PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of bmjclinevidLink to Publisher's site
 
BMJ Clin Evid. 2008; 2008: 1902.
Published online 2008 September 15.
PMCID: PMC2908003

Venous leg ulcers

E Andrea Nelson, BSc (Hons) RGN PhD, Reader in Wound Healing and Director of Research# and Ms June Jones, MSc, RGN, Clinical Nurse Specialist#

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 interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ 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 80 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, short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, self-help (advice to elevate leg, advice to keep leg active, advice to modify diet, advice to stop smoking, advice to reduce weight), 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, or therapeutic ultrasound are beneficial, as we found few studies.

Oral pentoxifylline increases ulcer healing in people receiving compression, and oral flavonoids, sulodexide, and mesoglycan may also be effective.

Compression bandages and stockings reduce recurrence of ulcers compared with no compression, and should ideally be worn for life.

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 more than 6 weeks to heal. 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. Most leg ulcers are secondary to venous disease; other causes include arterial insufficiency, diabetes, and rheumatoid arthritis. The annual cost to the NHS in the UK has been estimated at £300 million. 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. 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. 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).

Aims of intervention

To promote healing; to reduce recurrence; to improve quality of life, with minimal adverse effects.

Outcomes

Ulcer area; number of ulcers healed; time to complete ulcer healing; number of ulcer-free limbs; recurrence rates; number of new ulcer episodes; number of ulcer-free weeks or months; number of people who are ulcer free; frequency of dressing/bandage changes; quality of life; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to September 2007, Embase 1980 to September 2007, and The Cochrane Library (all databases) 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, including open studies (as most interventions cannot be effectively blinded) and containing more than 20 people. We included studies with fewer than 20 people if limbs were randomised. There was no maximum loss to follow-up or minimum length of follow-up required to include studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for venous leg ulcers

Glossary

Cultured allogenic bilayer skin replacement
Also called human skin equivalent. This is made of a lower (dermal) layer of bovine collagen containing human living dermal fibroblasts, and an upper (epidermal) layer of human living keratinocytes.
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 either 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.
Laser treatment (low-level)
Application of treatment energy (less than 10 J/cm2 ) using lasers of 50 mW or less.
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.
Non-elastic legging
Compression device consisting of a series of interlocking, non-elastic bands that encircle the leg and are held together by hook-and-loop fasteners.
Perforator ligation
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.
Short-stretch bandages
Minimally extensible bandages, usually made of cotton, with few or no elastomeric fibres. They are applied at near full extension to form a semirigid bandage.
Subfascial endoscopic perforator surgery
is a minimally invasive endoscopic procedure, which 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.

Notes

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.

Contributor Information

E Andrea Nelson, University of Leeds, Leeds, UK.

Ms June Jones, Southport and Formby PCT, Southport, UK.

