>30 days) ulcer healing rate in the case

series ranged from 76.4% to 100% (Table 17).

In the conference abstracts, one RCT72 reported that 15 (75%) of 20 ulcers healed in the foam

sclerotherapy group compared with 9 (45%) of 20 in the compression group.

63

6.3 Recurrence of venous disease and development of new veins


In the English language studies, one RCT29 involving 45 patients treated by foam

sclerotherapy reported venous recanalisation at one year after treatment, with a rate of 4.4%.

This was lower than that in the liquid sclerotherapy group but not statistically significant

(relative risk 0.5, 95% CI 0.1 to 2.5). One non-randomised comparative study41 involving 37

patients treated by foam sclerotherapy reported venous disease recurrence also at one year

after treatment, with a rate of 8.1%, which was also lower than that in the liquid

sclerotherapy group (relative risk 0.32, 95% CI 0.1 to 1.1) (Table 16). One case series53

involving 105 patients reported recurrence of ulcers at a rate of 5.7% at two year follow-up

(Table 17).

One RCT21 involving 129 patients and two case series44,63 involving 186 patients and 116

limbs respectively treated with foam sclerotherapy reported development of new veins

(Tables 16 and 17). In the RCT, 51.2% of patients developed new veins ten years after foam

sclerotherapy, which was marginally higher than the surgery (ligation) group (relative risk

1.4, 95% CI 1.02 to 1.8) and surgery (ligation) combined with liquid sclerotherapy group

(relative risk 1.4, 95% CI 1.1 to 1.9). The development of new veins in the two case series

varied from 0.4% to 5.9% at two years or more following treatment.

Conference abstracts

In the conference abstracts, recurrence was reported in one RCT71 involving 100 patients and

in two case series81,94 involving 35 veins and 20 patients respectively treated with foam

sclerotherapy, with the rates varying from 0.1% to 50% at a follow-up of three months or

longer. Recanalisation was reported in three case series,83,91,98 with rates ranging from 8.1%

to 12.0% at follow-up of three months or longer (Table 17).


In the non-English language studies, one non-randomised comparative study102 and two

case series reported data on recanalisation with rates ranging from 4.1% to 12.5% at a follow-

up of six months or longer (note in Table 16 and 17).

64

Table 16 Efficacy: complete occlusion of veins, recurrence of venous disease and development of new veins (comparative studies)

Complete occlusion of veins Recurrence or developed new veins

Foam sclerotherapy

Comparator Relative

Risk (95% CI) Foam

sclerotherapy Comparator

Relative Risk (95% CI)


Comparator

No. % No. % No. % No. %

RCT English language full text studies Alos 200620 1y Liquid sclerotherapy (1-

2.5% POL) 67/71 94.4 38/71 53.5 -

Belcaro 200321 10y Liquid sclerotherapy (STS) 119/129 92.2 111/123 90.2 1.02 (0.95, 1.10) 66/129 51.2 69/123 56.1 0.9 (0.7, 1.2) Liquid sclerotherapy (STS

high dose) 103/112 92.0 1.0 (0.9, 1.1) 55/112 49.1 1.0 (0.8, 1.3)

Surgery (ligation) 118/132 89.4 1.03 (0.96, 1.11) 50/132 37.9 1.4 (1.02, 1.8) Surgery (stab avulsion) 85/122 69.7 1.3 (1.2, 1.5) 50/122 41.0 1.3 (0.95, 1.6) Surgery (ligation+STS

solution) 123/131 93.9 1.0 (0.9, 1.1) 48/131 36.6 1.4 (1.1, 1.9)

Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion)

23/29 79.3 18/23 78.3 1.0 (0.8, 1.4)

Hamel-Desnos 200329 1y Liquid sclerotherapy (3% POL)

38/45 84.4 17/43 39.5 2.1 (1.5, 3.2) 2/45 4.4 4/43 9.3 0.5 (0.1, 2.5)

Wright in press a36 1y ‘Home made foam or liquid sclerotherapy (1% POL)

243/259 93.8 111/125 88.8 1.1 (1.0, 1.1)

Wright in press b36 1y Surgery (ligation, stripping, avulsion)

120/178 67.4 81/94 86.2 0.8 (0.7, 0.9)

Conference abstracts Martimbeau 200371 1y Liquid sclerotherapy 11/25 (LSV)

21/25 (SSV) 24/25 (perfora. v.) 25/25 (tributaries)

44.0 84.0 96.0 100

3/25 (LSV) 12/25 (SSV) 23/25 (perforat. v.) 22/25 (tributaries)

12.0 48.0 92.0 88.0

3.7 (1.2, 11.6) 1.8 (1.1, 2.7) 1.0 (0.9, 1.2) 1.14 (0.98, 1.31)

Total: 81/100 patients 81.0 60/100 patients 60.0 1.4 (1.1, 1.6) 1/100 1.2 2/100 1.7 0.5 (0.1, 5.4)

65

Table 16 Efficacy: complete occlusion of veins, recurrence of venous disease and development of new veins (comparative studies) CONT

Complete occlusion of veins Recurrence or developed new veins

Foam sclerotherapy

Comparator Relative

Risk (95% CI) Foam

sclerotherapy Comparator

Relative Risk (95% CI)


Comparator

No. % No. % No. % No. %

Non-randomised comparative studies English language full text studies Yamaki 200441 1y Liquid sclerotherapy (POL) 25/37 67.6 7/40 17.5 3.9 (1.9, 7.8) 3/37 8.1 10/40 25.0 0.3 (0.1, 1.1) Conference abstracts Gobin 200374 3m Liquid sclerotherapy 153/157 (LSV)

42/43 (SSV) 3/3 (LSV+SSV) Total: 198/203 patients

97.5 97.7 100 97.5

69/72 (LSV) 20/21 (SSV) 1/1 (LSV+SSV) 90/94 patients

95.8 95.2 100 95.7

1.02 (0.96, 1.07) 1.0 (0.9, 1.1) - 1.02 (0.97, 1.07)

25/26 (Recurrent) 96.2 18/19 (Recurrent) 94.7 1.0 (0.9, 1.2)

Gonzalez 200588 1m Foam sclerotherapy (3% POL+low molecular weight heparin)

8/10 80.0 10/10 100 0.8 (0.6, 1.1)

Grondin 2003a77 3 yrs Foam 1-3 sessions NR (LSV) (SSV)

85 80

NR(LSV) (SSV)

88 89

-

Surgery NR (LSV) (SSV)

85 73

-

Liquid sclerotherapy NR (LSV) (SSV)

75 82

-

Grondin 2003b76 1m Liquid sclerotherapy 80/86 (LSV) 35/38 (SSV)

93.0 92.1

68/82 (LSV) 34/40 (SSV)

82.9 85.0

1.12 (1.0, 1.26) 1.1 (0.9, 1.3)

Total: 115/124 patients 92.7 102/122 patients 83.6 1.11 (1.01, 1.22) Non-English language studies Demagny 2002 102 6m STS liquid 101/150 vein (LSV)

42/50 vein(SSV) 67.3 84

71/150 vein(LSV) 32/50 vein (SSV)

47.3 64

1.4 (1.2, 1.7) 1.31 (1.03, 1.67)

16/150 2/50

10.7 4.0

33/150 7/50

22.0 14.0

Notes: 1. The RCT by Alos and colleagues20 was a within-patient study, therefore the relative risk was not calculated. 2. Foam sclerotherapy in the RCT by Bountouroglou and colleagues26 was combined with saphenofemarol junction ligation. 3. Complete occlusion of veins:

(1) Reported as ‘required new treatment after 10 years’ in the RCT by Belcaro,21 results in the table were calculated by (total number of patients – number of patients requiring new treatment); (2) Reported as ‘elimination of reflux’ in the RCT by Hamel-Desnos and colleagues.29 (3) Grondin and colleagues77 reported outcome as ‘successful treatment’. (4) Number of patients in the study by Demagney was not reported, 254 patients (400 veins) in total; reported as success rate.102

4. Healing of venous ulcer: a RCT by Rybak72 reported 15/20 (75%) ulcers healed with foam sclerotherapy compared with 9/20 (45%) with compression. 5. Recurrence or development of new veins:

(1) Reported as ‘developed new veins’ in the RCT by Belcaro and colleagues;21 (2) Reported as ‘recanalisation’ in the RCT by Hamel-Desnos and colleague;29 (3) Reported as ‘recurrence’ in the RCT by Martimbeau;71 (4) reported as ‘recurrence’ in the non-randomised comparative study by Yamaki and colleagues;41 (5) Number of patients in the study by Demagney was not reported, 254 patients (400 veins) in total; reported ‘recanalisation’.

66

Table 17 Efficacy: complete occlusion of veins, healing of venous ulcers, recurrence of venous disease and development of new veins (case series)

Study id Length of follow-up

Sclerosant Short-term (≤ 30d) n/N %

Longer-term (> 30d) n/N %

Complete occlusion of veins English language full text studies

Barrett 200444 2y 3% STS or 1-2.5% POL 68/99 limbs (<10mm) 13/17 limbs (>10mm)

68.7 76.5

Bergan 200646 60d 1-3% POL 259/328 limbs 79.0 Cabrera 200151 4-6y POL (0.65-3% Lauromacrogol

400 microfoam) 400/500 limbs (LSV)

215/265 veins (recurrent v.) 80.0 81.1

Cavezzi 200256 1m STS 61/83 73.5 Cavezzi 199954 12-43w 1-3% STS, 1-4% POL 101/106 95.3 Coleridge Smith, in press58 6m 1% POL, 1% STS or 3% STS 318/363 veins (LSV)

116/141veins (SSV) 87.6 82.3

Hamada 200660 1y 0.5 - 5% ethanolamine oleate 88/112 veins 78.6 McDonagh 200263 2-6y 3% STS 165/168 98.2 Kakkos 200662 3w 3% STS 39/45 legs 86.7 Padbury 200464 6m STS 9/15 60.0

Conference abstracts Baker 200678 N/R POL 196/229 limbs 85.6 Tessari 200498 3m STS 394/532 74.1 Bhowmick 200179 2y POL (Varisolve®) 32/35 91.4 Cavezzi 200380 1y 0.5-1% STS or 1-2% POL 100/100 limbs 100 Vin 200599 1y 3% POL 238/280 limbs 85.0 207/280 limbs 73.9 McCollum 200191 3m POL (Varisolve®) 36/41 87.8 Coleridge Smith 200381 1y 1% POL (Varisolve®) 23/25 veins (LSV)

5/10 veins (SSV) 92.0 50.0

Schadeck 200195 N/R 3% STS 0.2-0.5% POL 0.2-0.5% POL

114/118 veins (Saphenous/great collateral vein) 99/100 veins (reticular veins) 92/100 veins (Telangiectatic)

96.6 99.0 92.0

Mackay 200290 1y STS or POL 14/14 limbs 100 Sierra 200296 5y POL 338/360 93.9 Forlee 200683 Mean 6m 0.5-3% POL 42/86 legs 48.8 Nitecki 200593 Mean 10m 3% POL 364/423 86.1 Gonzales 200588 2y 3% POL 91/106 veins (LSV)

62/69 veins (SSV) 85.8 89.9

Frullini 200184 3-5y STS NR 54.0 POL NR 77.0

67


CONT




Non-English language studies Breu 2004103 1-3y POL 332/342 97.1 Frullini 2000106 3-4% POL or STS 1-3% NR (LSV)

NR (SSV) NR (Reccurent VV)

80.5 88.3 95.7

Hamel-Desnos 2005108 2y POL (1% or 3%) 144/158 91.1 115/144 79.9 Lucchi 2003111 6m 3% STS or 8% or 12%

polyiodine iodine) 114/118 96.6

Schadeck 2004114 mean 14.7m POL (3% Lauromacrogol 400 microfoam)

101/108 93.5

Sica 2005116 1y 1% STS 142/148 95.9 93/107 veins (LSV) 37/41 veins (SSV)

86.9 90.2

Sica 2003115 2y 1% STS 79/97 veins (LSV) 25/29 veins (SSV)

81.0 87.0

Uhl 2005118 N/R POL (0.5% or 3%) 105/140 75.0 Wildenhues 2005119 2y POL (1% or 3%) 203/213 95.3 187/213 87.8

Healing of venous ulcers English language full text studies

Bergan 200646 60d 1-3% POL 28/28 100 Cabrera 200453 > 6m 0.27-1% POL 98/116 84.4 Cabrera 200151 4-6y POL (0.65-3% Lauromacrogol

400 microfoam) 55/72 76.4

Recurrence or developed new veins English language full text studies

Barrett 200444 2y 3% STS or 1-2.5% POL 4/99 limbs (<10mm) 1/17 limbs (>10mm)

4.0 5.9

Cabrera 200453 2y 0.27-1% POL 6/105 5.7 McDonagh 200263 Mean 3.4y 3% STS 1/186 0.5

68


CONT




Conference abstracts Coleridge Smith 200381 1y POL (Varisolve®) 2/25 veins (LSV)

5/10 veins (SSV) 8.0 50.0

Forlee 200683 Mean 6m 0.5-3% POL 7/86 limbs 8.1 McCollum 200191 3m POL (Varisolve®) 5/41 12.2 Sadoun 200394 2y 3/20 15.0 Tessari 200498 3m STS 43/532 8.1

Non-English language studies Breu 2004103 6w POL 1/342 0.3 Hamel-Desnos 2005108 2y 1% or 3% POL 18/144 12.5

Notes: 1. Six limbs reported in case reports by De Waard and colleagues;67 and Lloret and colleagues68 were occluded by foam sclerotherapy; one limb in the case report by Van Neer and colleagues69 was reported as ‘eliminated reflux’.

2. Complete occlusion of veins: (1) Reported as ‘obliteration of the vessels or antegrade flow’ in the case series by Cavezzi and colleagues.56 (2) Reported as ‘stable sclerofibrosis or re-canalisation without reflux’ in the case series by Cavezzi and colleagues.54 (3) Frullini84 reported the total number of patients (21) but not for the subgroups separately; (4) Gonzales88 reported as reflux after two years of treatment, rate in the table was calculated by (1- percentage of reflux); (5) Hamel-Desnos108 reported as successful rate (no measurement provided); (6) Nitecki93 reported the outcome as successful treatment judged by ultrasound and patient satisfaction; (7) Frullini106 and Hamel-Desnos108 both reported their short-term results and long-term results as success rate respectively; (8) Lucchi111 reported results as elimination of reflux.

3. Recurrence or development of new veins: (1) Reported as ‘developed new varicosities’ in the case series by Barrett and colleagues;44 (2) Reported as ‘recurrence of ulcer’ in the case series by Cabrera and colleagues;53 (3) Reported as ‘neovascularisation’ in the case series by McDonagh and colleagues;63 (4) Reported as recanalisation in the series by Forlee,83 Hamel-Desnos,108 McCollum91 and Tessari;98 (5) Reported as recurrence in the series by Coleridge Smith81 and Sadoun;94 (6) Reported as ‘recanalisation’ in the case series by Breu103 and Hamel-Desnos.108

4. Three venous ulcers reported in case reports by De Waard and colleagues67 and Lloret and colleagues68 were healed.

69

6.4 Quality of life, disappearance of varicosities and changes of CEAP score

For quality of life, we included data on patient satisfaction, time to return to normal activity,

and the Aberdeen Vein Questionnaire score change. Table 18 summarises the data on

quality of life and changes of CEAP score.

In the English language studies, four RCTs20,26,31,36 reported quality of life. Two RCTs31,34

reported data on disappearance of varicosities (measured as ‘clearance of vessels’) (long-

term) using foam sclerotherapy compared with polidocanol liquid. Both studies used

analogue scales and reported no significant difference in scores on clearance of vessels

between foam and liquid sclerotherapy. Rao and colleagues34 also compared the

disappearance of varicosities (diameter 3-6mm before treatment) (measured as ‘clearance of

vessels’) between foam made of 0.5% STS and 1% polidocanol. Both groups scored a mean

of 3.75 using an analogue scale 0-5 (5 represents complete disappearance of vessels). One

study reported that, following foam sclerotherapy, patients required a median of two days

to return to normal activity, significantly less than the median 13 days following

surgery.20,26,31,36

In the conference abstracts, one non-randomised comparative study76 reported clinical

improvement as an early result in the study, in which the comparator was liquid

sclerotherapy. In patients with incompetent saphenous trunks, more than 65% of the foam

sclerotherapy group compared with 4%of the liquid sclerotherapy group achieved a greater

than 50%improvement in clinical and symptomatic score.

No non-English language studies reported outcomes under this category.

In the English language studies, one case series58 reported change of CEAP score six months

after treatment. The severity of venous disease assessed by CEAP score was alleviated

compared with baseline. No studies from conference abstracts reported change of disease

severity measured by CEAP score.

6.5 Procedure time

Only one RCT, by Bountouroglou and colleagues,26 available as an English language full text

study, reported data on operation time (foam sclerotherapy plus ligation was 45 minutes

70

versus 85 minutes for ligation plus stripping plus avulsion). The foam sclerotherapy was

combined with sapheno-femoral junction ligation. No studies from conference abstracts

reported operation time.

71

Table 18 Quality of life, disappearance of varicosities and changes of CEAP score (comparative studies)

Quality of life Study

Length of follow-up

Comparator Outcome measurements

Foam sclerotherapy

Comparator

RCTs Alos 200620 1y Liquid sclerotherapy (POL) Patient satisfaction: scale 0-10, mean (SD) 7.4 (1.2) 7.2 (1.5) Bountouroglou 200626 3m Surgery (ligation+stripping+avulsion) Time to return to normal activity: Median (range): 2 days (0-6) 8 days (15-20) 3m Surgery (ligation+stripping+avulsion) Aberdeen Vein Questionnaire:score change, median Baseline: 15.4

Follow-up: 9.3 Baseline: 26.1 Follow-up: 14.1

3m Surgery (ligation+stripping+avulsion) CEAP score change: Median (range) Baseline: 4 (2-6) Follow-up: 1 (0-5)

Baseline: 4 (2-6) Follow-up: 1 (0-5)

Kern 200431 5w+1m Liquid sclerotherapy (0.25% POL) Patient satisfaction: scale 0-100, mean (95% CI) 60.2 (53.7-66.7) 59.3 (52.3-66.3) Kern 200431 5w+1m Liquid sclerotherapy (100% chromated

glycerine) 69.1 (62.4-75.7)

Wright in press a36 1y Surgery (ligation, stripping, avulsion) Time to return to normal activity (median) 2 days 13 days Wright in press b36 1y Foam or liquid sclerotherapy Time to return to normal activity (median) 1 day 1 day Non-randomised comparative studies Grondin 2003b76 1m Liquid sclerotherapy Clnical and symptomatic score, >50% improvement 65.3% 4.1%

Notes: 1. All the RCTs were English language studies; the non-randomised comparative study was available as a conference abstract. 2. The RCT by Alos and colleagues20 was a within-patient study.

3. The foam sclerotherapy in the RCT by Bountouroglou and colleagues26 was combined with sapheno-femoral ligation.

72

6.6 Summary of efficacy

Table 19 provides an overall summary of the number of English language studies,

conference abstracts and non-English language studies reporting the efficacy of foam

sclerotherapy. Eighteen studies (6 English language full text studies, 12 conference abstracts

or non-English language studies) reporting data by number of limbs or veins but not at the

patient level were not included in the table for ease of interpretation. The median rate of

venous occlusion was 84.4 in both the English language RCTs and the English language case

series with rates of 60.0% or higher across all studies. The rates of ulcer healing were all 75%

or higher. The rate of recurrence or development of new veins varied across studies with a

range of 0.5% to 51.2%. The rate of 51.2% was reported by the study with the longest follow-

up (10 years).

In the meta-analysis of RCTs, venous occlusion favoured foam compared with liquid

sclerotherapy, and favoured surgery (ligation, stripping and avulsion) compared with foam

sclerotherapy, but neither result was statistically significant. In respect of recurrence and

development of new veins, in a 10 year RCT, foam sclerotherapy had (marginally)

significantly higher rates compared with surgery (ligation) and surgery (ligation combined

with liquid sclerotherapy).

73

Table 19 Summary of studies reporting efficacy of foam sclerotherapy for venous disease

No. of studies

n/N Median rate (%)

(range)

Complete occlusion of treated veins

RCT (English language studies) 521,26,29,36 543/640 84.4 (67.4, 93.8)

Non-randomised comparative studies (English language studies)

141 25/37 67.6

Case series (English language studies) 454,56,58,63,64 336/372 84.4 (60.0, 98.2)


1471,74,76,88,90,91,93,96,98,102,103,108,111,114,118,119 2488/2858 87.8 (74.1, 97.1)

Healing of venous ulcers

Case series (English language studies) 346,51,53 181/216 84.5 (76.4, 100.0)


172 15/20 75.0

Recurrence or development of new veins

RCT (English language studies) 221,29 68/174 27.8 (4.4, 51.2)

Non-randomised comparative studies (English languages studies)

141 3/37 8.1

Case series (English language studies) 253,63 7/291 3.1 (0.5, 5.7)


471,91,94,98,103,108 52/693 10.1 (1.0, 15.0)

Notes:

1. The report by Wright and colleagues consisted of two studies (RCTs).

74

7 DISCUSSION

This systematic review was prompted by concerns regarding the safety of foam

sclerotherapy.

In this review, we identified one registry report from France involving 12,173 treatment

sessions and 66 studies (26, 24, and 16 available as English language full text studies, English

language conference abstracts, and non-English language studies, respectively) involving

over 8000 patients in total. All the included studies date from 2000 onwards. A substantial

amount of evidence was available as conference abstracts and French or German language

reports, suggesting that foam sclerotherapy is still a novel technique and also more

commonly used in Europe.

The foam sclerotherapy techniques used were heterogeneous. Polidocanol was used by

most studies, although it is a weak sclerosing agent. A higher concentration and dose has to

be used to achieve the same sclerosing effect as STS. No studies compared polidocanol with

STS. An on-going RCT comparing 1% and 3% polidocanol is due to be completed by the

end of 2006. The strength of polidocanol and STS used both ranged from 0.25 – 3%, with the

foam dose increasing as the size of vein increased. Other sclerosing agents used for

producing foam included 0.3-5% ethanolamine oleate and polyiodine iodine which were

rarely used. Most studies used ultrasound guidance for identifying treated veins and

monitoring foam injection and/or foam flow. The Tessari technique was the most

commonly used foam-producing technique in the included studies. In most studies, one

injection was given during each session.

7.1 Safety: serious adverse events

7.1.1 Anaphylaxis

In all the included studies there were no reported cases of anaphylaxis.

7.1.2 Arterial events

Arterial events, particularly stroke and myocardial infarction (MI), can be life threatening.

