Abstract
Introduction
Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of advice about self-help interventions in people receiving usual care for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 101 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low-level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha2 antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, self-help (advice to elevate leg, to keep leg active, to modify diet, to stop smoking, to reduce weight), short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene-related peptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative pressure, recombinant keratinocyte growth factor, platelet-derived growth factor).
Key Points
Leg ulcers are usually secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders.
Compression bandages and stockings heal more ulcers compared with no compression, but we don't know which bandaging technique is most effective.
Compression is used for people with ulcers caused by venous disease who have an adequate arterial supply to the foot, and who don't have diabetes or rheumatoid arthritis.
The effectiveness of compression bandages depends on the skill of the person applying them.
We don't know whether intermittent pneumatic compression is beneficial compared with compression bandages or stockings.
Occlusive (hydrocolloid) dressings are no more effective than simple low-adherent dressings in people treated with compression, but we don't know whether semi-occlusive dressings are beneficial.
Peri-ulcer injections of granulocyte-macrophage colony-stimulating factor may increase healing, but we don't know whether other locally applied agents are beneficial, as we found few trials.
Oral pentoxifylline increases ulcer healing in people receiving compression, and oral flavonoids, sulodexide, and mesoglycan may also be effective.
We don't know whether therapeutic ultrasound, oral aspirin, rutosides, thromboxane alpha2 antagonists, zinc, debriding agents, intravenous prostaglandin E1, superficial vein surgery, skin grafting, topical antimicrobial agents, leg ulcer clinics, laser treatment, or advice to elevate legs, increase activity, lose weight, change diet, or give up smoking increase healing of ulcers in people treated with compression.
Larval therapy is not likely to be beneficial as it has no impact on healing and is painful.
Compression bandages and stockings reduce recurrence of ulcers compared with no compression, and should ideally be worn for life.
Superficial vein surgery may also reduce recurrence, but we don't know whether systemic drug treatment is effective.
Clinical context
About this condition
Definition
Definitions of leg ulcers vary, but the following is widely used: loss of skin on the leg or foot that takes >6 weeks to heal.[1] Some definitions exclude ulcers confined to the foot, whereas others include ulcers on the whole of the lower limb. This review deals with ulcers of venous origin in people without concurrent diabetes mellitus, arterial insufficiency, or rheumatoid arthritis.
Incidence/ Prevalence
Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years.[2] Most leg ulcers are secondary to venous disease; other causes include arterial insufficiency, diabetes, and rheumatoid arthritis.[3] The annual cost to the NHS in the UK has been estimated at £300 million.[4] This does not include the loss of productivity due to illness.
Aetiology/ Risk factors
Leg ulceration is strongly associated with venous disease. However, about a fifth of people with leg ulceration have arterial disease, either alone or in combination with venous problems, which may require specialist referral.[2] Venous ulcers (also known as varicose or stasis ulcers) are caused by venous reflux or obstruction, both of which lead to poor venous return and venous hypertension.
Prognosis
People with leg ulcers have a poorer quality of life than age-matched controls because of pain, odour, and reduced mobility.[5] In the UK, audits have found wide variation in the types of care (hospital inpatient care, hospital clinics, outpatient clinics, home visits), in the treatments used (topical agents, dressings, bandages, stockings), and in healing rates and recurrence rates (26–69% in 1 year).[6] [7]
Aims of intervention
To promote healing; to reduce recurrence; to improve quality of life, with minimal adverse effects.