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]
2. Callam MJ, Ruckley CV, Harper DR, et al. Chronic ulceration of the leg: extent of the problem and provision of care. BMJ 1985;290:1855–1856. [PMC free article] [PubMed]
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. [PMC free article] [PubMed]
4. Laing W. Chronic venous diseases of the leg. London: Office of Health Economics, 1992.
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.
6. Roe B, Cullum N. The management of leg ulcers: current nursing practice. In: Cullum N, Roe B, eds. Leg ulcers: nursing management. Harrow: Scutari, 1995:113–124.
7. Vowden KR, Barker A, Vowden P. Leg ulcer management in a nurse-led, hospital-based clinic. J Wound Care 1997;6:233–236. [PubMed]
8. Cullum N, Nelson EA, Fletcher AW, et al. Compression for venous leg ulcers. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2000; primary sources 19 electronic databases, hand searches, and personal contact.
9. O'Brien JF, Grace PA, Perry IJ, et al. Randomized clinical trial and economic analysis of four-layer compression bandaging for venous ulcers. Br J Surg 2003;90:794–798. [PubMed]
10. Clarke-Moloney M, O'Brien JF, Grace PA, et al. Health-related quality of life during four-layer compression bandaging for venous ulcer disease: a randomised controlled trial. Ir J Med Sci 2005;174:21–25. [PubMed]
11. Callam MJ, Ruckley CV, Dale JJ, et al. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. BMJ 1987;295:1382. [PMC free article] [PubMed]
12. Chan CLH, Meyer FJ, Hay RJ, et al. Toe ulceration associated with compression bandaging: observational study. BMJ 2001;323:1099. [PMC free article] [PubMed]
13. Nelson EA, Ruckley CV, Barbenel J. Improvements in bandaging technique following training. J Wound Care 1995;4:181–184. [PubMed]
14. 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. [PubMed]
15. 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.
16. Meyer FJ, Burnand KG, Lagattolla NRF, et al. More venous leg ulcers are healed by three-layer paste than by four-layer bandages: a randomised, controlled, prospective study. Proceedings of the First World Wound Healing Congress, 74–75, 2000. Australian Wound Management Association.
17. 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. [PubMed]
18. 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. [PubMed]
19. Partsch H, Damstra RJ, Tazelaar DJ, et al. Multicentre, randomised controlled RCT of four-layer bandaging versus short-stretch bandaging in the treatment of venous leg ulcers. VASA 2001;30:108–113. [PubMed]
20. 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. [PubMed]
21. Franks PJ, Moody M, 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. [PubMed]
22. Polignano R, Bonadeo P, Gasbarro S, et al. A randomised controlled study of four-layer compression versus Unna's Boot for venous ulcers. J Wound Care 2004;13:21–24. [PubMed]
23. 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. [PubMed]
24. Meyer F, Burnand KG, McGuiness C, et al. Randomized clinical RCT comparing the efficacy of two bandaging regimens in the treatment of venous leg ulcer. Br J Surg 2002;89:40–44. [PubMed]
25. Blecken SR, Villavicencio JL, and Kao TC. Comparison of elastic versus nonelastic compression in bilateral venous ulcers: a randomized trial. J Vasc Surg 2005;42:1150–1155. [PubMed]
26. 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.
27. 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. [PubMed]
28. Mani R, Vowden K, Nelson EA. Intermittent pneumatic compression for treating venous leg ulcers. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2001; primary sources Cochrane Wound Group Trials Register; hand searches of journals, relevant conference proceedings, and citations within obtained reviews and papers; and personal contact with relevant companies.
29. 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. Search date 2001; primary sources Medline, Embase, and Amed. [PubMed]
30. 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; primary sources 19 electronic databases (including the Cochrane Wounds Group Specialised Register); hand searches of specialist wound care journals, conference proceedings, and bibliographies of retrieved relevant publications; and personal contact with appropriate companies and an advisory panel of experts.
31. Thomas S. Wound management and dressings. London: Pharmaceutical Press, 1990.
32. Cameron J, Wilson C, Powell S, et al. Contact dermatitis in leg ulcer patients. Ostomy Wound Manage 1992;38:10–11. [PubMed]
33. 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; primary sources The Cochrane Library, Medline, Embase, and Cinahl.