One case of stroke was reported in a conference abstract83 with details given in a case

75

report;82 one MI was reported in an unpublished case report (Personal communication: P

Kritzinger, York Vein and Laser Clinic, Newmarket, Ontario). Five cases of transient

‘embolic’ events, not otherwise described, were reported in a conference abstract involving

181 patients.78 A rate of 0.2% for transient ischaemic attacks was reported in another

conference abstract (number of patients not stated).77

One possible explanation for arterial events is the existence of a Patent Foramen Ovale

(PFO), especially with right-to-left shunt. The prevalence of PFO is reported as around

10%.124 In a patient with PFO, injected foam particles could potentially pass from the right

side of the heart to the circulatory system through the PFO, leading to occlusion in the

cerebral or coronary arteries, or arteries in other organs. The patient who suffered stroke82,83

shortly after the injection of 20ml 0.5% polidocanol made foam (mixed with air) scored 7/42

on the National Institute of Health Stroke Severity Scale. A transoesophageal

echocardiogram revealed an 18-mm PFO with right-to-left shunt. However, in the patient

who suffered a myocardial infarct about thirty minutes after the injection, creatine kinase

was 800 IU, a right-to-left shunt was not demonstrated by echocardiography (type of

echocardiogram not specified). No other diagnostic results for confirmation of a myocardial

infarction were reported. (Personal communication: P Kritzinger, York Vein and Laser

Clinic, Newmarket, Ontario).

7.1.3 Pulmonary embolism and deep vein thrombosis

Pulmonary embolism usually arises from a venous thrombosis in the pelvis or legs. The

thrombus passes through the venous system and the right side of the heart before lodging in

the pulmonary circulation. Known risk factors include any causes of immobility or

hypercoagulability. Rarely, pulmonary embolism is caused by air or fluid embolism.

In this review pulmonary embolism was statistically rare and DVT was uncommon (< 5%).

Some studies attempted to prevent foam entering the deep vein system by elevating treated

legs to a certain degree or by manually pressing on the sapheno-femoral junction.

Investigating the effectiveness of these techniques was, however, outwith the scope of this

review.

76

7.1.4 Cutaneous necrosis and ulceration

Cutaneous necrosis and ulceration were uncommon (< 3%). One possible explanation for

the development of cutaneous necrosis and ulceration is the direct contact of the sclerosing

agent with cutaneous tissue, with the strong sclerosing effect causing tissue damage. In an

attempt to avoid such damage some studies used catheters or butterfly needles for foam

injection instead of direct puncture.


If the sclerosant is accidentally injected into an artery, its intense sclerosing effect can

occlude the artery, leading to severe tissue necrosis and even the requirement for

amputation. No intra-arterial injections were reported in the included studies. This may be

a benefit of the introduction of ultrasound guidance in identifying treated veins and

monitoring foam injection and flow.

One case of grand mal epileptic fit was reported in the unpublished case report by

Kritzinger (Personal communication: P Kritzinger, York Vein and Laser Clinic, Newmarket,

Ontario). The cause was uncertain and no information was provided on whether the patient

had a previous history of epilepsy.

7.2 Safety: adverse events

7.2.1 Visual disturbance

Visual disturbance was uncommon (< 6%). No long-term visual impairment was reported.

One possible explanation for visual disturbance, with or without headache, is that the

vasospastic effect of the sclerosing agent passing through a PFO leads to transient retinal or

cerebral oligaemia. However, no studies reporting visual disturbance recorded the existence

of PFO.

77

7.2.2 Central nervous system disturbance

Only a few studies reported central nervous system disturbance, including transient

confusion and headache. The occurrence of transient confusion was rare (< 2%). Headache

was more common (rates ranged from 0 to 23.0%).

7.2.3 Other systemic symptoms

Other systemic symptoms, including coughing, chest tightness/heaviness, panic attack and

malaise, vasovagal, rarely occurred (< 3%). In one study voluntary coughing after foam

injection was suggested to facilitate the clearance of bubbles in the right side of the heart.

7.2.4 Local effects

‘Minor’ vein thrombosis (rates ranged from 0 to 17.6%), thombophlebitis (rates ranged from

0 to 45.8%), and skin matting/pigmentation/staining (rates ranged from 0 to 66.7%), were

relatively common occurrences and their incidence was similar to those in comparator

groups, other than in one RCT36 where the risk of skin matting/pigmentation/staining was


Mixing low molecular weight heparin with the sclerosing foam or giving heparin injections

for several days before and after treatment were suggested as ways of minimising the risk of

‘minor’ vein thrombosis.77 Some researchers, however, did not consider mild

thrombophlebitis to be an adverse event, classing it as part of the inflammatory effect of

sclerotherapy.51 Anti-inflammatory drugs or adequate bandaging were suggested in order to

reduce the occurrence of thrombophlebitis.51

Local neurological injury was rare (<1%). Pain provoked by injection or long-term pain

localised at the area sclerosed was reported as ranging from 0.6 to 41.0%.

7.2.5 Other adverse events

Other adverse events including haematoma, allergic reaction, extravasation and lower back

pain occurred at a range of 0 to 11.2%.

78

7.3 Efficacy

The complete venous occlusion rates with foam sclerotherapy were over 50% in almost all of

the included studies, with a median rate across studies of over 80% (range of follow-up three

weeks to over three years). Meta-analysis of three heterogenous (I-square 93.4%) RCTs

comparing foam with liquid sclerotherapy and two RCTs (I-square 61.9%) comparing foam

with surgery failed to identify any significant difference in occlusion rates between foam

and comparators (RR compared to liquid slerotherapy: 1.39, 95% CI 0.91 to 2.11; RR

compared to surgery involving stripping: 0.86, 95% CI 0.67 to 1.10).

Healing of venous ulcers was achieved by occluding the associated veins. The rate of

healing of venous ulcers with foam sclerotherapy was over 75% in almost all studies, with a

median rate of over 80%.

The rates of recurrence of venous disease or development of new veins after foam

sclerotherapy varied across studies with a range of 0.4% to 8.1% at two years or over after

treatment, with no apparent pattern emerging according to length of follow-up. In the ten-

year RCT, the occurrence of new varicose veins following foam sclerotherapy was 51.2% and

significantly higher than those in comparator groups (relative risk (95% CI): to ligation, 1.4

(1.02 to 1.8); to ligation combined with liquid sclerotherapy 1.4 (1.1 to 1.9)).

Patients undergoing foam sclerotherapy required significantly fewer days to return to

normal activity compared with those undergoing open surgery. There were no significant

differences between foam or liquid sclerotherapy or surgery for patient satisfaction and

change of disease severity as measured by the Aberdeen Vein Questionnaire and CEAP.

7.4 Assumptions, limitations, and uncertainties

A substantial amount of evidence was available as conference abstracts and non-English

language reports. Safety and efficacy data were extracted for non-English language studies

and conference abstracts but these types of publication were not quality assessed and their

evidence should be interpreted with caution, as should the results of any analyses

combining these types of publications with full text English language studies. In general,

however, the results from conference abstracts and non-English language studies were

similar to those of English language full text studies (see result tables).

79

The methodological quality of the included RCTs was generally low. In most studies it was

unclear whether treatment allocation had been concealed and in most studies it was unclear

whether outcome assessors were blinded. Only one study conducted an intention to treat

analysis. In studies comparing foam sclerotherapy with open surgery blinding of patients

was not possible. One trial26 had very different baseline disease severity scores between

patient groups, suggesting inadequate randomisation.

Much of the evidence consisted of case series, which are more prone to systematic biases

than other study designs such as RCTs. In particular, selection bias in the type of

participants included, not adjusting findings for confounding factors (e.g. severity of venous

disease, age, comorbidities such as diabetes or other illness, and withdrawal rates) may

affect the reliability and size of the treatment effect in case series.

Many of the concerns expressed about foam sclerotherapy relate to reports of infrequently

occurring but serious adverse events. Infrequent adverse events are more likely to be

identified in large case series. The sample sizes of most of the included case series were

relatively large (>100 patients, see table 11). However, as these events are so infrequent their

estimated event rates may still be prone to random error.

Adverse event rates for each outcome were summarised across studies by presenting

medians and ranges, as standard approaches to generating confidence intervals for event

rates would have produced overly precise and potentially misleading estimates. For ease of

interpretation, 22 studies available as conference abstracts or non-English language studies

reporting the number of limbs or veins were not included in calculating the medians and

ranges. Details of these studies were presented separately; their results were similar to the

studies that did contribute data to medians and ranges.

Most studies reported results after more than 30 days follow-up, considered to be a

sufficient length of time for observing adverse events. Few studies reported outcomes at

more than three years following treatment and therefore data on longer-term efficacy were

limited. One RCT reported the development of new veins requiring treatment at a follow-

up period of 10 years. No studies reported methods of follow-up and details of how

outcomes were ascertained. The completeness of follow-up varied across studies. A few

prospective case series reported high dropout rates of over 30%.

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The results were considered generalisable as the majority of studies recruited participants

from routine practice without restriction on the type and severity of venous disease or other

patient characteristics.

Categorising the reported outcomes was problematic. One reason for this is that the

terminology for some outcomes was not used consistently across the included studies, for

example ‘minor’ vein thrombosis was reported variously as microthrombi or

sclerothrombus at superficial vein, and thrombophlebitis was reported as cutaneous

inflammation or varicophlebitis. The causes of some outcomes were unclear, for example

whether visual disturbance was due to retinal arterial spasm or retinal emboli.

The reporting of efficacy outcomes varied between studies. We grouped similar outcomes

by consensus. Successful treatment was classed as complete venous occlusion, elimination

of reflux (if complete venous occlusion was not reported) and success rate (if complete

venous occlusion or elimination of reflux were not reported) were used for judging

successful treatment. Veins remaining patent, partial occlusion, partial occlusion with

minimal retrograde flow, and having residual segments not occluded were classed as

treatment failure. In three studies not reporting occlusion rate but rather treatment failure

(as defined by the authors), the success rate was calculated (as 1 – rate of treatment failure).

Participant quality of life outcomes were not uniformly reported across the included studies,

for example for patient satisfaction some authors presented a mean score while others

reported the percentage of participants satisfied. Quality of life outcomes reported by case

series were not included as they were considered to be largely uninformative, having no

control group for comparison.

Comparative data for the outcome of complete occlusion of treated veins were limited, with

only three small trials of foam versus liquid sclerotherapy and two trials of foam

sclerotherapy versus open surgery. A meta-analysis of foam versus liquid sclerotherapy or

open surgery for complete venous occlusion showed no statistically significant differences

between treatments. The RCTs were considered too small for any meta-analysis to identify

differences in rare adverse events between treatments.

81

The effect of patient age on the safety and efficacy of foam sclerotherapy was unclear as no

studies presented data by age group.

Treatment of recurrent venous disease after previous treatment or treatment of complicated

venous disease may increase the risk of adverse events. However this was not assessed as

few studies reported the results of recurrent venous disease. Few studies reported the

results of ‘minor’ vein disease separately, therefore, a comparison of the risks between

treating ‘major’ and ‘minor’ vein disease was not undertaken.

Despite an extensive review there were insufficient data to determine the optimal volume of

foam, concentration, and foam-producing technique to minimise the risks associated with

the procedure and maintain efficacy.

The relative ease of administration of this treatment, in relation to surgery, however, may

mean that it may increase the overall number of patients who consider interventional

treatment for varicose veins. However, uncovering additional health need, as opposed to

substituting vein surgery alone, was outside the remit of this review.

Foam sclerotherapy requires a certain level of skill and training, which may impact on the

safety and efficacy of the procedure. However only one prospective case series gave details

of the clinical experience and skill of the practitioner. Procedure protocols differed between

studies with respect to type, strength and dose of sclerosing agent, foam-producing

technique, and number of injections at each session. As such it was not possible to compare

the different sclerosing agents in terms of their safety and efficacy.

The evolution of foam sclerotherapy technique to include physically resolvable gas may

have improved its safety and efficacy. Four case series used CO2 based foam, one of which

was an English language full text study, but these limited data were insufficient to fully

assess the impact of using CO2 based foam, and there were also limited data to assess the

effects of adding low molecular weight heparin injections, elevating legs prior to treatment

or increasing the pressure at the sapheno-femoral junction.

Some adverse events, such as stroke, myocardial infarction, other arterial events, visual

disturbance, and headache may be more common in people with a PFO. However only two

included studies (both case reports involving four patients in total) examined the existence

82

of PFO82 (Personal communication: P Kritzinger, York Vein and Laser Clinic, Newmarket,

Ontario).

One study125,126 and one animal study127 were identified that investigated the

pathophysiology of foam. In the human study, Morrison and colleagues125 identified foam

particles in the right heart of all 49 patients within 10 to 30 seconds after foam injection. In

four of seven patients in whom a PFO had already been detected, using transcranial Doppler

Ultrasound during foam sclerotherapy identified a few high-density transient signals in the

middle cerebral artery.126 The emboli were identified within 10 cardiac cycles.125 In the

animal study by Eckmann and colleagues,127 larger air-based bubbles were more likely to

obstruct arteriolar vessels and block blood flow than smaller, more uniform sized physically

resolvable gas-based bubbles. Larger numbers of bubbles were more likely to cause an

arterial accident than smaller numbers of bubbles.

When considering the occurrence of post-procedural events of low or very low frequency,

the potential of chance occurrence (i.e. due to “background” incidence) due to pathogenic

mechanisms unrelated to foam sclerotherapy treatment should not be discarded. This is

very difficult to quantify, but overall, events like CVA and myocardial infarction are

relatively common in the general population. As a whole, the reported associations with

adverse events do not elucidate the underlying pathophysiological mechanisms, and some

of the reported adverse events might not have been caused by the treatment. However these

adverse events occurred within around 30 minutes of the procedure, therefore a causal effect

cannot be ruled out.

83

8 CONCLUSIONS

Implications for the NHS

Venous disease of the lower limbs, including primary and chronic venous insufficiency, is

common. Although widely available in some European countries, the uptake of foam

sclerotherapy in the UK is not known. However it is a potentially useful treatment for both

main trunk and minor vein disease, and can be conducted as an outpatient procedure

without the requirement for general anaesthesia. This could have implications for the NHS

in terms of releasing theatre time and space for other surgical procedures. In addition, foam

sclerotherapy can be delivered in an outpatient setting, and possibly also a primary care

setting, as long as the surgeon is appropriately trained and adequate diagnostic and

monitoring facilities are available. However, for foam treatment several sessions may be

required.

Safety

Serious adverse events associated with foam sclerotherapy, including arterial events

including stroke and myocardial infarction, grand mal epileptic fit, pulmonary embolism,

and deep vein thrombosis were statistically rare, reported in rates of less than 6% (range 0 –

5.7). Cutaneous necrosis and ulceration were reported in rates of less than 4% (range 0 –

3.6).

Adverse events such as visual disturbance, transient confusion, other systemic symptoms

(panic attack, malaise, coughing, chest tightness or heaviness, and vasovagal) were reported

in rates of less than 6% (range 0 to 5.9%). Occurrence of headache ranged from 0 to 23.0%.

Local adverse events were relatively common. Rates of ‘minor’ vein thrombosis ranged from

0 to 17.6%, thrombophlebitis ranged from 0 to 45.8%, skin matting/staining/pigmentation

ranged from 0 to 66.7%, and pain at the site of injection ranged from 0.6 to 41.0%. Local

neurological injury ranged from 0 to 0.7%. Other adverse events including haematoma, local

allergic reaction and lower back pain ranged from 0 to 11.2%.

Risks of adverse events were not significantly different from those of liquid sclerotherapy or

open surgery, except in one study where the rate of visual disturbance was reported as

significantly higher for foam sclerotherapy compared with liquid sclerotherapy, and in

84

another study where the rate of skin matting/staining/pigmentation was reported as


Efficacy

Foam sclerotherapy appears to be efficacious in treating all types of superficial venous

disease, including both main trunk and minor vein disease. However, there was insufficient

evidence to reliably compare foam versus liquid sclerotherapy or surgery. Only six RCTs

reporting efficacy results were identified, whose follow-up period was mostly less than

three years. One six-arm RCT (n=749) comparing foam sclerotherapy with liquid

sclerotherapy and surgery (ligation, stripping, and avulsion) had a follow-up period of 10

years.

9 NEED FOR FURTHER AUDIT OR RESEARCH

The reports of studies currently available only as conference abstracts may be available as

full text studies in the near future. In the five ongoing studies (three comparative and two

case series), one RCT with 450 patients and two-year follow-up comparing foam

sclerotherapy with surgery is currently in progress in the Netherlands. Another RCT with

158 patients and about two-year follow-up comparing 3% and 1% polidocanol foam is

currently in progress in France. The sample sizes of the other three studies are all less than

200. The five ongoing studies, all with lengths of follow-up of less than three years, are due

to be completed by 2009. Further review incorporating these studies could be informative.

A period of over 30 days was considered sufficient for observing safety, but not for longer-

term efficacy. The follow-up period of the majority of the included studies was less than

three years. High quality RCTs of foam sclerotherapy compared with surgery and with

alternative minimally invasive treatments, and with a follow-up period of at least three

years, are required to determine the comparative effectiveness of foam sclerotherapy and its

optimal place in clinical practice.

85

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96 Sierra A, Redondo P, Cabrera J, Cabrera J, Jr., Garcia-Olmedo MA. Large volume microfoam therapy for recurrent variscose veins. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

97 Tessari L. Compression following trans-catheter foam sclerotherapy. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

98 Tessari L. Trans-catheter (short or long) foam sclerotherapy in the treatment of varicose veins. 5th Meeting of the European Venous Forum, Warsaw, Poland, June; 2004.

99 Vin F. Indications and outcome of greater saphenous vein foam sclerotherapy. 15th UIP World Congress, Rio de Janeiro, October; 2005.

100 Weiss R, Weiss MA. Observations on the use of foamed sodium tetradecyl sulfate for treatment of telangiectasias and reticular veins. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

101 Benigni J, Sadoun S, Thirion V, Sica M, Demagny A, Chahim M. Telangiectases and reticular veins treatment with a 0,25% aetoxisclerol foam presentation of a pilot study. Phlebologie 1999;52(3):283-90.

102 Demagny A. Comparative study into the efficacy of a sclerosant product in the form of liquid or foam in echo-guided sclerosis of the arches of the long and short saphenous veins. Phlebologie 2002;55(2):133-7.

103 Breu FX, Marshall M, Guggenbichler S. Prospective study on foam sclerotherapy. Vasomed 2004;16(4):133.

104 Creton D. Sclerotherapie a la mousee dans les recidives apres chirurgie. Seance de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June: 2005.

105 Ferrara F, Bernach HR. Needle-size and efficacy of foam sclerotherapy. Phlebologie 2005;58(3):229-34.

106 Frullini A, Cavezzi A. Echosclerosis using sodium tetradecyl-sulphate and polidocanol foam: Two years experience. Phlebologie 2000;53(4):431-5.

107 Hamel-Desnos C, Allaert FA, Benigni J, Boitelle G, Chleir F, Ouvry P et al. Foam of polidocanol 3% versus 1% in greater saphenous vein sclerotherapy: preliminary results. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

108 Hamel-Desnos C, Allaert FA, Benigni J, Boitelle G, Chleir F, Ouvry P et al. Study 3/j.polidocanol foam 3% versus 1% in the great saphenous vein: early results. Phlebologie 2005;58(2):175-82.

109 Henriet J. One year of daily application of sclerotherapy (reticular veins and telangiectases) using polidocanol foam: Feasibility, results, complications. Phlebologie 1997;50(3):355-60.

110 Henriet J. Experiment covering three years with polidocanol foam in the treatment of reticular varices and varicosities. Phlebologie 1999;52(3):277-82.

93

111 Lucchi M, Bilancini S, Tucci S. Sclerosis of the great saphenous vein: short term results. Phlebologie 2003;56(4):389-94.

112 Milleret R, Garandeau C, Brel D, Allaert FA. Foam sclerotherapy of the great saphenous veins via ultrasound-guided catheter in an empty vein: the alpha-technique. Phlebologie 2004;57(1):15-8.

113 Milleret R, Garandeau C. Sclero-mousse des axes sapheniens par long catheter sur veine vide: alph-technique. Seance de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June: 2005.

114 Schadeck M. Sclerotherapy of the small saphenous vein: how to avoid bad results? Phlebologie 2004;57(2):165-9.

115 Sica M. Treatment of varices greater than 8mm in diameter with foam echosclerotherpy and compression. Phlebologie 2003;56(2):139-45.

116 Sica M. Echoguided sclerotherapy with 1% trombovar foam via short endovenous catheter (m.s.method): results. Phlebologie 2005;58(2):161-74.

117 Stucker M, Hermes N, Altmeyer P. A pilot study: Safety and effectiveness of periulcerous foam sclerotheraphy. Vasomed 2005;17(4):138.

118 Uhl JF, Creton D. La sclerotherapi a la moussemau cours de la chirurgie des varices: indications et resultats. Seance de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June: 2005.

119 Wildenhues B. Catheter-assisted foam sclerotherapy: A new minimally-invasive method for the treatment of trunk varicosis of the long and short saphenous veins. Phlebologie 2005;34(3):165-70.

120 Benigni J, Ratinahirana H, Bousser MG. Polidocanol 400 foam injection and migraine with visual aura. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

121 Benigni J, Ratinahirana H. Polidocanol foam: migraine with aura. Phlebologie 2005;58(3):289-91.

122 Ratinahirana H, Benigni JP, Bousser MG. Injection of polidocanol foam (PF) in varicose veins as a trigger for attacks of migraine with visual aura. Cephalalgia 2003;23(8):850-1.

123 Ceulen RPM, Shadid N, Sommer A. ZonMW foam study: Stripping versus duplex guided foam sclerotherapy as treatment far the greater varicose veins. Nederlands Tijdschrift voor Dermatologie & Venereologie 2006;16(5):196-7.

124 Fischer DC, Fisher EA, Budd JH. The incidence of patent foramen ovale in 1000 consecutive patients. A contrast transesophageal echocardiography study. Chest 1995;107:1504-9.

125 Morrison N. Simultaneous echocardiography and transcranial doppler woth ultrasound foam guided sclerotherapy. American Venous Forum, 18th Annual Meeting, Miami, Florida, February; 2006.

94

126 Morrison N, Cavezzi A, Bergan J. Regarding "stroke after varicose vein foam injection sclerotherapy". J Vasc Surg 2006;44(1):124-5.

127 Eckmann DM, Kobayashi S, Li M. Microvascular embolization following polidocanol microfoam sclerosant administration. Dermatol Surg 2005;31(6):636-43.