Outcomes
Healing rates: ulcer area, number of people who are ulcer-free, number of ulcers healed, number of ulcer-free limbs, time to complete ulcer healing. Recurrence rates: recurrence rates, number of new ulcer episodes, number of ulcer-free weeks or months, frequency of dressing/bandage changes, quality of life. Adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2011, Embase 1980 to June 2011, and The Cochrane Database of Systematic Reviews, June 2011 [online] (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We included all studies described as "open", "open label", or not blinded. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
Important outcomes | Adverse effects, Healing rates, Recurrence rates | ||||||||
Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
What are the effects of standard treatments for venous leg ulcers? | |||||||||
7 (467) | Healing rates | Compression bandages and stockings versus no compression | 4 | 0 | 0 | 0 | 0 | High | |
1 (140) | Recurrence rates | Compression bandages and stockings versus no compression | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data. Consistency point deducted for conflicting results |
11 (869) | Healing rates | Compression stockings or tubular garments versus compression bandages | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for incomplete reporting of data and methodological flaws. Directness points deducted for inclusion of people with different severities of ulcers and for differences in treatment regimens in both groups, affecting generalisability of results |
1 (138) | Recurrence rates | Compression stockings or tubular garments versus compression bandages | 4 | 0 | 0 | 0 | 0 | High | |
9 (679) | Healing rates | Multilayer elastomeric high-compression regimens versus other layered regimens | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of multiple interventions in comparison |
4 (280) | Healing rates | Multilayer high-compression bandages versus single-layer bandage | 4 | 0 | 0 | 0 | 0 | High | |
6 (850) | Healing rates | Multilayer elastomeric high-compression bandages versus short-stretch bandages or Unna's boot | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
1 (24) | Healing rates | Single-layer non-elastic system versus multilayer elastic system | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for uncertainty about generalisability of results in people with different conditions |
1 (38) | Healing rates | Single-layer non-elastic system versus multilayer non-elastic system | 4 | –2 | 0 | 0 | 0 | Low | Quality points deduced for sparse data and incomplete reporting of results |
1 (60) | Healing rates | Peri-ulcer injection of granulocyte-macrophage colony-stimulating factor | 4 | –1 | 0 | 0 | +1 | High | Quality points deduced for sparse data. Effect-size point added for RR <5 |
6 (459) | Healing rates | Semi-occlusive dressings (foam, film, hyaluronic acid-derived dressings, collagen, cellulose, or alginate) versus simple low-adherent dressings, in the presence of compression | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for spare data. Consistency point deducted for conflicting results |
1 (113) | Healing rates | Alginate dressings versus zinc oxide dressings | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data. Consistency point deducted for conflicting results |
4 (168) | Healing rates | Intermittent pneumatic compression plus compression stockings versus compression stockings or bandages alone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deduced for sparse data. Consistency point deducted for conflicting results |
27 studies at most (1401 at most) | Healing rates | Topical antimicrobial agents versus placebo or usual care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for assessing different outcome in 1 study and the inclusion of a mixed population in 1 review |
1 (213) | Recurrence rates | Topical antimicrobial agents versus placebo or usual care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of data |
1 (66) | Healing rates | Topical calcitonin gene-related peptide plus vasoactive intestinal polypeptide versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
1 (40) | Healing rates | Topical mesoglycan versus a plant-based extract | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
1 (60) | Healing rates | Topical negative pressure versus usual care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data. Directness points deducted for inclusion of people with non-venous ulcers and for uncertainty about generalisability of results outside a hospital setting |
1 (60) | Recurrence rates | Topical negative pressure versus usual care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data. Directness points deducted for inclusion of people with non-venous ulcers and for uncertainty about generalisability of results outside a hospital setting |
1 (94) | Healing rates | Topical recombinant human keratinocyte growth factor 2 plus compression versus placebo plus compression | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
2 (135) | Healing rates | Platelet-derived growth factor versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
at least 22 (at least 792) | Healing rates | Hydrocolloid (occlusive) dressings versus simple dressings in the presence of compression | 4 | 0 | 0 | 0 | 0 | High | |
4 (311) | Healing rates | Hydrocolloids versus other occlusive or semi-occlusive dressings | 4 | 0 | 0 | 0 | 0 | High | |
3 (388) | Healing rates | Different occlusive or semi-occlusive dressings (excluding hydrocolloids) versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
1 (86) | Healing rates | Topically applied autologous platelet lysate versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
1 (200) | Healing rates | Topically applied freeze-dried keratinocyte lysate versus vehicle or usual care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
What are the effects of adjuvant treatments for venous leg ulcers? | |||||||||
7 (659) | Healing rates | Oral pentoxifylline versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
2 (345) | Healing rates | Cultured allogenic bilayer skin replacement versus non-adherent dressing | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
5 (723) | Healing rates | Flavonoids plus compression versus compression alone | 4 | –1 | –1 | 0 | +1 | Moderate | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Effect-size point added for RR/OR >2 but <5 |