34. 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. Search date 2003; primary sources Medline, Cinahl, and Sweesnet, and Cochrane Controlled Trials Register. [PubMed]
35. Palfreyman SJ, Nelson EA, Lochiel R, et al. Dressings for healing venous leg ulcers. [Review] [241 refs]. Cochrane Database of Systematic Reviews 2006;3:CD001103- [PubMed]
36. 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. [PubMed]
37. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. J Wound Care 2002;11:335–341. [PubMed]
38. Zillmer R, Agren MS, Gottrup F, et al. Biophysical effects of repetitive removal of adhesive dressings on peri-ulcer skin. J Wound Care 2006;15:187–191. [PubMed]
39. 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. [PubMed]
40. Lachmann EA, Rook JL, Tunkel R, et al. Complications associated with intermittent pneumatic compression. Arch Phys Med Rehabil 1992;73:482–485. [PubMed]
41. O'Meara S, Cullum N, Majid M, et al. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds. Health Technol Assess 2000;4:1–237. Search date 1997; primary sources The Cochrane Library, Medline, Embase, and Cinahl. [PubMed]
42. Chambers H, Dumville JC, Cullum N. Silver treatments for leg ulcers: a systematic review. Wound Repair Regen 2007;15:165–173. [PubMed]
43. 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]
44. 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. [PubMed]
45. 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. [PubMed]
46. 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. [PubMed]
47. Evans D, Land L. Topical negative pressure for treating chronic wounds. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Cochrane Wounds Group specialised register, contact with experts and relevant companies, and hand searches.
48. 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, 2004. Agency for Healthcare Research and Quality, Rockville, MD. Search date 2004; primary sources Medline, Embase, and the Cochrane Controlled Trials Register. Available online at: http://www.ahrq.gov/clinic/epcsums/woundsum.htm (last accessed 15 August 2008).
49. Vuerstaek JDD, 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. [PubMed]
50. 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. [PubMed]
51. 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.
52. 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]
53. 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. [PubMed]
54. 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. [PubMed]
55. Stacey MC, Mata SD, Trengove NJ, et al. Randomised double-blind placebo controlled RCT of autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg 2000;20:296–301. [PubMed]
56. 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. [PubMed]
57. Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date February 2007, searches of Cochrane Wounds Group Specialised Register, CENTRAL, MEDLINE, EMBASE and Cinahl (date of last search was February 2007), and reference lists of relevant articles.
58. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. In: Cochrane Database of Systematic Reviews 2007; Searches of Cochrane Wounds Group Specialised Register (February 2006) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2006)Search date 2004; primary sources Cochrane Wounds Group specialised register; hand searches of reference lists, relevant journals, and conference proceedings; and personal contact with experts in the field.
59. 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. Search date 2003; primary sources Medline, Embase, and The Cochrane Library. [PubMed]
60. 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]
61. Scondotto G, Aloisi D, Ferrari P, et al. Treatment of venous leg ulcers with sulodexide. Angiology 1999;50:883–889. [PubMed]
62. Kucharzewski M, Franek A, Koziolek H. Treatment of venous leg ulcers with sulodexide. Phlebologie 2003;32:115–120.
63. 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.
64. 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. [PubMed]
65. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. [update of Cochrane Database Systematic Review. 2005;(1):CD001737; PMID: 15674883]. [Review] [70 refs]. Cochrane Database of Systematic Reviews. 2007:CD001737. [PubMed]
66. 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. [PubMed]
67. 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. [PMC free article] [PubMed]
68. Flemming K, Cullum N. Laser therapy for venous leg ulcers. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 1998; primary sources 19 electronic databases and hand searches of journals, conference proceedings, and bibliographies.