128 Milleret R, Allaert F, Garandeau C. Comparative study of veon shrinking after closure, laser and foam endovenous procedures. Montpellier, France: Clinique St Jean; 2006

95

APPENDIX 1 SEARCH STRATEGIES

MEDLINE (1966 – May Week 2 2006) EMBASE (1980 – 2006 Week 20) (Medline In Process 23rd May

2006) Ovid Multifile Search URL: http://gateway.ovid.com/athens

1 Telangiectasis/ 2 Venous Insufficiency/ use mesz 3 exp vein insufficiency/ use emez 4 ((venous or vein?) adj3 (incomp$ or insuffic$)).tw. 5 ((venous or vein?) adj3 ulcer$).tw. 6 telangiect$.tw. 7 ((reticular or thread or spider) adj3 (vein? or venous)).tw. 8 or/1-7 9 exp Lower Extremity/ use mesz 10 exp leg/ use emez 11 (lower limb$ or lower extremit$ or leg? or calf or valves or thigh?).tw. 12 or/9-11 13 8 and 12 14 saphenous vein/ 15 ((saphenous or perforator) adj3 (vein? or incompet$ or insuffic$)).tw. 16 exp varicose veins/ use mesz 17 varicosis/ or leg varicosis/ use emez 18 (varicos$ adj3 vein?).tw. 19 or/13-18 20 Sclerotherapy/ 21 Sclerosing Solutions/ 22 (sclerotherap$ or sclerosing$ or sclerosant$).tw. 23 or/20-22 24 9002-92-0.rn. 25 sodium tetradecyl sulfate.tw. 26 sodium tetradecyl sulphate.tw. 27 hypertonic saline.tw. 28 ethanolamine oleate.tw. 29 3282-75-5.rn. 30 2272-11-9.rn. 31 (polydocanol or polidocanol).tw. 32 sodium morrhuate.tw. 33 8031-09-2.rn. 34 sotradecol.tw. 35 1191-50-0.rn. 36 (aet?oxysclerol or aethoxyskerol).tw. 37 or/24-36 38 foam/ use emez 39 (foam$ or microfoam$).tw. 40 (tessari or monfreux or double syringe).tw. 41 or/38-40 (18 42 41 and (19 or 23 or 37) 43 varisolve.tw. 44 42 or 43 45 19 and (23 or 37) 46 ae.fs. 46 exp Venous Thrombosis/ 47 exp embolism/ 49 Ischemic Attack, Transient/

http://gateway.ovid.com/athens

96

50 cerebrovascular accident/ 51 exp Migraine Disorders/ use mesz 52 exp migraine/ use emez 53 (dvt or thrombo$ or embolism).tw. 54 isch?em$.tw. 55 stroke?.tw. 56 migraine?.tw. 57 (visual or vision).tw. 58 or/46-57 59 45 and 58 60 44 or 59 61 remove duplicates from 60

Science Citation Index (1970 - 20th May 2006)

ISI Proceedings (1990 – 23rd June 2006)

Biosis (1969 – 16th May 2006)

Web of Knowledge URL: http://wok.mimas.ac.uk/

#1 TS=(foam OR microfoam) #2 TS=(tessari OR monfreux) #3 TS=double syringe #4 #1 OR #2 OR #3 #5 TS=varicose vein* #6 TS=saphenous #7 TS=((venous or vein*) SAME incomp*) #8 TS=((venous or vein*) SAME insuffic*) #9 TS=telangiect* #10 TS=varicosis #11 TS=((reticular OR thread OR spider) SAME (vein* OR venous)) #12 #11 OR #10 OR #9 OR #8 OR #7 #13 TS=leg or legs #14 TS=lower extremit* #15 TS=limb or limbs #16 TS=thigh* #17 TS=calf or calves #18 #17 OR #16 OR #15 OR #14 OR #13 #19 #18 AND #12 #20 #19 OR #6 OR #5 #21 #20 AND #4 #22 TS=sclerosant* #23 TS=sclerosing #24 TS=sclerotherap* #25 #24 OR #23 OR #22 #26 #25 AND #4 #27 TS=(aethoxysclerol or aetoxysclerol or aethoxyskerol) #28 TS=sotradecol #29 TS=sodium morrhuate #30 TS=(polydocanol OR polidocanol) #31 TS=ethanolamine oleate #32 TS=hypertonic saline #33 TS=sodium tetradecyl #34 #33 OR #32 OR #31 OR #30 OR #29 OR #28 OR #27 #35 #34 AND #4

http://wok.mimas.ac.uk/

97

#36 TS=varisolve #37 #36 OR #35 OR #26 OR #21 #38 TS=thrombosis #39 TS=dvt or embolism #40 TS=ischemic #41 TS=ischaemic #42 TS=visual disturbance* #43 TS=vision #44 TS=migraine #45 TS=stroke #46 #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 #47 #20 AND #25 #48 #46 AND #47 #49 #37 OR #48 Cochrane Library Issue 2, 2006

URL: http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME

National Research Register (Issue 2, 2006)

URL: http://www.update-software.com/National/

#1 foam in All Fields or microfoam in All Fields #2 tessari in All Fields or monfreux in All Fields or double syringe in All Fields #3 (#1 OR #2) #4 varisolve in All Fields #5 (#3 OR #4) 660 #6 MeSH descriptor Sclerotherapy, #7 MeSH descriptor Sclerosing Solutions explode all trees #8 sclerotherap* in All Fields or sclerosing* in All Fields or sclerosant* in All Fields #9 (#6 OR #7 OR #8) #10 (#5 AND #9) DARE and HTA Databases (April 2006)

NHS Centre for Reviews & Dissemination URL:http://nhscrd.york.ac.uk/welcome.htm

Foam OR microfoam OR sclerotherapy OR sclerosant Clinical Trials (June 2006)

URL: http://clinicaltrials.gov/ct/gui/c/r

Foam OR microfoam OR sclerotherapy OR sclerosant* OR sclerosing Current Controlled Trials (June 2006)

URL: http://www.controlled-trials.com/

(Foam OR microfoam OR sclerotherap% OR sclerosing OR sclerosant%) AND (vein% or venous OR varic%)

http://www.controlled-trials.com/

http://clinicaltrials.gov/ct/gui/c/r

http://nhscrd.york.ac.uk/welcome.htm

http://www.update-software.com/National/

http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME

98

Conference Papers Index (2000 – June 2006)

CSA URL: http://uk1.csa.com/

(foam OR microfoam) AND (sclerotherapy OR scleros*) ZETOC Conference (June 2006)

URL: http://zetoc.mimas.ac.uk/

Foam sclerotherapy OR foam scleros* Microfoam sclerotherapy OR microfoam scleros* Vein sclerotherapy OR vein scleros* Venous sclerotherapy OR venous scleros* CONFERENCE PROCEEDINGS SEARCHED American College of Phlebology 14th Annual Congress, Atlanta, November 2000 15th Annual Congress, La Quinta, November 2001 16th Annual Congress, Fort Lauderdale, November 2002 American Venous Forum 16th Annual Meeting, Kissimmee, February 2004 17th Annual Meeting, San Diego, February 2005 18th Annual Meeting, Miami, February 2006 Euopean Venous Forum 4th Annual Meeting, Lisobon, June 2003 5th Annual Meeting, Warsaw, Poland, June 2004 6th Annual Meeting, Crete, June 2005 7th Annual Meeting, London, July 2006 French Society of Phlebology Foam Sclerotherapy Meeting, June 2005 Society for Vascular Technology of Great Britain & Ireland Annual General Meeting, Bournemouth, 2005 Union Internationale de Phlebologie 14th World Congress, Rome, Italy, September 2001 American Chapter Meeting, San Diego, August 2003 15th World Congess, Rio de Janeiro, October 2005 WEBSITES CONSULTED American College of Phlebology URL: http://www.phlebology.org/ American Venous Forum URL: http://www.americanvenousforum.com/

http://www.americanvenousforum.com/

http://www.phlebology.org/

http://zetoc.mimas.ac.uk/

http://uk1.csa.com/

99

Australasian College of Phlebology URL: http://www.phlebology.com.au/ BTG Plc URL:http://www.btgplc.com/ Canadian Society of Phlebology URL: http://www.scphlebologie.org/aboutsociety.html European Society for Vascular Society URL: http://www.esvs.org/start/index.asp European Venous Forum URL: http://www.europeanvenousforum.org/ French Society of Phelbology URL:http://www.sf-phlebologie.org/ International Union of Angiology URL: http://www.i.u.angiology.org/ Union Internationale de Phlebologie URL: http://www.uip-phlebologyonline.org/ Vascular Society of Great Britain & Northern Ireland URL:http://www.vascularsociety.org.uk/

http://www.vascularsociety.org.uk/

http://www.uip-phlebologyonline.org/

http://www.i.u.angiology.org/

http://www.sf-phlebologie.org/

http://www.europeanvenousforum.org/

http://www.esvs.org/start/index.asp

http://www.scphlebologie.org/aboutsociety.html

http://www.btgplc.com/

http://www.phlebology.com.au/

100

APPENDIX 2 Checklist of quality assessment of randomised controlled trials of an interventional procedure

Criteria Yes No Unclear Comment

1. Was the assignment to the treatment groups really random?

Adequate approaches to sequence generation?

2. Was the treatment allocation concealed? Adequate approaches to concealment of

randomisation?

3. Were the groups similar at baseline in terms of prognostic factors?

4. Were the eligibility criteria specified?


6. Were the groups treated in the same way apart from the intervention received?

7. Was there a follow-up period > 30 days?

8. Was the outcome assessor blinded to the treatment allocation?

9. Was the care provider blinded?

10. Were the patients blinded?

11. Were the point estimates and measures of variability presented for the primary outcome measures?

12. Was the withdrawal/drop-out rate likely to cause bias?

13. Did the analyses include an intention-to-treat analysis?

14. Was the operation undertaken by somebody experienced in performing the procedure?

101

APPENDIX 3 Checklist of quality assessment of non-randomised studies evaluating interventional procedures

Criteria Yes No Unclear Comments




4. Was selection of patients consecutive?

5. Was data collection undertaken prospectively?

6. Were the groups comparable on demographic characteristics and clinical features?



9. Were the staff, place, and facilities where the patients were treated appropriate for performing the procedure? (E.g. access to back-up facilities)

10. Were all the important outcomes considered?

11. Were objective (valid and reliable) outcome measure/s used?

12. Was the assessment of main outcomes blind?

13. Was follow-up long enough to detect important effects on outcomes of interest?

14. Was information provided on non-respondents, dropouts?

15. Were participants lost to follow-up likely to introduce bias? (e.g. high drop-out rate; differential drop-out; no description of those lost)

16. Was length of follow-up similar between comparison groups

17. Were all the important prognostic factors identified?

18. Were the analyses adjusted for confounding factors?

The same form was adapted to assess the quality of case series after taking out question 6, 12, 16 and 18.

102

APPENDIX 4 REFERENCE LIST OF INCLUDED STUDIES

Primary reports published as full text papers

Alos 2006

Alos J, Carreno P, Lopez JA, Estadella B, Serra-Prat M, Marinel-Lo J. Efficacy and safety of sclerotherapy using polidocanol foam: a controlled clinical trial. Eur J Vasc Endovasc Surg 2006;31(1):101-7.

Barrett 2004

Primary reference Barrett JM, Allen B, Ockelford A, Goldman MP. Microfoam ultrasound-guided sclerotherapy treatment for varicose veins in a subgroup with diameters at the junction of 10 mm or greater compared with a subgroup of less than 10 mm. Dermatol Surg 2004;30(11):1386-90.

Secondary references Barrett JM, Allen B, Ockelford A, Goldman MP. Microfoam ultrasound-guided sclerotherapy of varicose veins in 100 legs. Dermatol Surg 2004;30(1):6-12.

Barrett JM, Coldman M, Allen B, Ockelford A, JacobsenmK. Microfoam ultrasound-guided sclerotherapy for varicose veins in a subgroup with diameter at the junction of >10mm compared with a subgroup <10 mm. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Barrett JM, Allen B, Ockelford A, Goldman MP. Results of microfoam UGS tretament of varicose veins in one hundred legs, including a quality of life survey. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Belcaro 2003

Primary reference Belcaro G, Cesarone MR, Di Renzo A, Brandolini R, Coen L, Acerbi G et al. Foam-sclerotherapy, surgery, sclerotherapy, and combined treatment for varicose veins: a 10-year, prospective, randomized, controlled, trial (VEDICO trial). Angiology 2003;54(3):307-15.

Secondary reference Belcaro G, Cesarone M, Di Renzo A, Brandolini R, Coen L, Acerbi G et al. Treatments for varicose veins: Surgery, sclerotherapy, foamsclerotherapy and combined (surgery+sclerotherapy) options. A 10-year, prospective, randomised, controlled, follow-up study. The VEDICO* trial and EST (European Sclerotherapy Trial). Angeiologie 2003;55(1):29-36.

Bergan 2006 Primary reference Bergan J, Pascarella L, Mekenas L. Venous disorders: treatment with sclerosant foam. J Cardiovasc Surg (Torino) 2006;47(1):9-18.

Secondary references Pascarella L, Bergan JJ, Mekenas LV. Severe chronic venous insufficiency treated by foamed sclerosant. Ann Vasc Surg 2006;(1):83-91

103

Bergan JJ, Pascarella L. Severe chronic venous insufficiency: primary treatment with sclerofoam. Semin Vasc Surg 2005;18(1):49-56.

Bergan JJ, Mekenas LV. Treatment of severe CVI with sclerosant foam. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Bountouroglou 2006 Primary reference Bountouroglou DG, Azzam M, Kakkos SK, Pathmarajah M, Young P, Geroulakos G. Ultrasound-guided foam sclerotherapy combined with sapheno-femoral ligation compared to surgical treatment of varicose veins: early results of a randomised controlled trial. Eur J Vasc Endovasc Surg 2006;31(1):93-100.

Secondary references Bountouroglou DG, Azzam M, Kakkos SK. Prospective randomised study of ultrasound guided foam sclerotherapy and adjuvant high tie under local anaesthesia versus conventional surgery for primary varicose veins: early results. 5th Meeting of the European Venous Forum, Warsaw, Poland, June; 2004.

Bountouroglou DG, Azzam M, Kakkos SK, Pathmarajah M, Young P, Geroulakos G. Ultrasound guided foam sclerotherapy and adjuvant high tie under local anaethsthesia. Eupopean Society of Vascular Surgery, Innsbruck, Austria; 2004.

Bountouroglou DG, Azzam M, Kakkos SK. Prospective randomized study of ultrasound-guided foam sclerotherapy and adjuvant high tie under local anaethsthesia versus conventional surgery for primary varicose veins: early results: 14th UIP World Congress, Rome, September; 2001.

Cabrera 2004 Cabrera J, Redondo P, Becerra A, Garrido C, Cabrera J, Jr., Garcia-Olmedo MA et al. Ultrasound-guided injection of polidocanol microfoam in the management of venous leg ulcers. Arch Dermatol 2004;140(6):667-73.

Cabrera 2001 Primary reference Cabrera J, Cabrera J, Jr., Garcia-Olmedo MA. Sclerosants in microfoam. A new approach in angiology. Int Angiol 2001;20(4):322-9. Secondary references Cabrera J, Cabrera J, Jr., Garcia-Olmedo MA. Treatment of varicose long saphenous veins with sclerosant in microfoam form: Long-term outcomes. Phlebology 2000;15(1):19-23.

Cabrera J, Becerra A, Cobo M, Garrido C, Cabrera J, Jr. Ultrasound-guided injection of polodocanol microfoam in the management of venous leg ulcers. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Cabrera J, Cabrera J, Jr., Garcia-Olmedo MA. Widening the limits of sclerotherapy: new sclerosing products. Phlebologie 1997;2:181-8

104

Cavezzi 2002 Primary reference Cavezzi A, Frullini A, Ricci S, Tessari L. Treatment of varicose veins by foam sclerotherapy: Two clinical series. Phlebology 2002;17(1):13-8. Secondary reference Cavezzi A. Foam sclerotherapy according to Tessari's method: Multi-center study. Phlebologie 2002; 55(2):149-54. Cavezzi 1999

Cavezzi A, Frullini A. The role of sclerosing foam in ultrasound guided sclerotherapy of the saphenous veins and of recurrent varicose veins. Australian and New Zealand Journal of Phlebology 1999;3(2):49-50.

Coleridge Smith 2006 Primary reference Coleridge Smith P. Chronic venous disease treated by ultrasound guided foam sclerotherapy. Eur J Vasc Endovasc Surg 2006 ;32(5):577-83.

Seconadary reference Coleridge Smith P. Varicose veins treated by ultrasound guided foam sclerotherapy - a clinical series. Br J Surg 2006;93(S1):99-100.

De Waard 2005 de Waard MM, der Kinderen DJ. Duplex ultrasonography-guided foam sclerotherapy of incompetent perforator veins in a patient with bilateral venous leg ulcers. Dermatol Surg 2005;31(5):580-3.

Frullini 2002

Frullini A, Cavezzi A. Sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications. Dermatol Surg 2002;28(1):11-5.

Guex 2005 Primary reference Guex JJ, Allaert FA, Gillet JL, Chleir F. Immediate and midterm complications of sclerotherapy: report of a prospective multicenter registry of 12,173 sclerotherapy sessions. Dermatol Surg 2005;31(2):123-8.

Secondary reference Guex JJ, Allaert F, Gillet JL, Chleir F. Complications of sclerotherapy: analysis of a registry of 12173 sesssions. Phlebologie 2005;58(2):189-96.

Bergan J. Immediate and midterm complications of sclerotherapy: report of a prospective multicentre registry of 12,173 sclerotherapy sessions. Commentary. Dermatol Surg 2005;31:128.

105

Gillet JL, Guex JJ, Chleir F. Incidence des complications de la sclerotherapie a la mouse-resultats de l’etude de la societe franciase de phlebologie. Séance de la Societe Francaise de Phlebologi, La Sclerotherapie a la mouse en pratique; June: 2005.

Hamada 2006

Hamada T, El Hamid MA. Foam treatment for varicose veins; efficacy and safety. Scientific Medical Journal 2006;18(1)

Hamel-Desnos 2003

Primary reference Hamel-Desnos C, Desnos P, Wollmann JC, Ouvry P, Mako S, Allaert FA. Evaluation of the efficacy of polidocanol in the form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: initial results. Dermatol Surg 2003;29(12):1170-5.

Secondary references Hamel-Desnos C, Desnos P, Ouvry P. New therapeutic methods in the management of varicose disease: Echo-sclerotherapy and foam. Phlebologie 2003;56(1):41-8.

Hamel-Desnos C, Guex JJ, Desnos P, Ouvry P, Allaert F. Echo-sclerotherapy of the greater saphenous vein by direct puncture using sclerosing foam. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Ouvry P. Efficacy of lauromacrogol foam vs liquid in sclerotherapy of the greater saphenous vein: a 2-yesr follow-up. 15th UIP World Congress, Rio de Janeiro, October; 2005.

Kakkos 2006 Primary reference Kakkos SK, Bountouroglou DG, Azzam M, Kalodiki E, Daskalopoulos M, Geroulakos G. Effectiveness and safety of ultrasound-guided foam sclerotherapy for recurrent varicose veins: immediate results. Journal of Endovascular Therapy 2006;13(3):357-64.

Secondary reference Kakkos SK, Bountouroglou D, Azzam M, Kalodiki E, Geroulakos G. Utrasound-guided foam sclerotherapy for recurrent varicose veins: safety and effectiveness of a minimally invasive procedure performed in an outpatient basis. Phlebology 2005;20(3):152.

Kern 2004

Primary reference Kern P, Ramelet AA, Wutschert R, Bounameaux H, Hayoz D. Single-blind, randomized study comparing chromated glycerin, polidocanol solution, and polidocanol foam for treatment of telangiectatic leg veins. Dermatol Surg 2004;30(3):367-72.

Secondary reference Kern P. Foam sclerotherapy of telangiectases: a controlled study. Phlebologie 2005;58(2):183-8

106

Kritzinger (unpublished)

Kritzinger P. Complications of foam sclerotherapy: three case presentations. Newmarket, Ontario, Canada: York Vein and Laser Clinic; 2006.

Lloret 2006 Lloret P, Redondo P, Sierra A, Cabrera J. Mixed skin ulcers misdiagnosed as pyoderma gangrenosum and rheumatoid ulcer: successful treatment with ultrasound-guided injection of polidocanol microfoam. Dermatol Surg 2006;32(5):749-52. McDonagh 2002 McDonagh B, Huntley DE, Rosenfeld R, King T, Harry JL, Sorenson S et al. Efficacy of the comprehensive objective mapping, precise image guided injection, anti-reflux positioning and sequential sclerotherapy (COMPASS) technique in the management of greater saphenous varicosities with saphenofemoral incompetence. Phlebology 2002;17(1):19-28. Padbury 2004 Padbury A, Benveniste GL. Foam echosclerotherapy of the small saphenous vein.

Australian and New Zealand Journal of Phlebology 2004;8(1):5-8.

Rao 2005 Rao J, Wildemore JK, Goldman MP. Double-blind prospective comparative trial between foamed and liquid polidocanol and sodium tetradecyl sulfate in the treatment of varicose and telangiectatic leg veins. Dermatol Surg 2005;31(6):631-5. Tessari 2001

Tessari L, Cavezzi A, Frullini A. Preliminary experience with a new sclerosing foam in the treatment of varicose veins. Dermatol Surg 2001;27(1):58-60.

Van Neer 2004

van Neer PA. Perforans varicosis: treatment of the incompetent perforating vein is important. Dermatol Surg 2004;30(5):754-5.

Weaver 2004 Weaver PR. Recurrent scintillating scotomata precipitated by sclerotherapy. Australian and New Zealand Journal of Phlebology 2004;8(1):9-10.

Wright in press Primary reference Wright D, Gobin JP, Bradbury A, Coleridge Smith P, Spoelstra H, Berridge D et al. Varisolve® polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence: European randomised controlled trial. Phlebology 2006 in press

107

Secondary references Harvey, I. Provensis teach-in [document on the Iinternet]. BTG {accessed May 2006]. Available from: URL: http://www.btgplc.com/compliant/newsevents/article.cfm?id=293 Wright D. European randomized controlled trial of Varisolve PD microfoam compared with

alternative therapy in management of moderate-to-severe varicose veins: preliminary results.

UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Yamaki 2004

Yamaki T, Nozaki M, Iwasaka S. Comparative study of duplex-guided foam sclerotherapy and duplex-guided liquid sclerotherapy for the treatment of superficial venous insufficiency. Dermatol Surg 2004;30(5):718-22.

Primary reports published as abstracts

Baker 2006 Baker SJ, Darke SG. Ultrasound guided foam sclerotherapy (UGFS) early outcome of treatment in 220 limbs. Br J Surg 2006;93(S1):92.

Bhowmick 2001

Bhowmick A, Harper D, Wright D, McCollum C. Polidocanol microfooam sclerotherapy for long saphenous varicose veins. Phlebology 2001;16(1):43.