4 (488) | Healing rates | Oral sulodexide plus compression versus compression alone | 4 | 0 | 0 | 0 | 0 | High | |
1 (183) | Healing rates | Systemic mesoglycan plus compression versus placebo plus compression | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
2 (71) | Healing rates | Cultured allogenic single-layer dermal replacement versus usual care | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
1 (87) | Healing rates | Intravenous prostaglandin E1 versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological flaws |
1 (267) | Healing rates | Larval therapy versus usual care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
7 (301) | Healing rates | Low-level laser treatment versus sham treatment | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for incomplete reporting of results and for differences in length of follow-up. Directness points deducted for treatment inconsistencies between groups and for assessing different measures of healing |
1 (reported as "small") | Healing rates | Oral aspirin versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data and for methodological weaknesses |
1 (reported as "small") | Healing rates | Oral rutosides versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
1 (165) | Healing rates | Oral thromboxane alpha2 antagonists versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
1 (120) | Healing rates | Skin grafts versus usual care or versus each other | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for poor studies and insufficient evidence. Directness point deducted for generalisability of results |
1 (47) | Healing rates | Perforator ligation versus no surgery or versus surgery plus skin grafting in the presence of compression | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and no intention-to-treat analysis |
2 (215) | Healing rates | Minimally invasive surgery versus compression bandages or usual care | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
5 (at least 341 people) | Healing rates | Venous surgery (based on duplex scan) plus compression versus compression alone | 4 | 0 | 0 | 0 | 0 | High | |
3 (745 legs) | Recurrence rates | Venous surgery (based on duplex scan) plus compression versus compression alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
1 (39) | Healing rates | Open perforator surgery versus subfascial endoscopic perforator surgery | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
1 (39) | Adverse effects | Open perforator surgery versus subfascial endoscopic perforator surgery | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
1 (337) | Healing rates | Therapeutic ultrasound versus no or sham ultrasound | 4 | 0 | 0 | 0 | 0 | High | |
1 (337) | Recurrence rates | Therapeutic ultrasound versus no or sham ultrasound | 4 | 0 | 0 | 0 | 0 | High | |
What are the effects of organisational interventions for venous leg ulcers? | |||||||||
4 (at least 279 people) | Healing rates | Leg ulcer clinics versus usual care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for differences in treatments received by both groups and uncertainty about generalisability of results |
2 (246) | Recurrence rates | Leg ulcer clinics versus usual care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of data. |
What are the effects of interventions to prevent recurrence of venous leg ulcers? | |||||||||
1 (153) | Recurrence rates | Compression stockings versus no compression | 4 | –1 | 0 | 0 | +1 | High | Quality point deducted for sparse data. Effect-size point added for RR <0.5 |
2 (466) | Recurrence rates | Compression stockings versus other forms of compression | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for change-over |
4 (673) | Recurrence rates | Surgery plus compression versus compression alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological flaws |
1 (39) | Recurrence rates | Open versus endoscopic surgery | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting |
1 (139) | Recurrence rates | Oral rutoside versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting |
1 (48) | Recurrence rates | Oral stanozolol versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and weak methods (unit of randomisation and unit of assessment differed) |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Intermittent pneumatic compression
External compression applied by inflatable leggings or boots over, or instead of, compression bandages or stockings. A pump successively inflates and deflates the boots to promote the return of blood from the tissues. Newer systems have separate compartments in the boots so that the foot is inflated before the ankle, which is inflated before the calf.
- Iontophoresis
The delivery of an ionic substance by application of an electrical current.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Minimally invasive surgery
Surgery in which small incisions are made in the skin, and the use of surgical instruments with cameras or direct viewing through eyepieces allows the surgeon to operate. Often performed under local anaesthetic and as a day case.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Multilayer elastomeric high-compression bandages
Usually a layer of padding material followed by one to four additional layers of elastomeric bandages.
- Perforator ligation
A procedure that involves tying off the blood vessels that link the deep and superficial venous systems. The one-way valves in these veins prevent flow from the deep to the superficial system. Malfunctioning perforator vessels may be responsible for increasing venous pressure in the superficial venous system, leading to ulceration.
- Subfascial endoscopic perforator surgery
A minimally invasive endoscopic procedure that eliminates the need for a large incision in the leg. An endoscope is used to visualise directly and tie off incompetent medial calf perforating veins, to decrease venous reflux and reduce ambulatory venous pressure.
- Therapeutic ultrasound
Application of ultrasound to a wound, using a transducer and a water-based gel. Prolonged application can lead to heating of the tissues; but, when used in wound healing, the power used is low and the transducer is constantly moved by the therapist, so that the tissue is not heated significantly.
- Topical negative pressure
Negative pressure (suction) applied to a wound through an open-cell dressing (e.g., foam, felt).