69. Schneider WL, Hailey D. Low level laser therapy for wound healing. Alberta Heritage Foundation Report 1999. Search date 1999; primary sources Medline, Healthstar, Embase, Dissertation Abstracts, Current Contents, Cinahl, The Cochrane Library, and the Internet.
70. Lagan KM, McKenna T, Witherow A, et al. Low-intensity laser therapy/combined phototherapy in the management of chronic venous ulceration: a placebo-controlled study. J Clin Laser Med Surg 2002;20:109–116. [PubMed]
71. 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. [PubMed]
72. 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. [PubMed]
73. 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] [PubMed]
74. Layton AM, Ibbotson SH, Davies JA, et al. Randomised RCT of oral aspirin for chronic venous leg ulcers. Lancet 1994;344:164–165. [PubMed]
75. 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.
76. 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]
77. 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. [PubMed]
78. Wilkinson EAJ, Hawke CI. Does oral zinc aid the healing of chronic leg ulcers? A systematic literature review. Arch Dermatol 1998;134:1556–1560. Search date 1997; primary sources Medline, Embase, Cinahl, Science Citation Index, Biosis, British Diabetic Association Database, Ciscom, Cochrane Controlled Register of Clinical RCTs, Dissertation Abstracts, Royal College of Nursing Database, electronic databases of ongoing research, hand searches of wound care journals and conference proceedings, and contact with manufacturer of zinc sulphate tablets. [PubMed]
79. 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. [PubMed]
80. 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. [PMC free article] [PubMed]
81. Warburg FE, Danielsen L, Madsen SM, et al. Vein surgery with or without skin grafting versus conservative treatment for leg ulcers. Acta Dermatol Venereol 1994;74:307–309. [PubMed]
82. 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. [PubMed]
83. 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. [PubMed]
84. 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. [PubMed]
85. 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. [PMC free article] [PubMed]
86. 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. Search date 2003, primary sources Medline (restricted to English studies), reference lists of review articles and retrieved studies, and consultation with local experts. [PubMed]
87. 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. [PubMed]
88. 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. [PubMed]
89. Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. In: The Cochrane Library, Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 1999; primary source Wounds Group Specialised Register and hand searches of citation lists.
90. 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. Macmillan, 1996.
91. Weichenthal M, Mohr P, Stegmann W, et al. Low-frequency ultrasound treatment of chronic venous ulcers. Wound Repair Regen 1997;5:18–22. [PubMed]
92. Thurlby K, Griffiths P. Community leg ulcer clinics vs home visits: which is more effective? Br J Community Nurs 2002;7:260–264. Search date 2001; primary sources The Cochrane Library, Medline, Cinahl, RCN database, Embase, hand searches of Effective Health Care bulletins and other journals, references from articles, and contact with local specialist nurses. [PubMed]
93. 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. [PubMed]
94. 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; primary sources Cochrane Wounds Group specialised register, 19 electronic databases (up to 1999); hand searches of relevant journals, conference proceedings, and bibliographies of retrieved publications; and personal contact with manufacturers and an advisory panel of experts.
95. Vandongen YK, Stacey MC. Graduated compression elastic stockings reduce lipodermatosclerosis and ulcer recurrence. Phlebology 2000;15:33–37.
96. Cullum N, Fletcher A, Semlyen A, et al. Compression therapy for venous leg ulcers. Qual Health Care 1997;6:226–231. Search date 1997; primary sources 18 databases, including Medline, Embase, Cinahl with no restriction on date, hand searches of relevant journals, conference proceedings, and correspondence with experts to obtain unpublished papers. [PubMed]
97. 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. [PubMed]
98. Taylor HM, Rose KE, Twycross RG. A double-blind clinical RCT of hydroxyethylrutosides in obstructive arm lymphoedema. Phlebology 1993;8:22–28.
2008; 2008: 1902.
Published online 2008 September 15.