Cavezzi 2003

Cavezzi A. Combination of phlebectomy and duplex-guided foam sclerotherapy. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Chung 2003

Chung JK, Chung IM, Kim SJ. Foam sclerotherapy in telangiectatic leg veins. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Coleridge Smith 2003

Primary reference Coleridge Smith P. Compression implication of large vein sclerotherapy with sclerosant foam. UIP World Congress, American Chapter Meeting, San Diego, August; 2003. Secondary reference Coleridge Smith P. Foam sclerotherapy of the incompetent saphenous vein. London: The Middlesex Hospital Vascular Laboratory, University College Hospital Medical School; 2006.

http://www.btgplc.com/compliant/newsevents/article.cfm?id=293

108

Forlee 2006

Primary reference Forlee MV, Dowdall JF, Haider SN, McDonnell CO, Nyheim T, Malik V et al. Foam injection sclerotherapy cures veins with a single injection: fact ot fiction? 7th Annual Meeting of the European Venous Forum, London, July; 2006.Paper 5.24.

Secondary references

Forlee MV, Grouden M, Moore DJ, Shanik G. Stroke after varicose vein foam injection

sclerotherapy. J Vasc Surg 2006;43(1):162-4.

Grouden M, Forlee MV, Colgan MP, Madhavan P, Moore D. Stroke following ultrasound guided foam sclerotherapy: a case report. Society for Vascular Technology of Great Britain and Ireland, Annual General Meeting, Bournemouth; 2005.

Frullini 2001

Frullini A. Duplex-guided sclerotherapy of cavernoma. 14th UIP World Congress, Rome, September; 2001.

Gobin 2003

Gobin JP. French experience with Varisolve PD microfoam in the management of moderate to severe varicose veins. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Gonzalez 2005

Primary reference Gonzalez R, Barahona-Cruz S. Clinical and hemodynamic outcomes of duplex-guided foam sclerotherapy: a 24 month follow-up study. 15th UIP World Congress, Rio de Janeiro, October; 2005.

Secondary references Gonzalez Zeh R. Duplex guided foam sclerotherapy (DGFS): a 12 month follow-up study. American College of Phlebology, 15th Annual Congress, La Quinta,November; 2001.

Gonzalez Zeh R. Clinical and haemodinamical outcomes of duplex guided foam sclerotherapy (DGFS): a 24 month follow-up study. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

Gonzalez Zeh R. Expanding sclerosing properties of polidocanol foam with Gelofusine. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Gonzalez 2003

Gonzalez R. Foam closure of the long saphenous vein: preliminary report. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Grondin 2003a

Grondin L. Foam echosclerotherapy of incompetent saphenous veins. Phlebolymphology 2003;42:S24.

109

Grondin 2003b

Grondin L. Foam echo-sclerotherapy of incompetent saphenous veins. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Mackay 2002

Mackay E. Combination therapy for the treatment of recurrent varicose veiins after ligation and stripping using transcatheter sclerotherapy, endovenous laser and phlebectomy. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

Martimbeau 2003

Martimbeau PR. A randomized clinical trial comparing the effects of foam vs liquid formulas for sclerotherapy of primary varicose veins. Perfluoropropane-filled albumin microspheres-sodium tetradecyl sulfate vs air-filled sodium tetradecyl sulfate for foam sclerotherapy of great saphenous vein incompetence. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

McCollum 2001

McCollum C, Harper D. UK experience with Varisolve polidocal microfoam. 14th UIP World Congress, Rome, September; 2001.

Morrison 2003

Morrison N, Rogers C, Neuhardt D, Melfy K. Large-volume, ultrasound guided polidocanol foam sclerotherapy: a prospective study of toxicity and complications. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Nitecki 2005

Nitecki S, Bass A. Short-term results of ultrasound-guided sclerotherapy for venous insufficiency. Phlebology 2005;20(3):155.

Rybak 2003

Rybak Z. Aethoxysclerol foam obliteration of insufficient perforating veins in patients suffering from leg ulcers: a clinical recommentation. UIP World Cognress Chapter Meeting, San Diego, August; 2003

Sadoun 2003

Sadoun S. Long-term follow-up study of ultrasound findings in varicose greater saphenous veins treated with foam. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Schadeck 2001

Schadeck M. Sclerotherapy: comparison of techniques. Introductory lecture: state of the art. 14th UIP World Congress, Rome, September; 2001.

110

Sierra 2002

Sierra A, Redondo P, Cabrera J, Cabrera J, Jr., Garcia-Olmedo MA. Large volume microfoam therapy for recurrent variscose veins. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

Tessari 2004

Primary reference Tessari L. Trans-catheter (short or long) foam sclerotherapy in the treatment of varicose veins. 5th Meeting of the European Venous Forum, Warsaw, Poland, June; 2004.

Secondary reference Tessari L. Compression following trans-catheter foam sclerotherapy. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Vin 2005

Vin F. Indications and outcome of greater saphenous vein foam sclerotherapy. 15th UIP World Congress, Rio de Janeiro, October; 2005.

Weiss 2002

Weiss R, Weiss MA. Observations on the use of foamed sodium tetradecyl sulfate for

treatment of telangiectasias and reticular veins. American College of Phlebology, 16th

Annual Congress, Fort Lauderdale, November; 2002.

Primary reports published in a non- English language

Benigni 1999

Benigni J, Sadoun S, Thirion V, Sica M, Demagny A, Chahim M. Telangiectases and reticular veins treatment with a 0,25% aetoxisclerol foam presentation of a pilot study. Phlebologie 1999;52(3):283-90.

Benigni 2005

Primary reference Benigni J, Ratinahirana H. Polidocanol foam: migraine with aura. Phlebologie 2005;58(3):289-91

Secondary references Ratinahirana H, Benigni JP, Bousser MG. Injection of polidocanol foam (PF) in varicose veins as a trigger for attacks of migraine with visual aura. Cephalalgia 2003;23(8):850-1.

Benigni J, Ratinahirana H, Bousser MG. Polidocanol 400 foam injection and migraine with visual aura. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November 2002.

111

Breu 2004

Breu FX, Marshall M, Guggenbichler S. Prospective study on foam sclerotherapy. Vasomed 2004;16(4):133.

Creton 2005 Creton D. Sclerotherapie a la mousee dans les recidives après chirurgie. Séance de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June:2005 Demagny 2002 Demagny A. Comparative study into the efficacy of a sclerosant product in the form of liquid or foam in echo-guided sclerosis of the arches of the long and short saphenous veins. Phlebologie 2002;55(2):133-7.

Ferrarra 2005

Ferrara F, Bernach HR. Needle-size and efficacy of foam sclerotherapy. Phlebologie 2005;58(3):229-34. Frullini 2000 Frullini A, Cavezzi A. Echosclerosis using sodium tetradecyl-sulphate and polidocanol foam: Two years experience. Phlebologie 2000;53(4):431-5. Hamel-Desnos 2005

Primary reference Hamel-Desnos C, Allaert FA, Benigni J, Boitelle G, Chleir F, Ouvry P et al. Study 3/j.polidocanol foam 3% versus 1% in the great saphenous vein: early results. Phlebologie 2005;58(2):175-82.

Secondary reference Hamel-Desnos C, Allaert FA, Benigni J, Boitelle G, Chleir F, Ouvry P et al. Foam of polidocanol 3% versus 1% in greater saphenous vein sclerotherapy: preliminary results. UIP World Congress, American Chapter Meeting, San Diego, August; 2003.

Lucchi 2003

Lucchi M, Bilancini S, Tucci S. Sclerosis of the great saphenous vein: short term results. Phlebologie 2003;56(4):389-94. Milleret 2004

Primary reference Milleret R, Garandeau C, Brel D, Allaert FA. Foam sclerotherapy of the great saphenous veins via ultrasound-guided catheter in an empty vein: the alpha-technique. Phlebologie 2004;57(1):15-8.

Secondary reference Milleret R, Allaert F, Garandeau C. Comparative study of veon shrinking after closure, laser and foam endovenous procedures. Montpellier, France: Clinique St Jean; 2006.

112

Milleret R, Garandeau C. Sclero-mousse des axes saphenies par long catheter sur veine vide: alph-technique. Searce de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June: 2005

Schadeck 2004

Schadeck M. Sclerotherapy of the small saphenous vein: how to avoid bad results? Phlebologie 2004; 57(2):165-9. Sica 2005

Sica M. Echoguided sclerotherapy with 1% trombovar foam via short endovenous catheter (m.s.method): results. Phlebologie 2005;58(2):161-74.

Sica 2003

Sica M. Treatment of varices greater than 8mm in diameter with foam echosclerotherpy and compression. Phlebologie 2003;56(2):139-45.

Stucker 2005

Stucker M, Hermes N, Altmeyer P. A pilot study: Safety and effectiveness of periulcerous foam sclerotheraphy. Vasomed 2005;17(4):138.

Uhl 2005

Uhl JF, Creton D. La sclerotherapi a la moussemau cours de la chirurgie des varices: indications et resultats. Séance de la Societe Francaise de Phlebologi, La sclerotherapie a la mousse en pratique; June, 2005

Wildenhues 2005

Wildenhues B. Catheter-assisted foam sclerotherapy: A new minimally-invasive method for the treatment of trunk varicosis of the long and short saphenous veins. Phlebologie 2005;34(3):165-70.

113

APPENDIX 5 Characteristics of the included studies: English language studies and registry

Study details Participant characteristics Intervention characteristics Results

Alos 200620 Study design: RCT Location: out patient clinic of the Department of Angiology and Vascular Surgery of a general hospital, Spain Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with primary reticular varices (>2mm of diameter) or postoperative varices in more than one region that did not involve the SFJ. Exclusion criteria: patients with truncal varices with junctional and extra-junctional incompetence, postoperative varices that involved the SFJ, post-thrombotic varices with occluded deep veins, varices secondary to arteriovenous fistulas, bilateral varices of asymmetric calibre, unilateral varices with asymmetric calibre between regions, chronic ischaemia of the lower limbs, severe arterial hypertension (BP>180/95 mmHg), and being treated with anticoagulants and anti-inflammatories and/or diuretics for other pathologies. Number of patients: 75, each had two veins treated (located at the same limb or different limbs), one with foam, the other with liquid Mean age (range): 59 (23-78) Gender: 6M; 69F Venous disease: primary reticular veins or postoperative varices Length of follow-up: 1y Number of patients lost to follow-up:

15d 30d 90d 365d

(a) 0 1 4 12 (b) 1 1 4 12

(a) UGFS Strength & type of sclerosant for producing foam: polidocanol, 0..5% for veins diameter 1-2mm; 0.65% for 2.1-3mm; 0.75% for 3.1-4mm; 1% for 4.1-5mm; 1.25% for 5.1-6mm Foam-producing technique: Tessari technique Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins Number of injections for each session: one Amount of foam injected for each session: 2ml/vein Number of sessions: one as pre-specified in trial protocol Total amount of foam for scheduled treatment: 2ml/vein Duration of compression after injection: 48h (b) Liquid sclerotherapy Strength & type of sclerosant: polidocanol, 1% for veins diameter 1-2mm; 1.25%

for 2.1-3mm; 1.5% for 3.1-4mm; 2% for 4.1-5mm; 2.5% for 5.1-6mm

Use of ultrasound guidance for identifying vein or monitor injection: used for

identifying veins

Number of injections for each session: one Amount of sclerosing liquid injected for each session: 2ml/vein Number of sessions: one as pre-specified in trial protocal Total amount of sclerosing liquid for scheduled treatment: 2ml/vein Duration of compression after injection if compression applied: 48h

SAFETY Serious adverse events, n Dizziness: (a) 0; (b) 0 Adverse events, n Blurred vision: (a) 0; (b) 0 Local inflammation:

15d 30d 90d

(a) 25.3% 9.5% 1.4% (b) 9.5% 0% 0%

Skin pigmentation:

15d 30d 90d 365d

(a) 47% 53% 49% 33% (b) 15% 15% 13% 6.3%

Pain provoked on injection: (a) 0; (b) 0 Pain localised in the sclerosis region:

15d 30d 90d

(a) 64% 36.5% 8.5% (b) 26.8% 8.1% 1.4%

EFFICACY Complete occlusion of treated veins

15d 30d 90d

(a) 88% 93% 94.4% (b) 47% 54% 53%

EFFECTIVENESS Patient satisfaction: numerical scale 0-10 Mean (SD): (a) 7.2 (1.5); (b) 7.4 (1.2) OTHERS Differences between risks of pigmentation related to concentration used were not found.

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Barrett 200442-45 Study design: case series (retrospective) Location: the USA Recruitment/Treatment dates: since 1999 Source of funding: not reported

Inclusion criteria: patients with truncal incompetence in primary LSV or SSV as defined by reflux of >0.5 sec assessed by duplex/Doppler ultrasound scanning Exclusion criteria: not reported Number of patients: 99 limbs with veins diameter

<10mm; 17 limbs with veins diameter ≥10mm Length of follow-up: 2y; <10mm: mean (range), 23.7 months (19-29);

≥10mm: mean (range), 24.5 months (20-28). Mean age (range): <10mm: 52y (22-85); ≥10mm: 50y (36-77)

Gender: <10mm: 31%M; ≥10mm: 37.5%M Venous disease: truncal incompetence in primary LSV or SSV

CEAP II III IV V VI

<10mm 78% 10% 18% 0 2%

≥10mm 40% 20% 30% 0 5%

Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 3% STS for sapheneous trunks, 1-2.5% varying dose of polidocanol depending on the size of the sapheneous branches and associated varicosities Foam-producing technique: Tessari technique Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins Number of injections for each session: 4 Amount of foam injected for each session: 2ml

Number of sessions: <10mm: mean 2.15; ≥10mm: mean 2.80 Total amount of foam for scheduled treatment: mean: <10mm: 8.37ml STS plus varying dose of polidocanol to visible varicosities depend on size;

≥10mm: 13.9ml STS plus varying dose of polidocanol to visible varicosities depend on size Duration of compression after injection if compression applied:

≥2w; one week continuously applied and one week during the daytime only.

SAFETY Not reported EFFICACY

<10mm ≥10mm

Complete sclerosis 69% 77% Fibrosed vein <2 to 3mm and minimal flow

19% 21%

Reduced diameter but persistent reflux

12% 4%

Develop of new varicositiesa 4% 6% agenerally minor, mostly to perforator incompetence Visual assessment of visible varicosisties: <10mm: 92% completely removed; 8% significantly removed;

≥10mm: 94% completely removed; 6% significantly removed. Patients ‘believe their legs were successfully treated’: <10mm: 86% complete success; 14% partial success;

≥ 10mm: 94% complete success; 6% partial success Patients reported ‘symptom relief’: <10mm: 35% gone; 51% improved;

≥10mm: 69% gone; 19% improved Patients reported ‘quality of life’: <10mm: 80% significantly improved; 14% partly improved;

≥10mm: 88% significantly improved; 12% partly improved

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Belcaro 200321,22 Study design: RCT Location: Italy Recruitment/Treatment dates: not reported Source of funding: institutional grants

Inclusion criteria: patients (age range 25-65y) with uncomplicated primary varicose veins (no thrombosis/phlebitis, haemorrhage, or skin changes due to prolonged chronic venous insufficiency) Exclusion criteria: pregnancy, obesity, post-thrombolic occlusion, and history of previous thrombosis, coagulation disorders, any cardiovascular or systemic disease requiring treatment, tumors, bone and joint problems, diabetes, and any possible cause of venous obstruction. Also severe venous insufficiency, lipodermatosclerosis, and ulcerations. Number of patients: (a) 150 (211 limbs); (b) 148 (221 limbs); (c) 136 (222 limbs); (d) 155 (239 limbs); (e) 144 (244 limbs); (f) 154 (234 limbs) Length of follow-up: 10 years Mean age (SD): (a) 42 (6); (b) 44.3 (3); (c) 45 (5); (d) 44 (7); (e) 45 (5); (f) 42 (6) Gender: (a) 46M, 104F; (b) 49M, 99F); (c) 42M, 94F; (d) 50M, 105F; (e) 43M, 101F; (f) 49M, 105F Venous disease: incompetence of the LSV at the SFJ associated with one or more incompetent venous sites; patients with associated incompetence of the SSV were excluded. Number of patients lost to follow-up: At 10y, (a) 21; (b) 25; (c) 24; (d) 23; (e) 22; (f) 23

(a) UGFS Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: Irvine technique (two 5-10ml syringes connected with 10cm of standard infusion set tubing. Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitoring injection and foam flow (injected foam also contained a type of ultrasound contrast agent). Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection: 10 days (b) liquid sclerotherapy Strength & type of sclerosant: 1-2ml 3% STS for veins diameter >3mm; 1-2ml 2% STS for 2-3mm

Duration of compression after injection: 10-30d (3w for veins ≥3mm; 2w for ≤2mm)

Other information: not reported (c) liquid sclerotherapy (high dose)

Strength & type of sclerosant: 3-6ml 3% STS for veins diameter ≥3mm Duration of compression after injection: 1-2w for larger veins.

Other information: not reported (d) Ligation (e) Stab avulsion

(f) ligation combined with liquid sclerotherapy

SAFETY Not reported EFFICACY Number of failures (need new intervention after 10y):

(a) 10 (b) 12 (c) 9 (d) 14 (e) 37 (f) 8

Number of new veins not present at initial evaluation:

5y 10y

(a) 44% 51% (b) 48% 56% (c) 41% 49% (d) 34% 38% (e) 40% 41% (f) 34% 37%

EFFECTIVENESS Not reported OTHERS

Has a non-randomised comparative group (stripping), n 140. At 5 years the per cent of limbs with new varicose veins was 39% and at 10 years it was 45%.

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Bergan 200646-48,65 Study design: case series (retrospective) Location: USA Recruitment/Treatment dates:

not reported

Source of funding: grants from the Vein Institute of La Jolla Foundation

Inclusion criteria: (1) patients with varicose veins, or (2) patients with CVI presented with complains of severe lipodermatosclerosis, healed but inflamed venous ulcers or unhealed venous ulcers in one or both lower extremities Exclusion criteria: not reported Number of patients: Group1: 261 (328 limbs) with varicose veins; Group 2: 17 (23 limbs) with CVI were treated by UGFS; Group 3: 27 (37limbs) with CVI were treated by compression first, 12 (16 limbs) of them who failed after compression were crossovered to UGFS Length of follow-up: 6w Mean age (range): Group 1: 44y (14-82); Group 2: 67y (47-78); Group 3: 64.7y (25-88) Gender: Group 1: 45M, 216F; Group 2: 10M, 7F Group 3: 17M, 10F (9M and 3F were crossovered to UGFS) Venous disease: varicose veins or CVI with ulcers

CEAP (limbs) II III IV V VI

Group1 201 127 0 0 0 Group 2 0 0 1 7 15 Group 3 0 0 5 10 22 Crossed-over from group 3

0 0 0 4 13


UGFS Strength & type of sclerosant for producing

foam: 1-3% polidocanol

Foam-producing technique: Tessari

technique

Sclerosant: air: 1:4

Use of ultrasound guidance for identifying

vein, monitor injection or foam flow: used

for identifying vein, monitoring injection and

foam flow

Number of injections for each session: not

reported

Amount of foam injected for each session: 1-

16ml

Number of sessions: mean 2.89 per limb

Total amount of foam for scheduled

treatment: not reported

Duration of compression after injection if

compression applied: 48h continuously

apply then 14d day time only

SAFETY Serious adverse events, n Pulmonary embolism or lung complications: 0 reported in the abstract (one case pulmonary embolism reported in the text, happened 4m after UGFS, patient had history of leukaemia)

Gastrocnemius vein thrombosis (occurred in ≤7d): 1

Posterior tibial vein thrombosis (occurred in ≤7d): 1 Cutaneous necrosis: 1 Adverse events, n Ocular migraine: 2 Other visual disturbance: 3 True migraine: 2 Dry cough lasting 3-20min: 4 Chest tightness: 2 Panic attack: 2 Paresthesias: 2 EFFICACY Group 1: Complete occlusion of treated veins: 259/328 limbs (79.8%); Residual varicosities present: 69/328 limbs (21.2%) Healing of ulcers, limbs

2w 4w 6w

Group 2 9 6 All 15 healed Group 3 0 1 10 Crossed-over from group 3 9 1 All 13 healed

OTHER

Mentioned in the text that 17 of 316 patients with varicose veins (5.3%) experienced foam reaching the lung or escaping into the left heart through a patent foramen ovale. No event lasted more than a few, 3 to 4 min and none required any treatment. The number of 316 is in conflict with the one (n 290) reported in the ‘methods’ section.

117


Bountouroglou 200623-26 Study design: RCT Location: UK Recruitment/Treatment dates: 7/2003 – 2/2004 Source of funding: supported by unrestricted ground from STD pharmaceuticals, Hereford, UK

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: (a) 30 (30 limbs); (b) 30 (30 limbs) Length of follow-up: 3m Median age (range): (a) 43 (21-72); (b) 43 (20, 76) Gender: (a) 16M, 14F; (b) 12M, 18F Venous disease: varicose veins involving LSV. CEAP class

II III IV V VI

(a) 11 8 7 3 1 (b) 8 14 6 1 1

Number of patients lost to follow-up:

3w 3m

(a) 0 2 (b) 1 7

(a) UGFS combined with FSJ ligation Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: Tessari Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitor injection and foam flow

Number of injections for each session: not reported Amount of foam injected for each session: 6ml Number of sessions: mean 1.13 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: 3w: 2w continuously, 1w daytime only. (b) Ligation+stripping+avulsion

SAFETY Serious adverse events, n Deep vein thrombosis: (a) 0; (b) 0 Skin ulceration: (a) 0; (b) 1 Adverse events, n Thrombophlebetis: (a) 3; (b) 0 Saphenous nerve injury: (a) 0; (b) 2 Skin pigmentation: (a) 5; (b) 0 Allergic reaction: (a) 0; (b) 0 Haematoma, retention: (a) 0; (b) 2 EFFICACY Full obliteration:

3w 3m

(a) 25 (83%) 23 (79%) (b) 25 (89.3%) 18 (78.3%)

Partial obliteration without reflux:

3w 3m

(a) 1 (3.3%) 2 (7%) (b) 2 (7%) 1 (4.3%)

Partial obliteration with reflux:

3w 3m

(a) 4 (13.3%) 4 (14%) (b) 2 (7%) 4 (17.4%)

No obliteration, n:

3w 3m

(a) 0 0 (b) 0 0

EFFECTIVENESS Time to return to normal activity, median (range): (a) 2d (0-6d); (b) 8d (5-20d) Aberdeen vein questionnaire score change, median: (a) 15.4 � 9.3; (b) 26.1 � 14.1 OTHERS The skin pigmentation was resolvable (disappearing).