- Unna's boot
An inner layer of zinc oxide-impregnated bandage, which hardens as it dries to form a semirigid layer against which the calf muscle can contract. It is usually covered in an elastomeric bandage.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Dale JJ, Callam MJ, Ruckley CV, et al. Chronic ulcers of the leg: a study of prevalence in a Scottish community. Health Bull (Edinb) 1983;41:310–314. [PubMed] [Google Scholar]
- 2.Callam MJ, Ruckley CV, Harper DR, et al. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J (Clin Res Ed) 1985;290:1855–1856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Callam MJ, Harper DR, Dale JJ, et al. Arterial disease in chronic leg ulceration: an underestimated hazard? Lothian and Forth Valley leg ulcer study. Br Med J (Clin Res Ed) 1987;294:929–931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Laing W. Chronic venous diseases of the leg. London, UK: Office of Health Economics, 1992. [Google Scholar]
- 5.Roe B, Cullum N, Hamer C. Patients' perceptions of chronic leg ulceration. In: Cullum N, Roe B, eds. Leg ulcers: nursing management. Harrow: Scutari, 1995:125–134. [Google Scholar]
- 6.Roe B, Cullum N. The management of leg ulcers: current nursing practice. In: Cullum N, Roe B, eds. Leg ulcers: nursing management. Harrow, UK: Scutari, 1995:113–124. [Google Scholar]
- 7.Vowden KR, Barker A, Vowden P. Leg ulcer management in a nurse-led, hospital-based clinic. J Wound Care 1997;6:233–236. [DOI] [PubMed] [Google Scholar]
- 8.O'Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2012. [Google Scholar]
- 9.Callam MJ, Ruckley CV, Dale JJ, et al. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. Br Med J (Clin Res Ed) 1987;295:1382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Chan CL, Meyer FJ, Hay RJ, et al. Toe ulceration associated with compression bandaging: observational study. BMJ 2001;323:1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nelson EA, Ruckley CV, Barbenel J. Improvements in bandaging technique following training. J Wound Care 1995;4:181–184. [DOI] [PubMed] [Google Scholar]
- 12.Amsler F, Willenberg T, Blattler W, et al. In search of optimal compression therapy for venous leg ulcers: a meta-analysis of studies comparing divers bandages with specifically designed stockings. J Vasc Surg 2009;50:668–674. [DOI] [PubMed] [Google Scholar]
- 13.Taradaj J, Franek A. Randomized trial of medical compression stockings versus two-layer short-stretch bandaging in the management of venous leg ulcers. Phlebologie 2009;38:157–163. [Google Scholar]
- 14.Brizzio E, Amsler F, Lun B, et al. Comparison of low-strength compression stockings with bandages for the treatment of recalcitrant venous ulcers. J Vasc Surg 2010;51:410–416. [DOI] [PubMed] [Google Scholar]
- 15.Szewczyk MT, Jawień A, Cierzniakowska K, et al. Comparison of the effectiveness of compression stockings and layer compression systems in venous ulceration treatment. Arch Med Sci 2010;6:793–799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Milic DJ, Zivic SS, Bogdanovic DC, et al. A randomized trial of the Tubulcus multilayer bandaging system in the treatment of extensive venous ulcers. J Vasc Surg 2007;46:750–755. [DOI] [PubMed] [Google Scholar]
- 17.Junger M, Wollina U, Kohnen R, et al. Efficacy and tolerability of an ulcer compression stocking for therapy of chronic venous ulcer compared with a below-knee compression bandage: results from a prospective, randomized, multicentre trial. Curr Med Res Opin 2004;20:1613–1623. [DOI] [PubMed] [Google Scholar]
- 18.Junger M, Partsch H, Ramelet A, et al. Efficacy of a ready-made tubular compression device versus short-stretch compression bandages in the treatment of venous leg ulcers. Wounds 2004;16:313–320. [Google Scholar]
- 19.Vowden KR, Mason A, Wilkinson D, et al. Comparison of the healing rates and complications of three four-layer bandage regimens. J Wound Care 2000;9:269–272. [DOI] [PubMed] [Google Scholar]
- 20.Moffatt CJ, Edwards L, Collier M, et al. A randomised controlled 8-week crossover clinical evaluation of the 3M Coban 2 Layer Compression System versus Profore to evaluate the product performance in patients with venous leg ulcers. Int Wound J 2008;5:267–279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Moffatt CJ, McCullagh L, O'Connor T, et al. Randomized trial of four-layer and two-layer bandage systems in the management of chronic venous ulceration. Wound Repair Regen 2003;11:166–171. [DOI] [PubMed] [Google Scholar]