Compression bandages and stockings versus no compression

Summary

HEALING RATES Compared with no compression: Compression (bandages, stockings, Unna’s boot) is more effective at increasing healing rates ( high-quality evidence ).

Benefits

Compression bandages and stockings versus no compression:

We found one systematic review and one additional RCT. Overall, the studies found that compression (e.g. multilayer elastomeric high-compression bandages, short-stretch bandages, double-layer bandages, compression stockings, or Unna's boot) healed more venous leg ulcers compared with no compression (dressing alone, non-compressive bandages, usual care). The review (search date 2000, 6 RCTs, 267 people) compared all forms of compression versus no compression. The RCTs included in the review were heterogeneous, using different forms of compression in different settings and populations. Therefore, the results were not pooled. The first RCT (50 people) identified by the review found that compression healed a significantly higher proportion of ulcers compared with no compression (19/27 [70%] with compression v 6/23 [26%] with no compression; RR 2.70, 95% CI 1.30 to 5.60). The second RCT (34 people) identified by the review found no significant difference in healing between compression and no compression (9/17 [53%] with compression v 7/17 [41%] with no compression; RR 1.29, 95% CI 0.62 to 2.65). The third RCT (69 people) found that compression healed a significantly higher proportion of ulcers compared with no compression (21/30 [70%] with compression v 15/39 [38%] with no compression; RR 1.82, 95% CI 1.15 to 2.89). The fourth RCT (36 people) found significantly higher healing with compression compared with no compression (18/19 [95%] with compression v 7/17 [41%] with no compression; RR 2.30, 95% CI 1.29 to 4.10). The fifth RCT (42 people) found no significant difference in healing between compression and no compression (17/21 [81%] with compression v 15/21 [71%] with no compression; RR 1.13, 95% CI 0.81 to 1.59). The sixth RCT (36 people) found significantly higher healing with compression compared with no compression (12/18 [67%] with compression v 4/18 [22%] with no compression; RR 3.00, 95% CI 1.19 to 7.56). The additional RCT (200 people) found that, over 12 weeks, four-layer elastomeric high-compression bandaging healed a significantly higher proportion of ulcers compared with no compression (54% with compression v 34% with no compression; P less than 0.001). A sub-analysis of this RCT (reported in a 2nd publication) focused on the effect of four-layer elastomeric high-compression bandaging on quality of life. This RCT found that people treated with compression had a greater improvement in the physical dimensions of quality of life compared with people continuing with their usual care (no compression) as measured by condition-specific and generic questionnaires.

Harms

High levels of compression applied to limbs with insufficient arterial supply or inexpert application of bandages can lead to tissue damage and, at worst, amputation. One observational study (194 people) found that four-layer compression bandaging for several months was associated with toe ulceration in 12 (6%) people.

Compression bandages and stockings versus no compression:

No adverse effects were reported for this comparison in either the review or RCT.

Comment

People thought to be suitable for high-compression therapies (bandages, stockings, and compression leggings) are those with clinical signs of venous disease (ulcer in the gaiter region, from the upper margin of the malleolus to the bulge of the gastrocnemius; staining of the skin around an ulcer; or eczema), no concurrent diabetes mellitus or rheumatoid arthritis, and adequate arterial supply to the foot as determined by ankle/brachial pressure index. The precise ankle/brachial pressure index below which compression is contraindicated is often quoted as 0.8; however, many RCTs used the higher cut-off of 0.9. Effectiveness is likely to be influenced by the ability of those applying the bandage to generate safe levels of compression, and by the fitting of appropriately sized compression stockings or leggings. Bandages may be applied by the person with the leg ulcer, their carer, nurse, or doctor. We found no comparisons of healing rates between specialist and non-specialist application of compression. Training improves bandaging technique among nurses. Bandages containing elastomeric fibres can be applied weekly as they maintain their tension over time. Bandages made of wool, cotton, or both, such as short-stretch bandages, may need to be reapplied more frequently as they do not maintain their tension.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Compression stockings versus short-stretch bandages

Summary

HEALING RATES Compared with short-stretch bandages: We don’t know whether compression stockings are more effective at increasing healing rates ( very low-quality evidence ).

Benefits

Compression stockings versus short-stretch bandages:

We found two RCTs. The first RCT (134 people) reported a higher proportion of people healing with a stocking than with short-stretch bandages (29/66 [44%] with stocking v 19/68 [28%] with short-stretch bandages), but the results were only significant if a one-sided test was performed (P = 0.0129). These results should, therefore, be approached with caution, as a one-sided test is less conservative than a two-sided test, the RCT reported the outcomes for only 121/134 (90%) people randomised, and people using short-stretch bandages had larger and older ulcers than people using compression stockings. The second RCT (188 people randomised; 178 analysed) found similar rates of complete healing of ulcers at 12 weeks with short-stretch bandagescompared with a heel-less open-toed elastic compression stocking (51/88 [58%] with stocking v 51/90 [57%] with short stretch bandage; significance not assessed). This result should be treated with caution, as only one short-stretch bandage was applied, which may have delivered less compression than is commonly used. In addition, the bandage was replaced once a week, despite other studies finding that more frequent replacement is required for this treatment to maintain compression.