118


Cabrera 200453 Study design: case series (retrospective) Location: private vascular surgery clinic in Granada and dermatology department at a hospital in Pamplona, Spain Recruitment/Treatment dates: 7/1993-1/2003 Source of funding: not reported

Inclusion criteria: patients with chronic leg

ulceration ≥1m, venous insufficiency, and moderate to severe dermatosclerosis and absence of significant arterial insufficiency Exclusion criteria: not reported Number of patients: 116 (151 ulcers)

Length of follow-up: ≥4y Mean age (range): 57y (25-85) Gender: 39M, 77F Venous disease: ulcers linked to saphenous vein, perforator vein, deep vein alone or any combination

Veins ulcers linked to n

Saphenous vein (SV) 34 Perforator vein (PV) 8 SV & PV 41 SV & deep vein (DV) 11 DV & PV 13 SV, PV & DV 11

Number of patients lost to follow-up: 1 patient lost follow-up at 6m; 70% patients were followed

up till 2y; 25% patients till 3y; 14% ≥4y

UGFS Strength & type of sclerosant for producing foam: 0.27-1% (depending on the size of the vein and the hemodynamic characteristics of the treated area) polidocanol Foam-producing technique: confidential, the technique was patented (EP 656 203; US 5 676 962) Sclerosant: air: not reported, but gas used was carbon dioxide Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitor injection and foam flow

Number of injections for each session: not reported Amount of foam injected for each session: 20-30ml for sapheneous vein, 1-4ml for isolated valveless perforators Number of sessions: mean (range): 3.6 (1-17) Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: 7-15d

SAFETY Serious adverse events, n Pulmonary embosism: 0 Deep vein thrombosis: 0 Adverse events, n Transient visual disturbance (lasting <2min): 2 Temporary dry cough (lasting <1min): 2 Superficial phlebitis: 10% Neurological lesions: 0 Skin pigmentation: 20%, but spontaneously resolved in 90% of them after 6m EFFICACY Healing of venous ulcer (full reepithelialization of the wound with absence of drainage): 85%

Veins ulcers linked to Healed

Saphenous vein (SV) 90% Perforator vein (PV) 85% SV & PV 94% SV & deep vein (DV) 85% DV & PV 79% SV, PV & DV 64%

Time to wound closure, median: 2.7m Recurrence of ulcer (epithelial breakdown in the healed limb): 6.3% at 24m OTHERS The authors argued ‘the aim of the treatment is to induce an inflammation in the endothelium, thus, phlebitis cannot be considered an adverse event’.

119


Cabrera 200149-52 Study design: case series (retrospective) Location: Spain Recruitment/Treatment dates: (a) 1993-1996; (b) 1993-1999; (c) 1993-1999 Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: (a) 415 (500 limbs); (b) 265; (c) 72 (75 ulcers) Length of follow-up: (a) 4-6y; (b) not reported; (c) mean 2.5y Mean age (range): (a) not reported; (b) not reported; (c) 60.7y (31-87) Gender: not reported Venous disease: (a) incompetent LSV with vein diameter >9mm; (b) recurrent saphenous varicose vein after surgery; (c) venous ulcers Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: not reported, mentioned 0.25-3% Lauromacrogol 400 microfoam which is patented microfoam, product of a commercial company, the microfoam was undergoing clinical trials at the time the study was conducted. Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow. Number of injections for each session: not reported, mentioned two phases at each session, injecting at proximal and distal saphenoeous vein respectively Amount of foam injected for each session: first phase 15-25cc, second phase 10-20cc Number of sessions: mean: (a) 8; (b) 10 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: compression applied, no mention duration

SAFETY Serious adverse events, n Pulmonary embolism: 0 Deep vein thrombosis: 0 Adverse events, n Scotoma: 0 Transient photopsia: 1% Coughing (lasted <15min): number of patients not reported Inflammation: number of patients not reported, mentioned the inflammation always resolved with anti-inflammatory drugs and adequate bandaging. Neurological injury: 0 EFFICACY Complete occlusion of treated veins: (a) 80%; (b) 81% Healing of venous ulceration (ulcers remain closed after a mean of 2.5y): (c) 55 (77%) Disappearance of visible superficial branches: (a) 95%; (b) 90% OTHERS Used catheter during foam injection

120


Cavezzi 200255,56 Study design: case series (prospective) Location: three different centres (private offices or clinics), Italy Recruitment/Treatment dates: (a) 3-12/2000; (b) 3-4/2001 Source of funding: STS pharmaceuticals

Inclusion criteria: not reported Exclusion criteria: patients for treatment for minor varicosities, reticular veins or telangiectases, known allergy to STS, deep venous thrombosis within the previous year, immobility, severe general diseases (cardiac or renal failure etc), pregnancy, puerperium or thrombophilic state Number of patients: (a) 177 (177 limbs); (b) 17 (17 limbs) Length of follow-up: all patients were reviewed at 1m, 66 in (a) had a further follow-up 45-370 days after treatment Mean age: (a) 56y; (b) 53y Gender: (a) 39M, 138F; (b) 1M, 16F Venous disease: (a) varicose veins related to incompetence of saphenous veins, recurrence, perforators or collaterals; (b) patients with major varicose veins (CEAP and varicose vein type distribution similar to (a)

CEAP II III IV V VI

(a) 115 (65%)

26 (15%)

28 (16%)

7 (4%)

1 (1%)

(b) 7

(41%) 5

(29%) 3

(18%) 2

(12%) -

Number of patients lost to follow-up: 0 at 1m

UGFS Strength & type of sclerosant for producing foam: 0.2-3% STS Foam-producing technique: Tessari technique Sclerosant: air: 1:4 or 1:5 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow Number of injections for each session: not reported Amount of foam injected for each session: (a) mean (SD): 2.9ml (1.0); (b) mean: 3.2 Number of sessions: (a) mean (SD): 1.6 (0.8); (b) mean 1.4 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: applied, duration of compression was not reported

SAFETY Serious adverse events, n Extension of sclerothrombus from superficial to deep vein: (a) 2 (1%); (b) 0 Adverse events, n Scotoma: (a) 1 (0.5%); (b) 0 Malaise: (a) 1 (0.5%); (b) 0 Allergic reaction: (a) 1 (0.5%); (b) 0 EFFICACY Obliteration of the vessel or antegrade flow:

1m Mean 138d

(a) 161 (91%) 44 (67%) (b) 17 (100%) -

Minimal retrograde flow in the treated vein, without visible varicose vein:

1m Mean 138d

(a) 15 (8.4%) 5 (8%) (b) - -

Persistence of vessel patency with retrograde flow and visible varicose vein (failure):

1m Mean 138d

(a) 1 (0.6%) 5 (8%) (b) - -

OTHERS Also reported: 1. There was no significant relationship between vein type, vein diameter, CEAP class and outcome after 30d follow-up; 2. The larger diameter vein (>7mm) negatively influenced the oucome at the 2nd follow-up in comparison with results at 1m; 3. Limbs with complicated varicose veins, such as CEAP III-VI, had a slightly worse result at the 2nd follow-up compared with limbs with CEAP II.

121


Cavezzi 199954 Study design: case series (unclear prospective or retrospective) Location: Italy Recruitment/Treatment dates: 11/1997-12/1998 Source of funding: not reported

Inclusion criteria: patients with incompetent sapheneous veins or recurrent varicose veins Exclusion criteria: not reported Number of patients: 98 (106 disease axes) Length of follow-up: mean (range): 21 w (12-43) Mean age (range): not reported Gender: not reported Venous disease: 51 incompetent LSV axes, 29 incompetent SSV axes, 26 recurrent varicose vein axes Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 1-4% polidocanol or 1-3% STS Foam-producing technique: Monfreux technique Sclerosant: air: 0.5ml sclerosing solution gives a mixture that on average consists of 2-3ml foam

Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported, mentioned that the treatment was ultrasound guided in the abstract

Number of injections for each session: ≥1 Amount of foam injected for each session: 1-1.5ml for the first injection, and 0.5-1ml for the second injection if required Number of sessions: mean (range): 1.8 (1-3) Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: elastic stocking was worn in the daytime only between all treatment sessions and for 1m after the last session

SAFETY Serious adverse events, n Pulmonary embolism: 0 Adverse events, n Scotomas: 1 (1%) Temporary mental confusion: 1 (1%) Superficial thrombophlebitis: 3 (3%) EFFICACY Stable sclerofibrosis or re-canalisation without reflux: 101 (95%) Complete unsuccessful after three treatments: 3 (3%) OTHERS It was unclear the ‘disease axes’ indicate number of limbs, veins or treatment sessions.

122


Coleridge Smith 200657,58 Study design: case series (prospective) Location: private practice consulting room (Thames Valley Nuffield Hospital, Wexham, Bucks, UK) Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with chronic venous disease due to truncal sapheneous incompetence (reverse flow in the vein under examination >0.5sec) Exclusion criteria: patients without truncal vein incompetence Number of patients: 808 (1411 limbs), 1109 limbs were treated Length of follow-up: mean (range): 11m (6-46) Mean age (range): men: 56y (17-95); women: 52y (19-91) Gender: 142M, 666F Venous disease: LSV reflux alone: 766 limbs (69%); SSV reflux alone: 223 limbs (20%); LSV and SSV reflux 120 limbs (11%) CEAP, n (%):

I II III IV V VI

212 (15%)

1154 (81%)

6 -

29 (2%)

3 -

7 -

Primary LSV reflux

618 Recurrent LSV reflux

267 (30% of LSVs)

Primary SSV reflux

283 Recurrent SSV reflux

60 (17% of SSVs)

Number of patients lost to follow-up: 459 limbs were examined at 6m

UGFS Strength & type of sclerosant for producing foam: 1% polidocanol (treated 107 limbs), 1% STS (treated 102 limbs) or 3% STS (treated 900 limbs) Foam-producing technique: Tessari technique Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow

Number of injections for each session: not reported Amount of foam injected for each session: 2ml/injection, total amount <20ml Number of sessions: n (%)

1 2 3 >3

Patients with unilateral varices

187 (43%)

207 (48%)

34 (8%)

3 (1%)

Patients with bilateral varices

20 (6%)

153 (40%)

173 (46%)

31 (8%)

Total amount of foam for scheduled treatment: ml

Median IQR

All veins 10 6-14 LSV 10 6-14 SSV 6 5-10

Duration of compression after injection if compression applied: initially 3-5 days continuously compression, later in the series changed to 10-14 days continuously compression

SAFETY Serious adverse events, n Anaphylaxis: 0 Transient ischaemic attacks or stroke: 0 Deep vein thrombosis: 3 (one case had short occlusive thrombus arose in the common femerol vein 2w following treatment; another two cases had non-occlusive thrombus extended from SFJ and SPJ into the femoral and popliteal vein) Adverse events, n Visual disturbances: 14 (2%) occurred following treatment, managed by resting supine, resolved in most cases within 30min. Calf vein thrombosis (confined to isolated gastrocnemius or to part of the posterior tibial vein): 10 Thrombophlebitis: 5% Nerve damage: 0 Skin pigmentation: 115/459 limbs at 6m; 11/115 limbs at 1y EFFICACY Complete occlusion of treated veins by sclerosing agent used:

1% polidocanol 1% or 3% STS

All

LSV 33/39 (80%)

285/324 (88%)

318/363 (88%)

SSV 11/15

(73%) 105/126 (84%)

116/141 (82%)

Change of CEAP score 6m after treatment:

0 I II III IV V VI

LSV pre- 0 12 332 1 15 0 3 LSV post- 157 174 19 0 10 2 1

SSV pre- 0 4 133 0 4 - - SSV post- 44 88 0 7 2 - -

OTHERS The author’s preparation for this clinical series included treating 50 patients in clinical trials under the supervision of an experienced practitioner of UGFS. The author also had 20y of experience of vascular duplex ultrasonography.

123


De Waard 200567 Study design: case report Location: the Netherlands Recruitment/Treatment dates: not reported Source of funding: not reported

Number of patients: 1 (2 limbs) Length of follow-up: 3w Age: 56 Gender: F Venous disease: incompetent perforator vein above venous ulcers

UGFS Strength & type of sclerosant for producing foam: 1% polidocanol Foam-producing technique: Tessari technique Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitoring injection and foam flow Number of injections for each session: not reported Amount of foam injected for each session: not reported, the foam was made of 2ml polidocanol Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: compression applied, duration not reported

SAFETY Not reported EFFICACY One ulcer was closed 10d after treatment; both ulcers were closed 3w after treatment, perforator veins and LSV were occluded

124


Frullini 200259 Study design: case series (retrospective) Location: Italy Recruitment/Treatment dates: (a) 11/1997 to the end of 10/2000; (b) 12/1999-10/2000 Source of funding: not reported

Inclusion criteria: patients varicose veins and telangiectases Exclusion criteria: not reported Number of patients: (a) 257; (b) 196 Length of follow-up: 20-180d Mean age (range): not reported Gender: not reported Venous disease:

Minor varicosities (reticular vein or telangictasias)

Medium to large varices

(a) 90 167 (b) 36 170


(a) UGFS: Monfreux foam-producing technique used Strength & type of sclerosant for producing foam: polidocanol or STS, strength was not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins and monitor injection for large veins Number of injections for each session: not reported Amount of foam injected for each session: in general <4ml foam (contain 0.4-0.6ml sclerosing liquid) Number of sessions: a mean of 1.8 (foam was made of STS or polidocanol) for large veins; a mean of 5 (foam was made of polidocanol) for reticular vein or telangiectasias Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: applied during daytime, duration not reported b) UGFS: Tessari foam-producing technique used Strength & type of sclerosant for producing foam: 0.2-3% STS Sclerosant: air: 0.5-1.0ml sclerosing liquid: 2-5ml air Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins and monitor injection for large veins Amount of foam injected for each session: mean 2.7ml foam Number of sessions: 1-6 in general, a mean of 1.8 for large veins Duration of compression after injection if compression applied: applied during daytime, duration not reported Other information: not reported

SAFETY Severe adverse events, n (%) Partial popliteal DVT: (a) 1 (0.4%); (b) 1 (0.5%); Partial gastrocnemius DVT: (a) 0; (b) 1 (0.5%);

Skin necrosis: (a) 4 (1.6%); (b) 2 (1%) Adverse events, n (%) Transient visual disburbance: (a) 3 (1.2%); (b) 1 (0.5%) Transient confussional status: (a) 3 (1.2%) (twice in the same patient in different sessions; (b) 0 Malaise: (a) 0; (b) 1 (0.5%) Varicophlebitis: (a) 5 (2.0%); (b) 7 (3.6%) Lymphedema worsening: (a) 0; (b) 1 (0.5%) Skin pigmentation: (a) 6 (2.3%); (b) 0 EFFICACY Immediate success rate: (a) 88.1%; (b) 93.3% OTHERS Mentioned a comparison between the two groups (a) (b) is not possible because of the mismatch in patient populations and the different areas treated, complication rate was depending on learning curve.

125


Guex 200537-40 Study design: registry Location: 22 phlebology clinics in France Recruitment/Treatment dates: not reported, but reported median (SD) of registration period across clinics: 8 (3.1) w Source of funding: Board of the French Society

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: not reported, but reported number of treatment sessions: (a) 6395; (b) 5434; (c) 344 Length of follow-up: 1m (after the end of the registration period) Mean age (range): not reported Gender: not reported Venous disease: Number of sessions and type of injected veins

Foam Liquid Both

Reticular and spider veins

2,293 3,631 40

LSV trunk or junction

1,533 261 130

SSV trunk or junction

492 109 4

Main tributaries 714 422 34 Small varices or nonsaphenous veins

332 717 37

Perforating veins 199 77 2 Postsurgical recurrences

832 217 97

Total 6,395 5,434 344


(a) UGFS Strength & type of sclerosant for producing foam: not reported Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: 36% used ultrasound guidance, not reported for identifying veins, monitor injection or foam flow

Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported (b) Liquid sclerotherapy Use of ultrasound guidance for identifying vein or monitor injection: 0.9% used ultrasound guidance, not reported for identifying veins or monitor injection Other information: not reported (c) Used both foam and liquid in the same treatment session Information not reported

SAFETY Serious adverse events, n Anaphylactic shock: (a) 0; (b) 0; (c) 0 Femoral vein thrombosis: (a) 1; (b) 0; (c) 0 Skin necrosis: (a) 0; (b) 0; (c) 0 Intra-arterial injection: (a) 0; (b) 0; (c) 0 Adverse events, n Visual disturbance alone: (a) 8 (all resolved shortly); (b) 4 (further check revealed 3 cases involving of air); (c) 0 Visual disturbance associated with headache, nausea, vasovagal fainting: (a) 8; (b) 0; (c) 0 Vasovagal fainting alone: (a) 6; (b) 4; (c) 0 Nausea and vomiting alone: (a) 0; (b) 1; (c) 0 Headache alone: (a) 0; (b) 0; (c) 0 Coughing: (a) 4; (b) 0; (c) 0 Muscular venous thrombosis: (a) 1; (b) 0; (c) 0 Muscular venous extension: (a) 1; (b) 0; (c) 0 Perforating venous thrombosis: (a) 3; (b) 0; (c) 0 Intense superficial thrombophlebetis: (a) 3; (b) 0; (c) 0 Paraesthesia alone: (a) 1; (b) 2; (c) 0 EFFICACY Not reported EFFECTIVENESS Not reported OTHERS 22 medical doctors specialising in phlebology volunteered to report their daily activity and problems related to sclerotherapy injections. All had several years of experience in sclerotherapy and were equipped with duplex sonograms.

126


Hamada 200660 Study design: case series Location: Egypt Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with varicosities either long or short sapheneous vein or both. Exclusion criteria: pregnancy, breast feeding, DVT, known allergy to ethanolamine oleate and lack of morbility. Number of patients: 60 (40 with bilateral varicosities, 20 with unilateral varicosities, 112 veins treated in total) Length of follow-up: 12m Age (mean): 52y Gender: 32% men, 68% women (not clear the percentage of patients or veins) Venous disease: 72 legs had long sapheneous vein varicosies, 23 legs had short sapheneous vein varicosities, 12 legs had both, 30 legs had post surgical recurrent varicosities. CEAP II, III, IV, IV: 73%, 8%, 18%, 1%. Number of patients lost to follow-up: 0

UGFS Strength & type of sclerosant for producing foam: 5% ethanolamine oleate for sapheneous trunk(s) and 0.5-3% depending on the size of the saphenous branches and associated varicosities. Foam-producing technique: Tessari Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow. Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: 30% legs required a second treatment at the 3rd month follow-up, perforator veins often need further treatment Total amount of foam for scheduled treatment: mean (range) 8 ml (6-10) to close the incompetent vein. Duration of compression after injection if compression applied: one week continuously and another week daytime only

SAFETY Serious adverse events, n Pulmonary embolism: 0 Skin necrosis: 0

Adverse events, n Phlebitis: 2 legs with 1 each of 2 separate patients Minor DVT (soleal vein): 1 Drug reaction: 0 Transient visual disturbance: 0 Skin pigmentation: 0 Neurasthenia: 0 EFFICACY Complete sclerosis: 88/112 veins Fibrosed vein of less than 2-3mm and minimal flow: 20 veins Develep of some minor new varicosities unrelated to the treated vein: 4% veins

127


Hamel-Desnos 200327-29,33 Study design: RCT Location: France Recruitment/Treatment dates: after 2001 Source of funding: not reported

Inclusion criteria: (1) patients with incompetence in the LSV (pathological reflux in the LSV >1 sec) and (2) a diameter of vein 4-8mm (measured just below the SFJ while patients is standing; (3) 18-80y Exclusion criteria: same as the ‘traditional ones’ used for conventional liquid sclerotherapy: (1) mental or psychiatric impairment, chronic liver disease or renal insufficiency, (2) pregnancy or lactation or risk of pregnancy, progressive malignant disease, cardiac or respiratory insufficiency, (3) history of DVT, coagulopathy, and a known allergy to polidocanol or none of the ingredients of Aethorysclerol . Number of patients: (a) 45; (b) 43 Length of follow-up: 1y Age (range): 18-80y Gender: not reported Venous disease: incompetent LSV Number of patients lost to follow-up: not reported

(a) UGFS Strength & type of sclerosant for producing foam: 3% polidocanol Foam-producing technique: double syringe system Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins and monitor injection. Number of injections for each session: not reported Amount of foam injected for each session: 2ml to veins diameter 4-6mm; 2.5ml to veins 6-8mm. Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: compression applied only if secondary cutaneous inflammations occurred, duration not reported. (b) Liquid sclerotherapy Strength & type of sclerosant: 3% polidocanol

Use of ultrasound guidance for identifying vein, or monitor injection: used for

identifying veins and monitoring injection.

Amount of foam injected for each session: 2ml to veins diameter 4-6mm; 2.5ml to veins 6-8mm. Other information: not reported

SAFETY Serious adverse events, n Skin necrosis: (a) 0; (b) 0 Adverse events, n Venous thrombosis: (a) 0; (b) 0 Cutaneous inflammation at 3w: (a) 2; (b) 3 Allergic reaction: (a) 0; (b) 0 Haematoma: (a) 1; (b) 0 EFFICACY Elimination of reflux in the LSV at 3w: (a) 84%; (b) 40% Recanalisation at 6m, n: (a) 2; (b) 4. No additional recanalisation observed in either group at 1y. Immediate spasm after injection, n: (a) 29; (b) 12 EFFECTIVENESS Not reported.

128


Kakkos 200661,62 Study design: case series (retrospective) Location: England, UK Recruitment/Treatment dates: 7/2003-1/2005 Source of funding: not reported

Inclusion criteria: patients with symptomatic recurrent varicose veins after surgery (ligation and/or stripping) Exclusion criteria: patients with previous deep venous thrombosis, peripheral vascular disease, known allergy to sclerosing agents, and pregnancy, and patients with venous ulceration Number of patients: 38 (45 limbs) Length of follow-up: 3w Median age (IQR): 59 (53.5-66.0) Gender: 13M, 25F Venous disease: recurrent varicose veins

Number of limbs

Groin reflux 28 Perforator vein reflux 5 Isolated LSV remnant reflux 11 Isolated recurrent varicose veins with no junctional or truncal reflux

1

CEAP II III IV V

Number of limbs 13 13 13 6


UGFS Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: Tessari technique Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow Number of injections for each session: usually one

Amount of foam injected for each session: ≤6ml Number of sessions: mean (SD): 1.6 (0.9); one session with 6ml foam was

adequate in 26 limbs (58%), 5 (11%) limbs needing ≥3 sessions Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: continuously for 2w and in daytime only during the 3rd week

SAFETY Serious adverse events, n Deep vein thrombosis: 0 Small necrotic blister: 1 (2%) Adverse events, n Systemic complications: 0 Superficial thrombophlebitis: 6 out of 73 sessions (8.2%); legs with proximal reflux due to previous incomplete ligation or fed by an incompetent pelvic vein experienced superficial thrombophlebitis more frequently (4/12) than legs without proximal reflux (1/33) p 0.014. Skin pigmentation: 3 limbs (6.6%) EFFICACY Complete elimination of both varicose veins and all reflux points: 87% limbs OTHERS Found a positive association between the amount of injected foam (p 0.002) and CEAP class and venous clinical severity score (p 0.012)

129


Kern 200431,32 Study design: RCT Location: Switzerland Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: women presenting with primary telangiectasias and reticular veins on the lateral face of the thigh. Exclusion criteria: patients with pathologic colour-flow duplex imaging (reflux in the deep veins, saphenous trunk, saphenous junctions or saphenous collateral incompetent perforators, non compressible deep or superficial veins, recanalised thrombus), allergy against chrome or polidocanol, and previous sclerotherapy. Number of patients: (a) 51; (b) 48; (c) 51 Length of follow-up: 5w+1m Mean age (range): 46.5y (17-70) Gender: all female Venous disease: primary telangictasias (vein diameter 0.2-1mm) or reticular veins (1-3mm). Number of patients lost to follow-up: (a) 0; (b) 3; (c) 0.