- 22.O'Meara S, Tierney J, Cullum N, et al. Four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomised controlled trials with data from individual patients. BMJ 2009;338:1054–1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Partsch H, Damstra RJ, Tazelaar DJ, et al. Multicentre, randomised controlled trial of four-layer bandaging versus short-stretch bandaging in the treatment of venous leg ulcers. VASA 2001;30:108–113. [DOI] [PubMed] [Google Scholar]
- 24.Ukat A, Konig M, Vanscheidt W, et al. Short-stretch versus multilayer compression for venous leg ulcers: a comparison of healing rates. J Wound Care 2003;12:139–143. [DOI] [PubMed] [Google Scholar]
- 25.Franks PJ, Moody M, Moffatt CJ, et al. Randomized trial of cohesive short-stretch versus four-layer bandaging in the management of venous ulceration. Wound Repair Regen 2004;12:157–162. [DOI] [PubMed] [Google Scholar]
- 26.Nelson EA, Iglesias CP, Cullum N, et al. Randomized clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I). Br J Surg 2004;91:1292–1299. [DOI] [PubMed] [Google Scholar]
- 27.Blecken SR, Villavicencio JL, Kao TC. Comparison of elastic versus nonelastic compression in bilateral venous ulcers: a randomized trial. J Vasc Surg 2005;42:1150–1155. [DOI] [PubMed] [Google Scholar]
- 28.DePalma RG, Kowallek D, Spence RK, et al. Comparison of costs and healing rates of two forms of compression in treating venous ulcers. Vasc Endovasc Surg 1999;33:683–690. [Google Scholar]
- 29.Da Costa RM, Ribeiro Jesus FM, Aniceto C, et al. Randomized, double-blind, placebo-controlled, dose-ranging study of granulocyte-macrophage colony stimulating factor in patients with chronic venous leg ulcers. Wound Repair Regen 1999;7:17–25. [DOI] [PubMed] [Google Scholar]
- 30.Berliner E, Ozbilgin B, Zarin DA. A systematic review of pneumatic compression for treatment of chronic venous insufficiency and venous ulcers. J Vasc Surg 2003;37:539–544. [DOI] [PubMed] [Google Scholar]
- 31.Nelson EA, Mani R, Thomas K, et al. Intermittent pneumatic compression for treating venous leg ulcers. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2010. 21328252 [Google Scholar]
- 32.Bradley M, Cullum N, Sheldon T. The debridement of chronic wounds: a systematic review. Health Technol Assess 1999;3(17 Pt 1):1–78. Search date 1997. [PubMed] [Google Scholar]
- 33.Ramundo J, Gray M. Enzymatic wound debridement. J Wound Ostomy Continence Nurs 2008;35:273–280. [DOI] [PubMed] [Google Scholar]
- 34.Thomas S. Wound management and dressings. London, UK: Pharmaceutical Press, 1990. [Google Scholar]
- 35.Cameron J, Wilson C, Powell S, et al. Contact dermatitis in leg ulcer patients. Ostomy Wound Manage 1992;38:10–11. [PubMed] [Google Scholar]
- 36.Bradley M, Cullum N, Nelson EA, et al. Dressings and topical agents for healing of chronic wounds: a systematic review. Health Technol Assess 1999;3(17 Pt 2):1–35. Search date 1997. [PubMed] [Google Scholar]
- 37.Bouza C, Munoz A, Amate JM. Efficacy of modern dressings in the treatment of leg ulcers: a systematic review. Wound Repair Regen 2005;13:218–229. [DOI] [PubMed] [Google Scholar]
- 38.Palfreyman SJ, Nelson EA, Lochiel R, et al. Dressings for healing venous leg ulcers. In: The Cochrane Library, Issue 3, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. 16855958 [Google Scholar]
- 39.O'Donnell Jr, Lau J. A systematic review of randomized controlled trials of wound dressings for chronic venous ulcer. J Vasc Surg 2006;44:1118–1125. [DOI] [PubMed] [Google Scholar]
- 40.Briggs M, Nelson EA. Topical agents or dressings for pain in venous leg ulcers. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2009. [Google Scholar]
- 41.Taddeucci P, Pianigiani E, Colletta V, et al. An evaluation of Hyalofill-F plus compression bandaging in the treatment of chronic venous ulcers. J Wound Care 2004;13:202–204. [DOI] [PubMed] [Google Scholar]
- 42.Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. J Wound Care 2002;11:335–341. [DOI] [PubMed] [Google Scholar]
- 43.Wu P, Nelson EA, Reid WH, et al. Water vapour transmission rates in burns and chronic leg ulcers: influence of wound dressings and comparison with in vitro evaluation. Biomaterials 1996;17:1373–1377. [DOI] [PubMed] [Google Scholar]