Harms

High levels of compression applied to limbs with insufficient arterial supply, or inexpert application of bandages, can lead to tissue damage and, at worst, amputation.

Compression stocking versus short-stretch bandages:

The RCT reported a suspected causal relationship between the study treatment and four adverse events: increased pain from the ulcer (U-Stocking); enlarged ulcer due to poor wrapping of the bandage; restricted flexibility of the ankle due to pain (bandages); and an intolerance reaction to the compression material with suspected delayed allergic reaction. In the second RCT, 14% of people in the heelless-stocking group complained of pain, and were subsequently given a larger stocking.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Multilayer elastomeric high-compression regimens versus each other

Summary

HEALING RATES Multilayer elastomeric high-compression regimens compared with each other: Four-layer compression bandages (including Charing Cross four-layer bandages) and other multilayer high-compression bandages are equally effective at increasing healing rates ( low-quality evidence ).

Benefits

Multilayer elastomeric high-compression regimens versus each other:

We found one systematic review (search date 2000, 3 RCTs, 285 people) and three subsequent RCTs. The RCTs identified by the review compared the original “Charing Cross” four-layer bandages versus other types of four-layer compression, and one compared four-layer versus three-layer compression bandages. The review found no significant difference in the proportion of people healed with four-layer elastomeric bandages compared with other multilayer high-compression bandages (99/142 [70%] with 4-layer “Charing Cross” bandages v 98/143 [68%] with other high-compression multilayer bandages; RR 1.02, 95% CI 0.87 to 1.18). The first subsequent RCT (149 people) found no significant difference in healing rates at 20 weeks between an original Charing Cross four-layer bandage and two commercial “kits” making a four-layer bandage (87% with Charing Cross system v 84% and 83% with the two commercial kits; P = 0.56). The second subsequent RCT (133 people) found that three-layer paste significantly increased healing rates compared with four-layer bandages, and reduced time to complete ulcer healing (healing rates: 80% with 3-layer paste v 65% with 4-layer bandage; P = 0.031; median time to complete ulcer healing: 12 weeks with 3-layer paste v 16 weeks with 4-layer bandage).The third subsequent RCT (112 people) found no significant difference in healing rates at 24 weeks between a four-layer compression bandage and a two-layer system (HR for healing in 4-layer system 1.18, 95% CI 0.69 to 2.02).

Harms

High levels of compression applied to limbs with insufficient arterial supply, or inexpert application of bandages, can lead to tissue damage and, at worst, amputation. One observational study (194 people) found that four-layer compression bandaging for several months was associated with toe ulceration in 12 (6%) people.

Multilayer elastomeric high-compression regimens versus each other:

The review and the first and second subsequent RCTs gave no information on adverse effects for this comparison. The third subsequent RCT reported that the number of people with at least one device-related adverse incident was significantly greater in the two-layer bandaging system compared with four-layer bandaging (15/54 [28%] with 2-layer v 5/54 [9%] with 4-layer; P = 0.01). The adverse incidents included irritation, pain/discomfort, slippage, tissue breakdown, and excessive pressure.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Multilayer elastomeric high-compression bandages versus single-layer bandages

Summary

HEALING RATES Compared with single-layer bandage: Multilayer compression bandages are more effective at increasing the proportion of people with healed ulcers ( high-quality evidence ).

Benefits

Multilayer elastomeric high-compression bandages versus single-layer bandage:

We found one systematic review (search date 2000, 4 RCTs, 280 people), which compared multilayer high-compression bandages versus a single layer of bandage. It found a significant increase in the proportion of people whose reference ulcer had healed with multilayer compression bandages compared with single-layer bandages (82/139 [59%] with multilayer compression bandages v 59/141 [42%] with single-layer bandages; RR 1.41, 95% CI 1.12 to 1.77; NNT for variable periods of treatment 6, 95% CI 4 to 18).