(a) UGFS Strength & type of sclerosant for producing foam: 0.25% polidocanol Foam-producing technique: Monfreux technique Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins. Number of injections for each session: 60-100 Amount of foam injected for each session: <10ml Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: applied after 5min of treatment, but not reported duration. (b) Liquid sclerotherapy: polidocanol Strength & type of sclerosant: 0.25% polidocanol Number of injections for each session: 60-100 Amount of liquid injected for each session: <10ml Duration of compression after injection if compression applied: applied after 5min of treatment, but duration not reported (c) Liquid sclerotherapy: chromated glycerine Strength & type of sclerosant: 100% chromated glycerine Number of injections for each session: 60-100 Amount of liquid injected for each session: <10ml Duration of compression after injection if compression applied: applied after 5min of treatment, but duration not reported

SAFETY Serious adverse events, n Deep vein thrombosis: (a) 0; (b) 0; (c) 0 Skin ulceration: (a) 0; (b) 0; (c) 0 Adverse events, n Transient visual disturbance (<2h): (a) 3; (b) 0; (c) 0 Microthromboli: (a) 9; (b) 5; (c) 7 Thrombus in reticular vein: (a) 0; (b) 0; (c) 1 Thrombophlebetis: (a) 0; (b) 0; (c) 0 Skin pigmentation: (a) 1; (b) 2; (c) 0 Skin matting: (a) 3; (b) 1; (c) 0 Pain provoked on injection, assessed by visual score 0-100, mean (95% CI): (a) 20.69 (14.61-26.77); (b) 20.1 (13.44-26.76) (c) 35.05 (29.21-40.89); EFFICACY Not reported. EFFECTIVENESS Patient satisfaction at 5w, assessed by visual score 0-100, mean (95% CI): (a) 60.2 (53.7-66.7) (b) 59.3 (52.3-66.3) (c) 69.1 (62.4-75.7)

130


Lloret 200668 Study design: case report Location: Spain Recruitment/Treatment dates: not reported Source of funding: not reported

Number of patients: 2 (3 limbs) Length of follow-up: case 1: 2y; case 2: several months Age: 50y; 82y Gender: 1 M; 1F Venous disease: case 1: ulcers, bilateral LSV and SFJ incompetence; case 2: ulcer, right LSV incompetence

UGFS Strength & type of sclerosant for producing foam: 0.7% polidocanol Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitoring injection and foam flow Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: 3 Total amount of foam for scheduled treatment: case 1: 40ml; case 2: 30ml total for the first two sessions plus the dose used in the third session (amount not reported) Duration of compression after injection if compression applied: not reported

SAFETY Not reported EFFICACY Case 1: the pain disappeared after the 1st session, ulcers were healed several weeks after; LSVs were occluded after the 3rd session. No new ulcers after 2y follow-up. Case 2: the pain disappeared after the 1st session, ulcers were healed 10 weeks after; LSV was occluded after the 3rd session. No new ulcers several months later.

131


McDonagh 200263 Study design: case series (prospective) Location: six outpatient referral centres offering specialist sclerotherapy services around the USA Recruitment/Treatment dates: 1/1995-1/1997 Source of funding: not reported

Inclusion criteria: patients with chronic disease of primary undetermined cause, LSV varicosities with SFJ incompetent with or without thigh and calf incompetent perforators, minimum 3y follow-up Exclusion criteria: patients had surgery for large vein disease in the previous 3y, absence of conserved LSV or SFJ, deep venous reflux, deep venous thrombosis, allergy to sclerosant, systemic disease, injection, coagulation disorders, pregnancy, diabetes Number of patients: 162 (186 limbs) Length of follow-up: mean (SD) (range) : 3.4y (1.7) (2-6) Mean age (range): 48.2 (5.1) Gender: 22M, 140F Venous disease: LSV varicosities with SFJ incompetence

CEAP 0 I-II IV-V

Number of limbs

3 (2%) 100 (53%) 83 (45%)

Number of patients lost to follow-up: 18 limbs (9%) at 3y

UGFS (3 stages COMPASS technique) Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: using a disposable syringe, the agitation was generated by firmly tapping the syringe against a hard surface, later this was changed to using a vial by the pulling and pushing motion of the plunger of the syringe Sclerosant: air: 2:1 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow

Number of injections for each session: not reported Amount of foam injected for each session: <10ml unfoamed STS Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: no compression applied

SAFETY No serious adverse experience EFFICACY Sustained sclerosis at consecutive follow-up visit: 100% SFJ; 98% LSV Possible neovascularisation (new vein): 1 (0.5%) at a mean of 3.4y

132


Padbury 200464 Study design: case series (prospective) Location: Australia, specialised phlebology service in the radiology department of a local hospital with trained ultrasonographer performing the imaging Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients presenting with isolated SPJ reflux Exclusion criteria: patients with associated LSV or deep vein incompetence, and those who had had previous surgery Number of patients: 14 (15 limbs) Length of follow-up: 6m Median age (range): 50y (26-68) Gender: 1M, 13F Venous disease: isolated SPJ reflux Number of patients lost to follow-up: 0

UGFS Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: Tessari techqniue Sclerosant: air: 1:2 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins Number of injections for each session: one Amount of foam injected for each session: 1.5ml Number of sessions: mean (range): 2.5 (1-4) Total amount of foam for scheduled treatment: mean (range): 3.75ml (1.5-6) Duration of compression after injection if compression applied: 7d continuously and 1w daytime only

SAFETY Serious adverse events, n Anaphylaxis: 0 Deep vein thrombosis: 0 Skin ulceration: 0 Adverse events, n Nerve impairment: 0 Skin discolouration: 2 (13%) Pain provoked on injection: 23% required mild analgesia EFFICACY Complete occlusion of treated veins: 9 (60%) Patient satisfaction (as gauged by the Aberdeen Varicose Vein Qol Questionnaire): all patients recording a positive improvement, mean difference (range) of post-treatment and pre-treatment: -10 (-4 - -23) Resumed normal activities the following day: 14 (100%)

133


Rao 200534 Study design: RCT Location: USA Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients for treatment of varicose and telangiectatic leg veins. Exclusion criteria: patients with SFJ incompetence or with SPJ incompetence. Number of patients: (a) 10; (b) 19; (c) 15 Length of follow-up: 12w Mean age (range): not reported Gender: not reported Venous disease: varicose and telangiectatic leg veins Number of patients lost to follow-up: 0

(a) UGFS Strength & type of sclerosant for producing foam: 0.5% STS or 1% POL for veins diameter of 3-6mm Foam-producing technique: double syringe system

Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: 1w continuously applied (b) Liquid sclerotherapy Strength & type of sclerosant: 0.25% STS or 0.5% POL for veins diameter of

≤1mm Duration of compression after injection if compression applied: 1w continuously applied Other information: not reported (c) Liquid sclerotherapy Strength & type of sclerosant: 0.5% STS or 1% POL for veins diameter of 1-3mm Duration of compression after injection if compression applied: 1w continuously applied Other information: not reported

SAFETY Not reported separately by group but by type of sclerosant, n:

STS POL

Ecchymosis 18 17 Hyperpigmentation 10 9 Coagulum formation 7 8 Local urticaria 5 4 Telangiectatic matting 2 2 Skin necrosis 0 0 Allergic reaction 0 0

EFFICACY Not reported. EFFECTIVENESS Disappearance of vessels assessed by four independent physicians to high-quality digital photographs, scale 1-5 (3, minimal disappearance (50%); 4, moderate disappearance (75%); 5, complete disappearance (100%)), mean

STS POL

(a) 3.75 3.75 (b) 4.25 4.5 (c) 4.5 4.25

134


Tessari 200166 Study design: case series (unclear prospective or retrospective) Location: different centres (private offices), Italy Recruitment/Treatment dates: not reported, the duration of treatment was 6w

Source of funding: not reported

Inclusion criteria: incompetent LSV, SSV, recurrent varicosities, residual postsurgery varicose, varicosities due to incompetent perforators, single tributary disease Exclusion criteria: not reported Number of patients: 77 Length of follow-up: 1m Mean age (range): not reported Gender: not reported Venous disease: saphenous or recurrent varicosities affected 24 patients, 30 patients had collateral varices, and 23 patients had reticular varices and/or telangiectases Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: STS, 1-3% for saphenous and recurrent veins; 0.3-1% for collateral varicose veins and residual postsurgery vein; 0.2% for reticular vein; 0.1% for telangiectases Foam-producing technique: Tessari technique Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported, mentioned the treatment was ultrasound guided in the abstract Number of injections for each session: not reported Amount of foam injected for each session: mean (range): 3ml (1-8) for saphenous and recurrent veins; 4ml (3-5) for collateral varicose veins and residual postsurgery veins; 2-3ml for reticular veins; 2-3ml for telangiectases Number of sessions: 1-4 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: 30d daytime only

SAFETY Adverse events, n Transient scotomas: 2 Segmental phlebitis of a collateral vein: 1 EFFICACY Complete occlusion of treated veins: nearly 100% of the saphenous veins, recurrent varicose and tributaries

135


Van Neer 200469 Study design: case report Location: the Netherlands Recruitment/Treatment dates: not reported Source of funding: not reported

Number of patients: 1 Length of follow-up: 6w Age: 45y Gender: F Venous disease: incompetent perforator vein and varicose vein

UGFS Strength & type of sclerosant for producing foam: 1% polidocanol Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins Number of injections for each session: not reported Amount of foam injected for each session: 0.5ml to the perforator vein, 2ml to the varicose vein injected 1w after perforator vein Number of sessions: 2 Total amount of foam for scheduled treatment: 2.5ml Duration of compression after injection if compression applied: use of compression not reported

SAFETY Not reported EFFICACY No reflux at the perforator vein at 1w after injection; invisible varicose vein 6w after injection

136


Weaver 200470 Study design: case report Location: New Zealand Recruitment/Treatment dates: not reported Source of funding: not reported

Number of patients: 1 (2 limbs) Length of follow-up: 6m Age: not reported Gender: F Venous disease: reticular and telangictatic vein

UGFS Strength & type of sclerosant for producing foam: 0.5% polidocanol Foam-producing technique: not reported Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: use of ultrasound guidance not reported Number of injections for each session: not reported Amount of foam injected for each session: 18ml (the reticular vein was injected using 12ml foam; the spider vein was treated using 6ml foam) Number of sessions: 1 Total amount of foam for scheduled treatment: 18ml Duration of compression after injection if compression applied: compression applied, duration not reported

SAFETY Visual disturbance followed by headache: On arising from the treatment table the patient immediately complained of a visual disturbance comprising of blurred vision and flashing lights in the left visual field. She said this was exactly how her migraine attacks started (she had not previously volunteered a history of migraine). Paracetamol 1gram was administered orally. The patient was observed over the next 10-15min until the visual disturbance began to settle. The patient then felt well enough for a brief walk and to return home. Telephone contact 2h later revealed she had gone on to develop a right, unilateral headache and nausea which had settled with a non-steriodial anti-inflammatory. She claimed this was typical of her migraine attacks. Four days later she returned for her second sclerotherapy session to treat the left leg. On this occasion 9ml of 0.3% STS liquid was injected to both reticular and spider veins. On arising from the treatment tale the patient immediately complained of a recurrence of her visual disturbance in the left visual field. On this occasion the patient had brought her own migraine treatment and self administered a non-steroidal anti-inflammatory. On returning home she had right unilateral headache and nausea that settled over a 2h period, as before. Six months elapsed before the third sclerotherapy session. On this occasion the patient was advised to treat herself with prophylactic, non-steroidal anti-inflammatories 1-2 hours prior to sclerotherapy. This time 9ml of 0.3% polidocanol liquid was injected into the remaining reticular and spider veins bilaterally. On rising from the treatment table the patient experienced only momentary blurring of vision in the left visual field, which settled spontaneously and did not progress to more severe symptoms. EFFICACY Not reported.

137


Wright in press30,35,36 Study design: RCT Location: seven countries, fifteen centres, including the UK and the USA. Recruitment/Treatment dates: not reported Source of funding: not reported (Provensis is a registered pharmaceutical company)

Inclusion criteria: patients with moderate to severe varicosities at LSV or SSV. Exclusion criteria: history of major superficial thrombophlebitis, current or previous DVT, immobility, BMI>32kg/m2 , contradindications for polidocanol, severe hypertension, glomerulonephritis and nephroses, hepatopathy, active phlebitis, general febrile disease, diabetes, asthma, advanced arteriosclerosis, serious coexisting illness, concomitant treatment with disulfiram, systemic corticosteroids, oestrogen, or anticoagulants, abnormal clinically significant haematology or biochemistry profiles. Number of patients: (a) 178; (b) 94; (c) 259; (d) 125 Length of follow-up: 3m Mean age (SD; range): 50.0 (12.2; 19-75) Gender: 208M, 448 F Venous disease: moderate to severe varicosities at LSV or SSV n

(a) (b) (c) (d)

Primary LSV 141 77 169 76 SSV 12 8 47 23 LSV+SSV 8 0 3 1 Recurrent LSV 11 6 29 20 SSV 1 2 11 5 LSV+SSV 3 1 0 0 CEAP III 14 11 58 35 CEAP IV 20 10 18 11

Number of patients lost to follow-up: (a) 11, (b) 4, (c)10, (d) 1 at 1y

(a) (c) UGFS Strength & type of sclerosant for producing foam: 1% polidocanol Foam-producing technique: not reported (commercial and confidential, patent granted in the UK, the USA, and the Europe) Sclerosant: air: not reported (O2 and CO2 based foam) Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein, monitoring injection and foam flow Number of injections for each session: not reported Amount of foam injected for each session: >1 till no residual varicose veins Number of sessions: 1 2 3 >=4

(a) 141 29 2 0 (c) 236 19 1 0 (d) 93 20 9 3

Total amount of foam for scheduled treatment: <30ml Duration of compression after injection if compression applied: 14d (day and night for the first 7d) (b) Surgery High ligation was performed in 91.5%, stripping in 88.3%, and avulsion phlebectomy in 53.2% of patients (d) Foam (homemade) or liquid sclerotherapy Strength & type of sclerosant: 0.5-3% polidocanol for 61 patients; 0.5-3% STS for 64 patients

SAFETY Serious adverse events, n Deep vein thrombosis detected at d7: (a)+(c): 11, in which 9 were asymptomatic but detected on routine duplex scanning; (b) 0; (d) 1. Pulmonary embolism: (a) 0; (b) 0; (c) 0; (d) 0 Adverse events, n

(a) (b) (c) (d)

Coutusion 122 80 153 57 Skin discolouration

98 39 119 57

Pain in limb 73 39 77 31 Headache 41 20 14 7 Haematoma 11 1 29 9

There were six reports of non-specific transient neurological symptoms occurring <=24h of treatment, including paraesthesias, visual disturbance and speech disorders, these were short lived and no clinical findings during following examinations. EFFICACY Both occlusion of treated veins and no reflux, n:

3m 1y

(a) 120 111 (b) 82 81 (c) 243 232 (d) 111 95

Elimination of reflux, n:

3m 1y

(a) 143 130 (b) 84 83 (c) 248 235 (d) 120 104

EFFECTIVENESS Time to return to normal activity (median): (a) 2d; (b) 13d; (c) 1d; (d) 1d OTHERS Surgeon experience: investigators were supervised during the first five treatments or until basic proficiency was demonstrated.

138


Yamaki 200441 Study design: non-randomised comparative study Location: Japan Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with isolated LSV incompetence who refused to receive surgical interventions were selected for outpatient UGFS. Exclusion criteria: patients with myocardial ischaemia, arterial insufficiency with ankle brachial index of less than 0.8, active thrombophlebitis, and active ulcers. Number of patients: (a) 37 (37 limbs); (b) 40 (40 limbs) Length of follow-up: 12m Mean age (range): 54.6 (21-84) Gender: 15M, 62F Venous disease: isolated LSV incompetence CEAP

II III IV V

(a) 27 2 5 3 (b) 31 4 3 2


(a) UGFS Strength & type of sclerosant for producing foam: 1 or 3% polidocanol Foam-producing technique: Tessari technique Sclerosant: air: 1:5 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying vein Number of injections for each session: 2 Amount of foam injected for each session: 2ml foam made of 1% polidocanol for the first injection, 0.5ml foam made of 3% polidocanol for the second injection Number of sessions: 1 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: continuously applied for more than 2d (b) Liquid sclerotherapy

SAFETY No adverse events were found in either group. EFFICACY

LSV (a) (b)

Complete occlusion 25 (67.6%) 7 (17.5%) Partial recanalisation with no reflux

3 (8.1%) 2 (5%)

Partial recanalisation with reflux

4 (10.8%) 9 (22.5%)

Complete recanalisation

5 (13.5%) 22 (55%)

Recurrence 3 (8.1%) 10 (25%)

EFFECTIVENESS Not reported.

139

APPENDIX 6 Characteristics of the included studies: English language conference abstracts Study details Participant characteristics Intervention characteristics Results

Baker 200678 Study design: Case series Location: UK Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with varicose veins treated under the NHS. Exclusion criteria: not reported Number of patients: 192 consecutive patients, only 181 underwent UGFS (229 limbs), 39 were bilateral, 97 limbs with primary long saphenous vein incompetence, 23 with primary short short saphenous vein incompetence, 38 with non-saphenous varicose veins, 62 recurrent varicose veins, 6 with ulcers and 3 bleeding. Length of follow-up: not reported Mean age (range): median 52y Gender: 73M; 108F Venous disease: varicose veins Number of patients lost to follow-up: 3 limbs

UGFS Strength & type of sclerosant for producing foam: polidocanol, 1% for superficial veins, 3% for saphenous trunks Foam-producing technique: not reported Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for cannulation and injection Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: up to 14 ml Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n Transient ‘embolic’ events: 5/181 (2.8%)

One ulcer followed extravasation Adverse events, n Pigmentation and phlebitis were common EFFICACY Complete outcome (>85% varicosity closure): 196/229 limbs Partial outcomes (reduced closure and the patients were satisfied, e.g. LSV still open but varicosities all closed, or <85% varicosity closure): 31/229 limbs Failed to achieve partial outcomes (with primary long saphenous vein incompetence) : 2/229 limbs

140


Bhowmick 200179 Study design: Case series Location: UK Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 35 Length of follow-up: 3months Mean age (range): not reported Gender: not reported Venous disease: long saphenous vein incompetence Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: Polidocanol (Varisolve®) Foam-producing technique: Varisolve® is available as foam Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to guide cannula insertion and injection Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: 15-20ml Duration of compression after injection if compression applied: full length Class II compression stocking applied but duration not reported

SAFETY Serious adverse events, n DVT: 2/35 patients had an occlusion of short segments (5 and 8cms) of distal calf deep veins that did not propagate and were asymptomatic Adverse events, n Discomfort resembling superficial thrombophlebitis: 7 legs EFFICACY Complete occlusion: 32/35 (LSV) at 28 days

141


Cavezzi 200380 Study design: Case series Location: Italy Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: nearly 100 limbs Length of follow-up: 24months Mean age (range): not reported Gender: not reported Venous disease: primary varicose vein and incompetence of LSV and/or SSV Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 0.5-1% STS or 1-2% POL Foam-producing technique: Tessari Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: mentioned as duplex-guided foam sclerotherapy Number of injections for each session: not reported Amount of foam injected for each session: 2-5ml Number of sessions: mean 2 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n No major complications Adverse events, n Varicophlebitis: below 3%

EFFICACY One to two months after hook phlebectomy: Abolition of reflux: 80% and 95% of residual saphenous stem, LSV and SSV respectively Diameter reduction in nearly all the residual saphenous stem After UGFS: Immediate and mid-term end-point (spasm and vein obliteration) in 100% of residual saphenous stem OTHERS Veins were submitted to hook phlebectomy and subsequent UGFS. During hook phlebectomy, flush ligation at the connection of the upper incompetent tributary with saphenous stem was performed. One to two months after operation, UGFS was performed on the residual saphenous stem.

142


Chung 200373 Study design: non-randomised comparative study Location: South Korea Recruitment/Treatment dates: (a) since Feb 2000 (b) not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: (a) 52; (b) 76 Length of follow-up: not reported Mean age (range): 48y Gender: 9M; 43F Venous disease: Telangiectasias Number of patients lost to follow-up: not reported

a) UGFS Strength & type of sclerosant for producing foam: Ethamolamine on 30 patients, STS on 22 patients Foam-producing technique: Tessari Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: mean 2.3 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) Liquid sclerotherapy Strength & type of sclerosant: not reported Other information: not reported

SAFETY Adverse events, n Post-injection pain: a) 4/52; b) 23/ Telangiectatic matting: a) 10/52; b) 23/76 Extravasation of foam sclerotherapy was more frequent than with liquid EFFICACY Not reported OTHERS 76 telangiectatic patients were treated using diluted liquid sclerotherapy. Then starting in Feb 2000, 52 patients were treated with foam sclerotherapy.