- 44.Lachmann EA, Rook JL, Tunkel R, et al. Complications associated with intermittent pneumatic compression. Arch Phys Med Rehabil 1992;73:482–485. [PubMed] [Google Scholar]
- 45.O'Meara S, Cullum N, Majid M, et al. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technol Assess 2000;4:1–237. Search date 1997. [PubMed] [Google Scholar]
- 46.Chambers H, Dumville JC, Cullum N. Silver treatments for leg ulcers: a systematic review. Wound Repair Regen 2007;15:165–173. [DOI] [PubMed] [Google Scholar]
- 47.Carter MJ, Tingley-Kelley K, Warriner RA, et al. Silver treatments and silver-impregnated dressings for the healing of leg wounds and ulcers: a systematic review and meta-analysis. J Am Acad Dermatol 2010;63:668–679. [DOI] [PubMed] [Google Scholar]
- 48.Geske T, Hachmann E, Effendy I. Wound treatment with ethacridine lactate in venous leg ulcers: a prospective, randomized, placebo-controlled, single-blind study. Vasomed 2005;17:99–103. [In German] [Google Scholar]
- 49.Beckert S, Warnecke J, Zelenkova H, et al. Efficacy of topical pale sulfonated shale oil in the treatment of venous leg ulcers: a randomized, controlled, multicenter study. J Vasc Surg 2006;43:94–100. [DOI] [PubMed] [Google Scholar]
- 50.Michaels JA, Campbell B, King B, et al. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg 2009;96:1147–1156. [DOI] [PubMed] [Google Scholar]
- 51.Gherardini G, Gurlek A, Evans GRD, et al. Venous ulcers: improved healing by iontophoretic administration of calcitonin gene-related peptide and vasoactive intestinal polypeptide. Plast Reconstr Surg 1998;101:90–93. [DOI] [PubMed] [Google Scholar]
- 52.La Marca G, Pumilia G, Martino A. Effectiveness of mesoglycan topical treatment of leg ulcers in subjects with chronic venous insufficiency. Minerva Cardioangiol 1999;47:315–319. [In Italian] [PubMed] [Google Scholar]
- 53.Evans D, Land L. Topical negative pressure for treating chronic wounds. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002. [Google Scholar]
- 54.Samson D, Lefevre F, Aronson N. Wound-healing technologies: low-level laser and vacuum-assisted closure. Summary, Evidence Report/Technology Assessment: Number 111. AHRQ Publication Number 05-E005-1. December 2004. Available at: http://www.ahrq.gov/clinic/epcsums/woundsum.htm (last accessed 17 November 2015). [PMC free article] [PubMed] [Google Scholar]
- 55.Vuerstaek JD, Vainas T, Wuite J, et al. State-of-the-art treatment of chronic leg ulcers: a randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg 2006;44:1029–1037. [DOI] [PubMed] [Google Scholar]
- 56.Robson MC, Phillips TJ, Falanga V, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001;9:347–352. [DOI] [PubMed] [Google Scholar]
- 57.Wieman TJ. Efficacy and safety of recombinant human platelet-derived growth factor-BB (Becaplermin) in patients with chronic venous ulcers: a pilot study. Wounds 2003;15:257–264. [Google Scholar]
- 58.Vanscheidt W, Sibbald RG, Eager CA. Comparing a foam composite to a hydrocellular foam dressing in the management of venous leg ulcers: a controlled clinical study. Ostomy Wound Manage 2004;50:42–55. [PubMed] [Google Scholar]
- 59.Franks PJ, Moody M, Moffatt CJ, et al. Randomized trial of two foam dressings in the management of chronic venous ulceration. Wound Repair Regen 2007;15:197–202. [DOI] [PubMed] [Google Scholar]
- 60.Gottrup F, Jorgensen B, Karlsmark T, et al. Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers. Int Wound J 2007;4(Suppl 1):24–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Stacey MC, Mata SD, Trengove NJ, et al. Randomised double-blind placebo-controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg 2000;20:296–301. [DOI] [PubMed] [Google Scholar]
- 62.Harding KG, Krieg T, Eming SA, et al. Efficacy and safety of the freeze-dried cultured human keratinocyte lysate, LyphoDerm 0.9%, in the treatment of hard-to-heal venous leg ulcers. Wound Repair Regen 2005;13:138–147. [DOI] [PubMed] [Google Scholar]
- 63.Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Ho C, Tran K, Hux M, et al. Artificial skin grafts in chronic wound care: a meta-analysis of clinical efficacy and a review of cost-effectiveness (structured abstract). Ottawa: Canadian Coordinating Office for Health Technology Assessment, 2005: 63. [Google Scholar]
- 65.Jones JE, Nelson EA, Al-Hity A. Skin grafting for venous leg ulcers. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2012. [Google Scholar]
