Venous leg ulcers

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.

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.

GRADE Evaluation of interventions for Venous leg ulcers.

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.