143


Coleridge Smith 200381 Study design: case series (prospective) Location: patients from South Bucks/East Berks, referred by GP, UK Recruitment/Treatment dates: not reported Source of funding: not reported, sclerosing foam used was Varisolve

Inclusion criteria: symptomatic primary or recurrent varicose veins, SFJ/LSV or SPJ/SSV reflux Exclusion criteria: patients with previous DVT, unopposed oestrogen treatment, obesity Number of patients: 24 Length of follow-up: 1y Mean age (range): 49 (25-65) Gender: not reported Venous disease: symptomatic primary or recurrent varicose veins, SFJ/LSV or SPJ/SSV reflux (25 LSV; 10 SSV); CEAP class II: 22; class IV: 2. Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 1% polidocanol (Varisolve)

Foam-producing technique: Varisolve is available as foam Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used for identifying veins, monitoring injection and foam flow Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: two weeks

SAFETY Serious adverse events, n Popliteal DVT: 1 (4%), occurred at 4w after gastroenteritis and air travel Medial gastrocnemius vein thrombosis: 1 (4%) Adverse events, n Thrombophlebetis: 11 (44%) Residual lumps or pigmentation: 16 (65%) EFFICACY Complete occlusion of treated veins: LSV 90%; SSV, 5 (50%) Recurrence: LSV, 2 (8%); SSV, 5 (50%) Patient satisfaction with outcome: Satisfied or very satisfied: 22 (89%); Mild disappointment: 2 (11%)

144

Study details Participant characteristics

Intervention characteristics

Results

Forlee 200682,83,89 Study design: Case series Location: Ireland Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 89(103 legs); 54/103 legs had previous surgery for varicose veins; 65/103 legs were classified as CEAP clinical class II, 17 class IV, 11 class V and 5 class VI. Length of follow-up: mean (range): 6 months (0-24) Mean age (range): 59 (32-86) Gender: 20M; 69F Venous disease: symptomatic varicose veins Number of patients lost to follow-up: 17 (17 legs)

Foam sclerotherapy Strength & type of sclerosant for producing foam: 0.5-3% POL Foam-producing technique: Tessari Sclerosant: air: 4:1 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: applied but duration not reported

SAFETY Serious adverse events, n Peri-procedural stroke (with full recovery): 1/89; Calf DVT: 1/89

Adverse events, n Skin staining: 33/86 legs; Phlebitis (requiring analgesia): 11/86 legs

EFFICACY Complete abolition of reflux: 49/86 legs after an average of 1.1 treatments while 7 of out the 49 legs recanalised after an average of 11 months (range 6-18 months) post closure) Partial closure: 23/86 legs Remained open: 14/86 legs OTHERS 1. Details of the stroke were given in the case report by the same author: While the patient was getting dressed, he suddenly developed right upper-limb weakness associated with a frontal headache and sweating. A neurologic examination revealed a mild expressive aphasia and a right hemiparesis (right arm, 1/5; right leg, 4/5). The cranial nerves were intact. He had evidence of a peripheral neuropathy, with decreased vibration sense of the lower limbs bilaterally. He scored 7/42 on the National Institutes of Health Stroke Severity Scale. The power in the right upper limb improved to 4/5 over a period of 10min, and his speech returned to normal. A carotid duplex scan, performed immediately, showed normal arteries with rapidly moving echogenic particles within the left carotid lumen. This was similar to the duplex appearance of foam in the LSV. A magnetic resonance image of the brain was normal. His baseline blood glucose, serum electrolytes, full blood count, coagulation studies, and chest radiograph were normal. The electrocardiogram showed sinus rhythm, and a 24-hour Holter monitor did not reveal any paroxysmal arrhythmias. His transoesophageal echocardiogram revealed an 18-mm patent foramen ovale with an associated atrial septal aneurysm. A right-to-left shunt was demonstrated with a colour flow duplex scan and the bubble test. The cardiac valves were normal, and he had grade II atheroma of the distal arch of his aorta. Over the course of 2w, the power in the right upper limb returned to normal, although fine motor coordination remained mildly impaired. A repeat carotid duplex ultrasound scan was normal. The patient has been referred to the cardiac service and awaits percutaneous transcatheter closure of his patent foramen ovale. LSV was occluded up to the SFJ at 2w, peripheral varicosities below the knee were still patent. 2. Clinical and duplex examination and any necessary re-injection were performed at 6 weeks, 6 months and then 6 monthly intervals

145


Frullini 200184 Study design: Case series Location: Italy Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 21 (number of patients not provided for group (a) and (b) separately) Length of follow-up: 5 yrs Mean age (range): not reported Gender: not reported Venous disease: recurrent varicosities in the inguinal region Number of patients lost to follow-up: not reported

(a) UGFS (STS as sclerosing agent) Strength & type of sclerosant for producing foam: STS Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: mentioned as duplex-guided sclerotherapy Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported (b) UGFS (polidocanol as sclerosing agent) Strength & type of sclerosant for producing foam: polidocanol Other information: not reported

SAFETY Not reported EFFICACY Success rate: (a) 54% ; (b) 77%

146


Gobin 200374 Study design: non-randomised comparative study Location: France Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 342: (a) 229 ; (b) 113 Length of follow-up: 3 months Mean age (SD, range) and gender: Foam Liquid

Age: mean (y) (SD, range) 50.8 (12.4,19-75) 50.0 (12.0, 20-74) Sex 71M, 158F 32M, 81F CIVIQ mean (SD) 19.5 (15.5) 18.9 (15.3)

CIVIQ- Chronic Venous Insufficiency Questionnaire Venous disease: LSV and/ or SSV incompetence, with moderate-to-severe varicosities Number of patients lost to follow-up: not reported

a) UGFS Strength & type of sclerosant for producing foam: POL (Varisolve®) Foam-producing technique: not reported (Varisolve ® is available as foam already) Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: 1-3

(a) (%) (b) (%)

1 92.2 75.2

2 7.4 15.2

3 0.4 8.0

4 0 1.6

Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) Liquid sclerotherapy Number of injections for each session: 1-4 (See table above) Other information: not reported

SAFETY Serious adverse events, n DVT: (a) 1 (0.4%); (b) 1 (0.9%) Adverse events, n Visual symptoms: (a) 2 (0.9%); (b) 2 (1.8) Headache: (a) 7 (3.1%); (b) 7 (6.2%) Superficial thrombophlebitis: (a) 1 (0.4%); (b) 0 Pain in limb: (a) 70 (30.6%); (b) 28 (24.8%) EFFICACY Occlusion and elimination of reflux, n/N: (a) (b)

LSV 153/157 69/72 SSV 42/43 20/21 LSV& SSV 3/3 1/1 Recurrent 25/26 18/19

147


Gonzales Zeh 200585-88 Study design: Case series Location: Chile Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 143 (175 procedure performed, 106 on LSV, 69 on SSV) Length of follow-up: 24 months Mean age (range): not reported Gender: not reported Venous disease: not reported Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 3%POL Foam-producing technique: Tessari Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to monitor injection Number of injections for each session: not reported Amount of foam injected for each session: volume of injection was calculated for each patient depending on the diameter of the vein (mean: 7mm for LSV and 5mm for SSV) and the length of reflux. Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n DVT: one case was observed at one week EFFICACY Reflux, %:

LSV SSV

1year 9.4% 4.3% 2 years 14% 10%

148


Gonzales Zeh 200375 Study design: non-randomised comparative study Location: Chile/ US Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: LSV incompetence (3-9mm diameters) Exclusion criteria: Number of patients: 20, (a) 10; (b) 10 Length of follow-up: 1 month Mean age (range): not reported Gender: not reported Venous disease: LSV incompetence Number of patients lost to follow-up: not reported

a) UGFS (polidocanol as scleroing agent) Strength & type of sclerosant for producing foam: 3% POL Foam-producing technique: Tessari Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to monitor injection Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) UGFS (polidocanol added with Gelofusin &reg. as sclerosing agent) Strength & type of sclerosant for producing foam: 3% POL+Gelofusine Foam-producing technique: Tessari Sclerosant: air: 1:20 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to monitor injection Other information: not reported

SAFETY Not reported EFFICACY Completely sclerosed: (a) 8/10; (b) 10/10 OTHERS Gelofusine is a solution made up of a low molecular weight synthetic protein (modified fluid gelatine), which is used as a plasma volume substitute. The proteins act to stabilise the bubbles of foam

149


Grondin 2003a77 Study design: non-randomised comparative study Location: Canada Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: not reported Length of follow-up: 5 yrs Mean age (range): not reported Gender: not reported Venous disease: incompetence of LSV or SSV Number of patients lost to follow-up: not reported

a) Foam sclerotherapy (with one injection/shot only) Strength & type of sclerosant for producing foam: not reported Foam-producing technique: not reported Sclerosant: air: not reported, gas used was CO2 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: 1 Amount of foam injected for each session: not reported Number of sessions: 1 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) Foam sclerotherapy (with 1-3 sessions) Strength & type of sclerosant for producing foam: not reported Number of sessions: 1-3 Sclerosant: air: not reported, gas used was CO2

Other information: not reported c) Surgery d) Liquid sclerotherapy Detail information: not reported

SAFETY Serious adverse events, n Transient ischaemic accident: (a, b) 0.2%; (c) 0 Pulmonary embolism: (a, b) 0.01%; (c) 0.03 % DVT: (a, b) 0.12%; (c) 0.07% Skin necrosis: (a, b) 0.01%; (c) 0.03% Adverse events, n Dyspnea/chest pain: (a,b) 0; (c) 0

Phlebitis: (a,b) 10%; (c) 4.17%

Infection: (a,b):0.01%; (c) 0%

Oedema: (a,b) 1%; (c): 0.17)

Matting: (a, b) 1%; (c) 0.25%

Staining: (a, b) 4%; (c) 0.17%

Allergy: (a,b) 0.3%; (c) 0.7% EFFICACY Treatment success: LSV (%)

6m 1y 2y 3y 4y 5y

(a) 93 91 88 85 82 79 (b) 99 96 92 88 - - (c) 97 95 90 85 83 80 (d) 83 80 77 75 72 68

Treatment success: SSV (%)

6m 1y 2y 3y 4y 5y

(a) 92 87 83 80 79 76 (b) 97 95 91 89 - - (c) 85 81 77 73 68 54 (d) 85 85 83 82 80 78

150


Grondin 2003b76 Study design: non-randomised comparative study Location: Canada Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: (a) 150; (b) 150 Length of follow-up: a) 10m; b) 10 yrs Mean age (range): a) 49y; b) 52y Gender: a) 34M 116F; b) 33M 117F Venous disease: incompetent saphenous trunks: a) 86 LSV (64 virgin LSV, 22 REVAS) 38 SSV (24 virgin SSV, 14 REVAS) b) 82 LSV (63 virgin LSV, 19 REVAS), 40 SSV (27 virgin SSV, 13 REVAS) Number of patients lost to follow-up: (a) 26; (b) 28

a) Foam sclerotherapy Strength & type of sclerosant for producing foam: POL (Varisolve®) Foam-producing technique: Cabrera (Varisolve®) is available as foam) Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) Liquid sclerotherapy Strength & type of sclerosant: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Adverse events, n There was an increase in thrombosis with the use of foam sclerosant EFFICACY Short- term closure rate (1 month), n (%)

(a) (b)

LSV 80/86 (93) 68/82 (83) Virgin LSV 59/64 (92) 55/63 (87) REVAS LSV 21/22 (95) 13/19 (68) SSV 35/38 (92) 34/40 (85) Virgin SSV 22/24 (91.6) 24/27 (89) REVAS SSV 13/14 (93) 10/13 (77)

Clinical& symptomatic score, %

(a) (b)

No improvement 6 (<5) 57 (47) <50% improvement 37 (30) 60 (49) >50% improvement 81 (>65) 5 (4)

OTHERS 1. Virgin veins are veins that have received no previous treatments prior to the study, and REVAS are incompetent saphenous trunks originating from sites previously operated on. Success in both groups was defined as the abolition of reflux within the proximal 5 cms of the junction with the deep venous system.

151


MacKay 200290 Study design: Case series Location: Not reported Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 13 (14limbs) Length of follow-up: 1 year Mean age (range): not reported Gender: not reported Venous disease: Recurrent varicose veins following previous vein surgery Number of patients lost to follow-up: not reported

UGFS (combination therapy using transcatheter sclerotherapy, endovenous laser and stab-avulsion phlectomy) Strength & type of sclerosant for producing foam: STS or POL Foam-producing technique: not reported Sclerosant: air: 1:2 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n No major complications EFFICACY Occlusion: 14/14 limbs showed occlusion of the lasered portion of the vein (and significantly reduced neovascularisation) OTHERS No details of the procedure were provided on how sclerotherapy was combined with endovenous laser and stab-avulsion phlebectomy.

152


Martimbeau 200371 Study design: RCT Location: USA Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients with different categories of varicose veins Exclusion criteria: not reported Number of patients: (a) 100, (b) 100 Length of follow-up: 12 months Mean age (range): not reported Gender: not reported Venous disease: Primary varicose veins Number of patients lost to follow-up: not reported

a) UGFS Strength & type of sclerosant for producing foam: 1% STS Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: mean 1.3 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported b) Liquid Strength & type of sclerosant: 1% STS Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: mean 2.4 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Adverse events, n: (a) 0.2%, (b) 2.4% EFFICACY Sclerosing effect, n (%)

(a) (b)

LSV 11/25 (44) 3/25(12) SSV 21/25 (84) 12/25 (48) Perforating veins 24/25 (96) 23/25 (90.4) Tributaries 25/25 (100) 22/25 (88)

Recurrence rate: (a) 1.2%; (b) 1.7%

153


McCollum 200191 Study design: case series Location: UK Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 41 Length of follow-up: 3 months Mean age (range): not reported Gender: not reported Venous disease: LSV varicosities Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: POL (Varisolve®) Foam-producing technique: not reported (Varisolve® is available as foam) Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: 1-2 (66% of pts with a single injection, 34% with a second injection Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n Not reported Adverse events, n Local pain: 35% of the patients took some nonsteroidal anti-inflammatory drugs EFFICACY Occlusion rate: SFJ and LSV: 29/41 (71%) LSV without reflux: 7/41 (17%) There were 2 short occlusions of one posterior tibial vein. Recanalisation with reflux: 5/41 (12%) Mean diameter reduction: from 9.2mm to 5.4mm

154


Morrison 200392 Study design: Case series Location: USA Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 100 Length of follow-up: not reported Mean age (range): not reported Gender: not reported Venous disease: truncal or nontruncal venous insufficiency Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 1% POL Foam-producing technique: Tessari Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to guide injection Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: 8-52ml Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n DVT: 0 No significant physiologic changes and no serious or long-lasting sequelae. Adverse events, n Dry cough, chest discomfort, and visual disturbances were the most commonly occurring side effects

Side effects rarely lasted more than 1-4 hours, and resolved more quickly with ambulation and water ingestion. EFFICACY Not reported

155


Nitechi 200593 Study design: Case series Location: Israel Recruitment/Treatment dates: Oct 2003-Dec 2004 Source of funding: not reported

Inclusion criteria: 18 years and above of either gender with varicose veins, CEAP II - VI. Exclusion criteria: previous DVT, anticoagulant treatment, non-ambulant, presence of PVD or malignancy. Number of patients: 423 (97 patients underwent a previous surgery) Length of follow-up: mean 10 months Mean age (range): 57 Gender: 93M, 330F Venous disease: Venous insufficiency Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 3% POL Foam-producing technique: Tessari Sclerosant: air: 1:3 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to guide injection Number of injections for each session: 2 Amount of foam injected for each session: 5-8ml/injection Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: used but duration not reported

SAFETY Serious adverse events, n DVT: 2 Skin necrosis: 1 EFFICACY LSV occlusion after an average of 3.9 treatments (Men needed 3 treatments, women needed 4.5 to achieve good result) Successful treatment (judged by ultrasound and patient satisfaction): 364 (86%)

156


Rybak 200372 Study design: RCT Location: Poland Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: patients having leg ulcers with venous reflux Exclusion criteria: not reported Number of patients: (a) 20; (b) 20 Length of follow-up: 6 months Mean age (range): not reported Gender: not reported Venous disease: leg ulcers with venous reflux Number of patients lost to follow-up: 0

(a) Foam sclerotherapy Strength & type of sclerosant for producing foam: 3% polidocanol Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported (b) Conservative treatment (compression, local debridement, pharmacotherapy)

SAFETY Not reported EFFICACY Healing of ulcer: (a) 15; (b) 9

157


Sadoun 200394 Study design: Case series Location: France Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 20 Length of follow-up: 2 years Mean age (range): not reported Gender: not reported Venous disease: LSV varicosities Number of patients lost to follow-up: not reported

Foam sclerotherapy Strength & type of sclerosant for producing foam: not reported Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Adverse events, n Bruising: 90% Inflammation and pain: 25% Pigmentation: 50% (Resolved in 90% after 6 months) EFFICACY Persistence of a sclerosed varicose vein: 5% Total ‘disappearance’ of the varicose vein: 80% Recurrence: 15%

158


Schadeck 200195 Study design: Case series Location: France Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: a) 118 b) 100 c) 100 Length of follow-up: not reported Mean age (range): not reported Gender: not reported Venous disease:

a) Saphenous/ great collateral veins b) Reticular veins c) Telangiectasis


Foam sclerotherapy Strength & type of sclerosant for producing foam:

a) 3% STS (Trombovar) b) 0.2% POL foam/mousse c) 0.2-0.5% POL (Scleremo)

Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied:

a) 8d b) 7d c) 5 d

SAFETY Adverse events, n a b c

Inflammation (%) 12 NR NR Pigmentation (%) NR 5.4 2

Matting (%) NR 8.5 9

EFFICACY Occlusion/ no reflux (6 months): (a) 96.6%; (b) 99% (c) 91.7% OTHERS 1. Unclear whether Trombovar and Scleremo are commercial products which are available as foam 2. Was treated as case series as the patient had quite different venous disease across group.

159


Sierra 200296 Study design: Case series Location: not reported Recruitment/Treatment dates: 1996-2000 Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 360 (all had undergone surgery 3 months to 15 years earlier) Length of follow-up: 6 months to 5 years Mean age (range): not reported Gender: not reported Venous disease: Recurrent varicose veins after surgery (all had incompetence of one or more trunk veins with deep to superficial reflux) Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: POL Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: 30ml Number of sessions: mean 6 Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n No serious complications were observed

Adverse events, n Reported as ‘minor sequelae were quickly resolved’ EFFICACY Occlusion: 94% All superficial varicosities were eliminated. OTHERS Patients returned to work or normal activities immediately.

160


Tessari 200497,98 Study design: Case series Location: Italy Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 532 Length of follow-up: not reported Mean age (range): median 49 Gender: 181M, 351F Venous disease: varicose veins (89 LSV, 49 SSV, 394 collateral branches) Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: STS Foam-producing technique: Tessari Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: used to guide injection Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: not reported Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: used for 24 hours

SAFETY Not reported EFFICACY Complete obliteration: 394/532 (74%) Antigrade flow: 96/532 (18%) Recanalisation: 43/532 (8%)

161


Vin 200599 Study design: Case series Location: France Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: not reported Exclusion criteria: not reported Number of patients: 280 limbs Length of follow-up: 1 year Mean age (range): not reported Gender: not reported Venous disease: LSV Number of patients lost to follow-up: 21/280 (7.4%) at 1 year

UGFS Strength & type of sclerosant for producing foam: 3% POL Foam-producing technique: not reported Sclerosant: air: 1:4 Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: 1 Amount of foam injected for each session: 3cc (if needed, 5cc in total in the 2nd session, 3cc at the upper third of the thigh and 2cc at the lower third) Number of sessions: 1 (if needed, a second session was performed 2 weeks later) Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n DVT: 1 Adverse events, n Venous inflammation: 3.3% EFFICACY Occlusion of LSV

n (%)

At 1st session 238/280 (85) At 2nd session 260/280 (92.8) 1 year 207/280 (79.9)

12.7% did not occlude.

162


Weiss 2002100 Study design: Case series Location: not reported Recruitment/Treatment dates: not reported Source of funding: not reported

Inclusion criteria: small diameter vessels (0.3-3mm diameter) without saphenous system disease Exclusion criteria: not reported Number of patients: 60 Length of follow-up: 6 months Mean age (range): not reported Gender: not reported Venous disease: reticular and spider veins of thighs Number of patients lost to follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 0.1% or 0.2% STS Foam-producing technique: not reported Sclerosant: air: not reported Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported Number of injections for each session: not reported Amount of foam injected for each session: not reported Number of sessions: average 1.22 treatments per region (range 1-5) Total amount of foam for scheduled treatment: not reported Duration of compression after injection if compression applied: not reported

SAFETY Serious adverse events, n Skin necrosis: 0 Adverse events, n Telangiectatic matting: 3/60 (5%) Postsclerosis pigmentation: 8/60 (13%) EFFICACY

Improvement %

>50% 82.6 51-75% 43.5 76-100%) 39.1

163

APPENDIX 7 Characteristics of the included studies: non-English language studies Study details Participant characteristics Intervention characteristics Results

Benigni 1999101 Study design: non-randomised comparative study (pilot study) Location: France Recruitment/Treatment dates: not reported

Number of patients: (a) 10 (b) 10 Length of follow-up: 75 days

(a) UGFS Strength & type of sclerosant for producing foam: 0.25% d’Aetoxysclerol (polidocanol) Foam-producing technique: not reported Sclerosant: air: not reported (b) Liquid sclerotherapy Strength & type of sclerosant: 0.25% d’Aetoxysclerol (polidocanol)

SAFETY Serious adverse events, n Skin necrosis: (a) 0; (b) 0

Adverse events, n

(a) (b) Bruising 15 (reported as) 9/10

Microthrombi 3 24(reported as) Thrombi 3 2 Matting 0 3 Pigmentation 1 4

EFFICACY Not reported

164


Benigni 2005120-122 Study design: case report Location: France Recruitment/Treatment dates: not reported

Number of patients: 5 (5 limbs) Length of follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: case 1: 0.20% polidocanol; other cases: 0.15% polidocanol Foam-producing technique: not reported Sclerosant: air: not reported

SAFETY Case 1: visual disturbance: Three minutes later after the injection, the patient noticed a central blurring of vision, which turned into a typical scintillating scotoma, spreading to the periphery. The visual symptoms lasted 20min without subsequent headache. It was unclear whether the patient had migraine history or not.. Case 2: visual disturbance followed by headache: Ten minutes after the injection, the patient saw a white spot in the lower part of her visual field, rapidly expanding, associated with moving broken lines and blurred vision. This lasted 23min and was followed by a 2h bitemporal pulsatile headache without nausea, vomiting, photo- or phonophobia. Immediately after the previous injection, she also had blurred vision for a few minutes, followed by headache. It was unclear whether the patient had migraine history or not.. Case 3: visual disturbance followed by headache: The minutes after the injection, the patient progressively saw as through a kaleidoscope in her left visual field for 30min, and subsequently suffered fronto-temporal headache. The headache was slightly pulsatile, without nausea, vomiting, photo- or phonophobia. It was unclear whether the patient had migraine history or not.. Case 4: visual disturbance followed by headache: The patient had history of migraine with aura since the age of 12 with three to four attacks per year except during the previous year. 10min after injection, she experienced her typical scintillations lasting 25min and followed by a headache of 4h duration. Symptoms were the same as those she experienced before.

165


Breu 2004103 Study design: case series (prospective) Location: Germany Recruitment/Treatment dates: from March 2001

Number of patients: 342 Length of follow-up: 6w clinical follow-up; 1-3y by duplex scan

UGFS Strength & type of sclerosant for producing foam: polidocanol, strength not reported Foam-producing technique: Tessari Sclerosant: air: not reported

SAFETY Serious adverse events, n None

Adverse events, n Thrombophlebitis: 18 (5%)

Persistent pain for two weeks: 7%

EFFICACY Successfully sclerosed (complete obliteration) at 6w: 97%; Recanalised after one year: 4.5%; Recanalised after two years: 9.3%; All recanalisation were successfully treated. Persisting symptoms: 7%

Creton 2005104 Study design: case series Location: not reported Recruitment/Treatment

dates: not reported

Number of patients: 130 Length of follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: not reported Foam-producing technique: not reported Sclerosant: air: not reported

SAFETY Serious adverse events, n DVT at day3: 2/130 assymptomatic

EFFICACY All reflux closed; Risk of recanalisation is low; Risk of thrombosis is almost inexistent.