- 66.Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005;30:198–208. [DOI] [PubMed] [Google Scholar]
- 67.Coleridge-Smith PC. Daflon 500 mg and venous leg ulcer: new results from a meta-analysis. Angiology 2005;56(suppl 1):S33–S39. [DOI] [PubMed] [Google Scholar]
- 68.Coccheri S, Scondotto G, Agnelli G, et al. Randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thromb Haemost 2002;87:947–952. [PubMed] [Google Scholar]
- 69.Scondotto G, Aloisi D, Ferrari P, et al. Treatment of venous leg ulcers with sulodexide. Angiology 1999;50:883–889. [DOI] [PubMed] [Google Scholar]
- 70.Kucharzewski M, Franek A, Koziolek H. Treatment of venous leg ulcers with sulodexide. Phlebologie 2003;32:115–120. [Google Scholar]
- 71.Zou Y-X, Feng X, Jing Z-P. Efficacy and safety of sulodexide in the treatment of venous ulcers of leg. Pharm Care Res (Yaoxue Fuwu Yu Yanjiu) 2007;7:22–24. [Google Scholar]
- 72.Arosio E, Ferrari G, Santoro F, et al. A placebo-controlled, double blind study of mesoglycan in the treatment of chronic venous ulcers. Eur J Vasc Endovas Surg 2001;22:365–372. [DOI] [PubMed] [Google Scholar]
- 73.Milio G, Mina C, Cospite V, et al. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs. J Vasc Surg 2005;42:304–308. [DOI] [PubMed] [Google Scholar]
- 74.Gray M. Is larval (maggot) debridement effective for removal of necrotic tissue from chronic wounds? J Wound Ostomy Continence Nurs 2008;35:378–384. [DOI] [PubMed] [Google Scholar]
- 75.Dumville JC, Worthy G, Bland JM, et al. Larval therapy for leg ulcers (VenUS II): randomised controlled trial. BMJ 2009;338:b773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Petherick ES, O'Meara S, Spilsbury K, et al. Patient acceptability of larval therapy for leg ulcer treatment: a randomised survey to inform the sample size calculation of a randomised trial BMC Med Res Methodol 2006,6:43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Flemming K, Cullum N. Laser therapy for venous leg ulcers. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2001. [Google Scholar]
- 78.Schneider WL, Hailey D. Low level laser therapy for wound healing. Edmonton, Alberta: Alberta Heritage Foundation for Medical Research, 1999. [Google Scholar]
- 79.Franek A, Krol P, Kucharzewski M. Does low output laser stimulation enhance the healing of crural ulceration? Some critical remarks. Med Eng Phys 2002;24:607–615. [DOI] [PubMed] [Google Scholar]
- 80.Kopera D, Kokol R, Berger C, et al. Low level laser: does it influence wound healing in venous leg ulcers? A randomized, placebo-controlled, double-blind study. Br J Dermatol 2005;152:1368–1370. [DOI] [PubMed] [Google Scholar]
- 81.Kokol R, Berger C, Haas J, et al. Venous leg ulcers: no improvement of wound healing with 685-nm low level laser therapy. Randomised, placebo-controlled, double-blind study. Hautarzt 2005;56:570–575. [In German] [DOI] [PubMed] [Google Scholar]
- 82.Taradaj J, Franek A. Failure of low-level laser therapy to boost healing of venous leg ulcers in surgically and conservatively treated patients. Phlebologie 2008;37:241–246. [Google Scholar]
- 83.Leclère FM, Puechquiral IR, Rotteleur G, et al. A prospective randomized study of 980 nm diode laser-assisted venous ulcer healing on 34 patients. Wound Repair Regen 2010;18:580–585. [DOI] [PubMed] [Google Scholar]
- 84.Layton AM, Ibbotson SH, Davies JA, et al. Randomised RCT of oral aspirin for chronic venous leg ulcers. Lancet 1994;344:164–165. [DOI] [PubMed] [Google Scholar]
- 85.Schultz–Ehrenburg U, Müller B. Two multicentre clinical trials of two different dosages of O-(beta-hydroxyethyl)-rutosides in the treatment of leg ulcers. Phlebology 1993;8:29–30. [Google Scholar]
- 86.Stegmann WA, Hubner K, Deichmann B, et al. Efficacy of O-(beta-hydroxyethyl)-rutosides in the treatment of venous leg ulcers. Therapiewoche 1986;36:1828–1833. [In German] [PubMed] [Google Scholar]
- 87.Lyon RT, Veith FJ, Bolton L, et al. Clinical benchmark for healing of chronic venous ulcers. Venous Ulcer Study Collaborators. Am J Surg 1998;176:172–175. [DOI] [PubMed] [Google Scholar]
- 88.Wilkinson EAJ, Hawke CI. Does oral zinc aid the healing of chronic leg ulcers? A systematic literature review. Arch Dermatol 1998;134:1556–1560. [DOI] [PubMed] [Google Scholar]
- 89.Mostow EN, Haraway GD, Dalsing M, et al. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg 2005;41:837–843. [DOI] [PubMed] [Google Scholar]