166


Demagny 2002102 Study design: non-randomised comparative study Location: France Recruitment/Treatment dates: Jan 1999 – Mar 2001

Number of patients: 254

LSV SSV

(a) 150 veins 50 veins

(b) 150 veins 50 veins

Length of follow-up: 180 days

(a) UGFS Strength & type of sclerosant for producing foam: 1.5-3% STS Foam-producing technique: not reported Sclerosant: air: 1:5

SAFETY Serious adverse events, n None

Adverse events, n Vison weakness: 5, for a few seconds or for < 2 min. Loss of vision: 0 Allergic reaction: cutaneous at palms, regressed spontaneously

EFFICACY Success rate:

30 days 180d LSV SSV LSV SSV

(a) 58% 68% 67% 84%

(b) 30% 54% 47% 64%

Recanalisation:

30 days Between 60d and 180d LSV SSV LSV SSV

(a) 10.7% - - 7.5

(b) - 13.5% 22% - Ferrara 2005105 Study design: case series Location: France Recruitment/Treatment dates: not reported

Number of patients: 50 Length of follow-up: 90 days

UGFS Strength & type of sclerosant for producing foam: 0.2% aetoxysclerol (polidocanol) Foam-producing technique: not reported Sclerosant: air: not reported

SAFETY Serious adverse events, n Skin necrosis: 0

Adverse events, n General symptoms: 0

EFFICACY Not reported.

167


Frullini 2000106 Study design: case series (retrospective) Location: Italy Recruitment/Treatment dates: since 1995

Number of patients: Before 1997: 595 veins After 1997: 167 veins Length of follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: after 1997, 3-4% polidocanol(35%) or 1-3% STS (65%); information for before 1997 not reported Foam-producing technique: technique described in Frullini 2000 Sclerosant: air: not reported

SAFETY Serious adverse events, n Embolic reaction: 0

Adverse events, n Visual disturbance: 2 episodes, but reported not observed during the last months of the study due to better technique. Confusion (short-term): 1 Partial thrombosis: 1 Skin pigmentation: 6 Inflammatory reactions: 5 phlebitis Allergic reaction: 0

EFFICACY Immediate success rate LSV: 80.5%; SSV (88.3%); recurrent varicose vein (95.7%).

168


Hamel-Desnos 2005107,108 Study design: case series (prospective) Blinding stage of a RCT: 1% vs 3% foam Location: France Recruitment/Treatment dates: Sep 2003 to Jan 2004

Number of patients: 140 (70 treated by 1% polidocanol made foam; 70 treated by 3% polidocanol made foam); 158 veins treated Length of follow-up: 2y

UGFS Strength & type of sclerosant for producing foam: 1% or 3% polidocanol Foam-producing technique: not reported Sclerosant: air: 1:4

SAFETY Serious adverse events, n DVT: 1/158 veins

Adverse events, n Cutaneous inflammation: 17.6% Localised pain: 1 Lower back pain: 1 EFFICACY Interruption of pathological reflux: 91.1% at 3w Success rate: 80% at 6m Recanalisation: 18 (12%) at 6m

Lucchi 2003111 Study design: case series (prospective) Location: Italy Recruitment/Treatment dates: Nov 1993 to May 2000

Number of patients: 114; 127 LSV with 118 completed protocol Length of follow-up: 6m

UGFS Strength & type of sclerosant for producing foam: 3% STS Foam-producing technique: reported as ‘traditional technique’. Sclerosant: air: not reported

SAFETY Serious adverse events, n Not reported.

Adverse events, n Inflammation: 9 (7.7%) EFFICACY Complete occlusion of treated veins: 114/118 veins (96.6%) Scleroresistance: 1 (0.8%), a vein of 17mm. Reflux of small calibre: 3 (2.6%)

169


Milleret 2004112,113,128 Study design: Case series (prospective) Location: unclear (France or Canada) Recruitment/Treatment dates: May 2001 – May 2002

Number of patients: 165 Length of follow-up: 1m

UGFS (alpha technique) Strength & type of sclerosant for producing foam: 2% STS Foam-producing technique: Tessari Sclerosant: air: not reported

SAFETY Serious adverse events, n DVT: 1

Adverse events, n Infections: 0 Inflammatory reactions: 12%

Schadeck 2004114 Study design: case series (prospective) Location: France Recruitment/Treatment dates: not reported

Number of patients: 108 Length of follow-up: mean 14.7m

UGFS Strength & type of sclerosant for producing foam: 3% lauromacrogol 400 Foam-producing technique: double-syringe system Sclerosant: air: 1:4

SAFETY Serious adverse events, n Arterial injection: 0 Adverse events, n Visual disturbance: 0 Inflammatory reactions: 7 (6.6%) Skin pigmentation: 0

EFFICACY Complete occlusion after two sessions: 93%; Reflux: 4 Success rate: 97.2%

170


Sica 2005116 Study design: case series (prospective) Location: not reported Recruitment/Treatment dates: not reported

Number of patients: 148 (107 LSV; 71 SSV) Length of follow-up: 1y

UGFS Strength & type of sclerosant for producing foam: 1% STS Foam-producing technique: reported as MS method Sclerosant: air: not reported

SAFETY Adverse events, n Thoracic constriction (transitional): 1

EFFICACY Complete sclerosis: 95.7% (day 7) LSV: 86.3% (1y) SSV: 89.6% (1y)

Sica 2003115 Study design: case series (prospective) Location: France Recruitment/Treatment dates: Mar 2000 – May 2002

Number of patients: 52; 97 LSV and 29 SSV Length of follow-up: 2y

UGFS Strength & type of sclerosant for producing foam: 1% STS Foam-producing technique: (reported as) Luer-Lock Vygon Sclerosant: air: not reported

SAFETY Serious adverse events, n No major undesirable effects were observed.

Adverse events, n Inflammatory reactions: 7 veins (10%)

EFFICACY Absence of reflux: 95% (3m), both large and small veins; 81% (2y) large veins; 87% (2y) small veins.

171


Stucker 2005117 Study design: case series Location: Germany Recruitment/Treatment dates: not reported

Number of patients: 28 (12 had post thrombolic symdrom) Length of follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 2% polidocanol Foam-producing technique: not reported Sclerosant: air: 1:4

SAFETY Adverse events, n 1 phlebitis

Uhl 2005118 Study design: case series Location: not reported Recruitment/Treatment

dates: not reported

Number of patients: 140 Length of follow-up: not reported

UGFS Strength & type of sclerosant for producing foam: 0.5-3% polidocanol Foam-producing technique: Tessari Sclerosant: air: not reported

EFFICACY Incompressable: 79% of 86 + 57% of 34 + 88% of 20 = 105/140 (75%)

172


Wildenhues 2005119 Study design: not reported Location: not reported Recruitment/Treatment dates: not reported

Number of patients: 213 (192 LSV and 21 SSV varicosities) Length of follow-up: 2y

UGFS Strength & type of sclerosant for producing foam: 3% polidocanol Foam-producing technique: not reported Sclerosant: air: not reported

SAFETY Serious adverse events, n DVT: 2 (patients with coagulopathies) Thromboembolism: 0 Necrosis: 0 Adverse events, n ‘minor’ vein thrombosis following treatment for SSV: 2 Skin infection: 0 EFFICACY Closing rate at 2y: 88%

Notes: 1. Information was not extracted from non-English language studies for Source of funding, Inclusion/Exclusion criteria, Age, Gender, Venous disease, Number of patients

lost to follow-up, Use of ultrasound guidance for identifying vein, monitor injection or foam flow, Number of injections for each session, Amount of foam injected for each session, Number of sessions, Total amount of foam for scheduled treatment, Duration of compression after injection if compression applied.

173

APPENDIX 8 Characteristics of the included studies: unpublished study (case report) Study details Participant characteristics Intervention characteristics Results

Kritzinger, personal communication Study design: case report Location: not reported Recruitment/Treatment dates: not reported Source of funding: not reported

Number of patients: 4 (4 limbs) Length of follow-up: not reported Age: 70y, 70y, 39y Gender: 1M, 2F Venous disease: Case 1 Large lateral thigh perforator

Case 2 Left LSV due to preterminal vale incompetence, otherwise healthy, no medical history

Case 3 Bilateral SFJ incompetence with huge LSV varicose veins, otherwise healthy

UGFS Strength & type of sclerosant for producing foam: case 1: 1.5% or 3% STS (3% was used for the 3rd injection); case 2: 0.5% or 1% STS; case 3: 1% or 3% STS (3% was used for the 2nd injection) Foam-producing technique: double-syringe technique (proprietary connector using butterfly tubing) Sclerosant: air: 3:1; foam for the second treatment for case 3 was made of 2.5ml 3% STS, 0.5ml 6% iodine, plus 4ml air. Use of ultrasound guidance for identifying vein, monitor injection or foam flow: not reported, mentioned used of echosclerotherapy Number of injections for each session: not reported Amount of foam injected for each session: ml

Session 1st 2nd 3rd 4th

Case 1 3 5 5 na Case 2 8 6 5 8 Case 3 8 5.5 na na

Number of sessions: case 1: 3; case 2: 4; case 3: 2 Total amount of foam for scheduled treatment: case 1: 13ml; case 2: 27ml; case 3: 13.5ml Duration of compression after injection if compression applied: use of compression not reported

SAFETY Case 1: grand mal seizure: Approximately 40 min after the 3rd UGFS treatment while driving home, the patient began to experience scintillating scotomas. A few minute later, while at home, he developed a headache and a few minutes later he developed confusion then stupor. At the way to ER by ambulance he suffered a grand mal seizure. Diazepam 50mg total was given. He stayed in ICU for three days and was discharged at day 5. Physical examination including use of ECG, CT, MRI brain, venous duplex, echocardiogram, blood gases etc showed no myocardial infarction, no CVA, no septal defects (right-to-left shunt), no DVT, no pulmonary embolism, and no sepsis. His was on coumadin and digoxin for atrial fibrillation since CVA 16 years ago. No sequelae. No incident occurred after the first two sessions of UGFS. Case 2: myocardial infarction After 30 min following the 4th UGFS treatment while still in the office, she developed central chest tightness with radiation to left arm and jaw. She was given oxygen and ASA immediately. Four doses of NTG spray was given but failed to relieve pain. She was then transferred to emergency. Investigations confirmed a myocardial infarction (mild-moderate with CK of 800). V/Q scan was negative. Echocardiogram showed no right-to-left shunt. Coronary angiogram showed no haemodynamically significant stenosis. She reported scotomas following a previous treatment, no other incident occurred after the first three sessions of UGFS. Case 3: central chest heaviness Immediately after the 2nd UGFS treatment a female developed central chest heaviness. Oxygen and ASA was given but she refused NTG. Pain was still present but milder after 20min. Ambulance was then called. Paramedics 12-lead ECG was normal. By this time, the pain was gone and she was sent home. No recurrence of pain occurred. EFFICACY Efficacy of case 1 and case 2 was not reported. Proximal LSV of case 3 was closed at follow-up (time not reported).

174

APPENDIX 9 Number and type of excluded studies; reasons for exclusion Liquid sclerotherapy used (N=97): Abad C, Antunez M, Cabrero A. [Pulmonary thromboembolism after sclerotherapy of a varicose vein in the lower limb]. Anales de Medicina Interna 2004;21(8):415-6.

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175

Conrad P. A complication of sclerotherapy. Med J Aust 2000;`72(3):144.

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Air-block technique used (N=4):

Georgiev M. Postsclerotherapy hyperpigmentations. Chromated glycerin as a screen for patients at risk (a retrospective study). J Dermatol Surg Oncol 1993;19(7):649-52.

180

Labas P, Ohradka B, Cambal M, Ringelband R. The results of compression sclerotherapy: Comparative study of two techniques and two sclerosants. Phlebologie 2000;29(5):137-41.

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Results for foam sclerotherapy not presented separately (N=3):

McDonagh B, Sorenson S, Gray C, Huntley DE, Putterman P, King T et al. Clinical spectrum of recurrent postoperative varicose veins and efficacy of sclerotherapy management using the compass technique. Phlebology 2003;18(4):173-86.

Rao J, Wildemore JK, Goldman MP. Double-blind prospective comparative trial between foamed and liquid polidocanol and sodium tetradecyl sulfate in the treatment of varicose and telangiectatic leg veins. Dermatol Surg 2005;31(6):631-5.

Varcoe PF. Ultrasound guided sclerotherapy: efficacy, adverse events and dosing - an international survey. Aust N Z J Phlebol 2003;7(2):17-24.

No data (N=16):

Cabrera J. Widening the limits of sclerotherapy: new sclerosing products. Phlebologie 1997;(2):181-8.

Diamand JM. Will echo-guided foam sclerotherapy of the greater saphenous vein become an alternative to surgical stripping? a multicenter protocol study. UIP World Cogress Chapter Meeting, San Diego, August; 2003.

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Frullini A. Mid term follow-up of foam sclerotherapy for medium amd large veins. American College of Phlebology, 15th Annual Congress, La Quinta,November; 2001.

Grondin L. Micro foam sclerotherapy concomitance with endovenous laser ablation. UIP World Cogress Chapter Meeting, San Diego, August; 2003.

181

Isaacs M, Gardner M. Combined endovenous laser and duplex guided foam sclerotherapy in the treatment of varicose veins. UIP World Cogress Chapter Meeting, San Diego, August; 2003.

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Olivier P, Carpentier P. Treatment of the greater saphenous vein GSV incompetency by echo-guided sclerotherapy using Lauromacrogol 400 foam - protocol for a prospective study from 2002 to 2005. American College of Phlebology, 16th Annual Congress, Fort Lauderdale, November; 2002.

Ouvry PA. Sclerotherapy: General accidents, shocks, allergies. Phlebologie 1986;39(2):245-9.

Quintana AU. The CO2 bolus method: a new field of application and research in sclerotherapy. American College of Phlebology, 15th Annual Congress, La Quinta,November; 2001.

Thibault P. Echosclerotherapy using Tessari foam: the Audtralian ecperience. 15th UIP World Cogress, Rio de Janeiro, October; 2005.

Zubicoa ES, Sanchez CF, Arias C, Sainz Gonzalez F. Recurrent varicose veins: endovascular treatment with neojunctions selective embolization. Phlebology 2005;20(3):144-5

Foreign language not included in review. (N=9)

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Geller AN, Shargorodskaia AM. [Complications of varicoside injection therapy in varicose veins of the lower extremities]. Sovetskaia Meditsina 1970;33(2):64-7. (Russian)

Konno M, Hirakawa M, Ishii M, Ogawa Y, Hayashi J, Kojima T. Compression sclerotherapy for varicose veins. Japanese Journal of Plastic & Reconstructive Surgery 1997;40(6):553-8. (Japanese)

Kume A, Ueda K, Higashi N, Sano S. Clinical results of sclerotherapy for varicose veins of lower extremity. Skin Research 1995;37(5):643-50. (Japanese)

182

Morita K, Hayakawa M, Hayashi M. Cases report of hemantioma successfully treated with sclerotherapy and pulmonary embolism which occurred after sclerotherapy. Skin Research 1995;27(5):658-66. (Japanese)

Ohkuma M, Shindo H, Ishida O, Shindo K, Nishimatsu S, Ohyanagi H et al. Summarizing report on sclerotherapy of 50 cases with varicose vein. Skin Research 1995;37(5):651-7. (Japanese)

Saliu H, Shaqiri G, Kelmendi Z, Bajraktari S, Osmani E, Dalladaku F et al. [Postphlebitic syndrome due to inadequate indications for sclerotherapy]. Acta Chirurgica Iugoslavica 1989;36(Suppl 1):243-4. (Croatian)

Vasiutkov VI. [Indications for sclerosing theraph of superficial varicose veins and its possibilities]. Vestnik Khirurgii Imeni i - i – Grekova 1978;121(12):53-7. (Russian)

Other reasons (N=27):

Bilbao JI, Martinez-Custa A,Urtasun F. Complications of embolization. Semin Interv Radiol 2006;23(2)126-42. (Complications of embolization not related to sclerotherapy)

Bountouroglou D, Geroulakos G. Ultrasound-guided foam sclerotherapy for the treatment of primary varicose veins. Phlebology 2004;19(3):107-8. (Narrative review of sclerotherapy)

Feied CF. Deep vein thrombosis: the risks of sclerotherapy in hypercoagulable states. Semin Dermatol 1993;12(2):135-49.(Review of risk factors of DVT associated with liquid sclerotherapy)

Fischer R, Chandler JG, Stenger D, Puhan MA, MaeseneeR MG. Patient characteristics and physician-determined variables affecting saphenofemoral reflux recurrence after ligation and stripping of the great saphenous vein. J Vasc Surg 2006 43(1):81-7. (Liquid sclerotherapy – not focused on adverse events)

Fisher DA. Regarding extensive tissue necrosis following high concentration sclerotherapy for varicose veins. Dermatol Surg 2000;26(11):1082. (Advantage of polidocanol in sclerotherapy)

Gachet G. A new simple and cheap method of maing foam for echo-guided sclerosis. Phlebologie 2001;54(1):63-5. (Discusses manufacture of foam)

Gallagher PG. Varicose veins--primary treatment with sclerotherapy. A personal appraisal. J Dermatol Surg Oncol 1992;18(1):39-42. (Liquid sclerotherapy – no study conducted)

Gobin J-P. Complications in foam sclerotherapy. Angeiologie 2004;56(2):49-55. (narrative review)

Guex JJ. Indications for the sclerosing agent polidocanol (aetoxisclerol dexo, aethoxisklerol kreussler). J Dermatol Surg Oncol 1993;19(10):959-61. (Mentions air-block technique related to adverse event)

Hamel-Desnos C, Desnos P, Ouvry P. New therapeutic methods in the management of varicose disease: Echo-sclerotherapy and foam. Phlebologie 2003;56(1):41-8. (Review of foam sclerotherapy)

183

Hofmann WJ. Alternative therapy for superficial venous leg insufficiency. Gefasschirurgie 2006;11(3):217-28. (Review of sclerotherapy)

Leal MJ, Zubicoa ES, Grimberg M, Vergara CL, Jimenez Gutierrez JA. Subdiaphragmatic venous insufficiency: Embolization treatment using mixed technique (coils and foam). Phlebolymphology 2004;45:269-75. (Injected veins not in lower limbs)

Lees TA, Beard JD, Ridler BM, Szymanska T. A survey of the current management of varicose veins by members of the Vascular Surgical Society. Ann R Coll Surg Engl 1999; 81(6):407-17. (Survey – not foam sclerotherapy)

Levy JB, Levy F. Acute pain after injection of sclerosing agents. [French]. Journal des Maladies Vasculaires 1986;11(Suppl. A):12-5. (narrative review)

Lim A, Parsi K. Post-sclerotherapy hypertrichosis. Aust N Z J Phlebol 1999;3(2)59-62. (Post-sclerotherapy hypertrichosis, foam not mentioned)

Magee RH. A complication of sclerotherapy. Med J Aust 1999; 171(3):166. (Arterial injection in liquid sclerotherapy)

Min RJ. Lower extremity superficial venous insufficiency: Percutaneous techniques of management. Techn Vasc Interv Radiol 2000;3(1):54-9. (Review of use of sclerotherapy)

Miserey G, Reinharez D, Ecalard P. [Sclerotherapy with ultrasonography in various risk zones. Phlebologie 1991;44(1):85-90. (summary of video film)

Redondo P, Cabrera J. Microfoam sclerotherapy. Semin Cut Med Surg 2005; 24(4):175-83. (Review of foam sclerotherapy)

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Sadoun S, Benigni J. Good clinical practice and sclerosing agent foam: Propositions for a controlled prospective randomised multicenter blind comparative study on the sclerosing treatment with Aetoxisclerol(R) 0,20%. Phlebologie 1999;52(3):291-7. (description of proposed study)

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APPENDIX 10 Detailed quality assessment results for included English language studies: randomised controlled trials

Study ID Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14

Alos 200620 + ? + + + + + + ? + + ? - ?

Belcaro 200321 + + + + + ? + ? ? - + ? + ?

Bountouroglou 200626 + - ? + + ? + ? ? - + ? - ?

Hamel-Desnos 200329 + ? ? + + + + ? ? ? + - + ?

Kern 200431 + ? + + + ? + + ? + + ? - ?

Wright in press36 + ? ? + - ? + ? ? ? + ? ? ?

Rao 200534 + ? - + + + + + ? ? - - + ?

Note: 1. See Appendix 2 for checklist for quality assessment of randomised controlled trials of an interventional procesure 2. + Yes; -- No; ? Unclear

185

APPENDIX 11 Detailed quality assessment results for included English language studies: non-randomised comparative studies

Study ID Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15 Q16 Q17 Q18

Yamaki 200441 ? + - ? ? + + ? + + + ? + - ? + - -

Note: 1. See Appendix 3 for checklist of quality assessment of non-randomised comparative studies evaluating interventional procedures 2. + Yes; -- No; ? Unclear

186

APPENDIX 12 Detailed quality assessment results for included English language studies: case series

Study ID Q1 Q2 Q3 Q4 Q5 Q7 Q8 Q9 Q10 Q11 Q13 Q14 Q15 Q17

Barrett 200444 + + - ? - + ? ? + + + - ? -

Bergan 200646 + + - ? - + ? ? + + + - ? +

Cabrera 200453 + + ? + - + ? + + + + - ? +

Cabrera 200151 + + ? + - + ? ? + + + - ? +

Cavezzi 200256 + + ? ? + + ? ? + + + - ? -

Cavezzi 199954 + + ? + ? + ? ? + + + - ? -

Coleridge Smith in press58 + + - ? + + + + + + + - ? +

Frullini 200259 + + ? ? - + ? ? + + + - ? ?

Hamanet 200660 + + - ? ? + ? ? + + + - + +

Kakkos 200662 + + - ? ? + ? ? + + - - ? +

McDonagh 200263 + + - + + + ? ? + + + - ? +

Padbury 200464 + + ? + + + ? + + + + - - -

Tessari 200166 + - ? ? ? + ? ? + + + - ? -

Note: 1. See Appendix 3 for checklist of quality assessment of non-randomised comparative studies evaluating interventional procedures; the same checklist was adapted for case series by taking out question 6, 12, 16 and 18;

2. + Yes; - No; ? Unclear

systematic review of the safety and efficacy of foam .../file/foam-sclerotherapy-ipp.pdf ·...

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