- 90.Enoch S, Shaaban H, Dunn KW. Informed consent should be obtained from patients to use products (skin substitutes) and dressings containing biological material. J Med Ethics 2005;31:2–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Warburg FE, Danielsen L, Madsen SM, et al. Vein surgery with or without skin grafting versus conservative treatment for leg ulcers. A randomized prospective study. Acta Derm Venereol 1994;74:307–309. [DOI] [PubMed] [Google Scholar]
- 92.Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. Eur J Vasc Endovasc Surg 2003;25:313–318. [DOI] [PubMed] [Google Scholar]
- 93.Van Gent WB, Hop WC, van Praag MC, et al. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg 2006;44:563–571. [DOI] [PubMed] [Google Scholar]
- 94.Howard DP, Howard A, Kothari A, et al. The role of superficial venous surgery in the management of venous ulcers: a systematic review. Eur J Vasc Endovasc Surg 2008;36:458–465. [DOI] [PubMed] [Google Scholar]
- 95.Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004;363:1854–1859. [DOI] [PubMed] [Google Scholar]
- 96.Gohel MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007;335:83–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Tenbrook JA Jr, Iafrati MD, O'Donnell TF Jr, et al. Systematic review of outcomes after surgical management of venous disease incorporating subfascial endoscopic perforator surgery. J Vasc Surg 2004;39:583–589. [DOI] [PubMed] [Google Scholar]
- 98.Pierik EG, van Urk H, Hop WC, et al. Endoscopic versus open subfascial division of incompetent perforating veins in the treatment of venous leg ulceration: a randomized trial. J Vasc Surg 1997;26:1049–1054. [DOI] [PubMed] [Google Scholar]
- 99.Ghauri AS, Nyamekye I, Grabs AJ, et al. Influence of a specialised leg ulcer service and venous surgery on the outcome of venous leg ulcers. Eur J Vasc Endovasc Surg 1998;16:238–244. [DOI] [PubMed] [Google Scholar]
- 100.Cullum N, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ulcers. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2010. [Google Scholar]
- 101.Watson JM, Kang'ombe AR, Soares MO, et al. Use of weekly, low dose, high frequency ultrasound for hard to heal venous leg ulcers: The VenUS III randomised controlled trial. BMJ 2011;342:d1092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Peschen M, Vanscheidt W. Low frequency ultrasound of chronic venous leg ulcers as part of an out-patient treatment [abstract]. In: Cherry GW, Gottrup F, Lawrence JC, et al. Fifth European Conference on Advances in Wound Management. London, UK: Macmillan, 1996. [Google Scholar]
- 103.Weichenthal M, Mohr P, Stegmann W, et al. Low-frequency ultrasound treatment of chronic venous ulcers. Wound Repair Regen 1997;5:18–22. [DOI] [PubMed] [Google Scholar]
- 104.Thurlby K, Griffiths P. Community leg ulcer clinics vs home visits: which is more effective? Br J Community Nurs 2002;7:260–264. [DOI] [PubMed] [Google Scholar]
- 105.Edwards H, Courtney M, Finlayson K, et al. Improved healing rates for chronic venous leg ulcers: pilot study results from a randomized controlled trial of a community nursing intervention. Int J Nurs Pract 2005;11:169–176. [DOI] [PubMed] [Google Scholar]
- 106.Harrison MB, Graham ID, Lorimer K, et al. Nurse clinic versus home delivery of evidence-based community leg ulcer care: a randomized health services trial. BMC Health Serv Res 2008;8:243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Cullum N, Nelson EA, Flemming K, et al. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. Health Technol Assess 2001;5;1–221. Search date 2000. [DOI] [PubMed] [Google Scholar]
- 108.Vandongen YK, Stacey MC. Graduated compression elastic stockings reduce lipodermatosclerosis and ulcer recurrence. Phlebology 2000;15:33–37. [Google Scholar]
- 109.Cullum N, Fletcher A, Semlyen A, et al. Compression therapy for venous leg ulcers. Qual Health Care 1997;6:226–231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Sybrandy JE, van Gent WB, Pierik EG, et al. Endoscopic versus open subfascial division of incompetent perforating veins in the treatment of venous leg ulceration: long-term follow-up. J Vasc Surg 2001;33:1028–1032. [DOI] [PubMed] [Google Scholar]
- 111.Taylor HM, Rose KE, Twycross RG. A double-blind clinical RCT of hydroxyethylrutosides in obstructive arm lymphoedema. Phlebology 1993;8:22–28. [Google Scholar]