Harms

High levels of compression applied to limbs with insufficient arterial supply, or inexpert application of bandages, can lead to tissue damage and, at worst, amputation. One observational study (194 people) found that four-layer compression bandaging for several months was associated with toe ulceration in 12 (6%) people.

Multilayer elastomeric high-compression bandages versus single-layer bandage:

The review gave no information on adverse effects for this comparison.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Multilayer elastomeric high-compression bandages versus short-stretch bandages or Unna's boot

Summary

HEALING RATES Compared with short-stretch bandages or Unna’s boot: We don’t know whether multilayer elastomeric high-compression stockings are more effective at increasing healing rates ( moderate-quality evidence ).

Benefits

Multilayer elastomeric high-compression bandages versus short-stretch bandages or Unna's boot:

We found one systematic review (search date 2000, 4 small RCTs, 164 people) and five subsequent RCTs (744 people). The review found no significant difference in healing rate between multilayer elastomeric compression bandages, and short-stretch bandages or Unna's boot (37/83 [44%] with multilayer elastomeric bandages v 33/81 [41%] with short-stretch bandages or Unna's boot; RR 1.10, 95% CI 0.78 to 1.55). The first subsequent RCT (116 people) found no significant difference in healing rates between four-layer compression bandages and short-stretch bandages (33/53 [62%] with compression bandages v 43/59 [73%] with short-stretch bandages; P = 0.49). The second subsequent RCT (89 people) found that four-layer elastomeric multilayer compression bandages significantly increased healing at 12 weeks compared with short-stretch bandages (30% with elastomeric multilayer compression bandages v 22% with short-stretch bandages; HR 2.9, 95% CI 1.1 to 7.5). The third subsequent RCT (156 people) found no significant difference in healing over 24 weeks between four-layer bandages and cohesive short-stretch bandages (51/74 [69%] with 4-layer bandages v 60/82 [73%] with cohesive short-stretch bandages; HR 1.08, 95% CI 0.63 to 1.85). The fourth subsequent RCT (68 people) found no significant difference in healing at 24 weeks with a four-layer bandage compared with Unna's boot (HR for healing in 4-layer 1.62, 95% CI 0.87 to 3.02). The fifth subsequent RCT (387 people) found a significantly higher healing rate with a four-layer bandage than with a short-stretch bandage (HR for healing with short-stretch bandage 0.72, 95% CI 0.57 to 0.91).

Harms

Multilayer elastomeric high-compression bandages versus short-stretch bandages or Unna's boot:

The review gave no information on adverse effects for this comparison. The first subsequent RCT reported the withdrawal of two people (1 from each group) because of adverse incidents, but did not report the type of incident. The second subsequent RCT reported one withdrawal in the short-stretch bandage group attributable to pain. The third subsequent RCT reported 12 adverse events in the four-layer bandage group, and nine adverse events in the short-stretch bandage group which were definitely bandage related. The adverse events included tissue damage/new ulcer, eczema/reaction to bandage, pain, and maceration. The fourth subsequent RCT gave no information on adverse effects. The fifth subsequent RCT reported 255 adverse events involving 76 people in the four-layer bandage group that were possibly related to compression treatment, compared with 337 adverse events involving 91 people in the short-stretch bandage group. The adverse events included maceration, excoriation, skin damage, bandage failure, ulcer deterioration (including infection), skin deterioration, dryness, non-surgical admission to hospital related to leg ulceration, occurrence of new ulcer, and a medical event relating to the leg.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Multilayer elastomeric versus non-elastomeric high-compression bandages

Summary

HEALING RATES Compared with non-elastomeric high-compression bandages: We don’t know whether multilayer elastomeric high-compression stockings are more effective at increasing healing rates ( moderate-quality evidence ).

Benefits

Multilayer elastomeric versus non-elastomeric high-compression bandages:

We found one systematic review (search date 2000, 3 RCTs, 273 people) and one subsequent RCT. The review found that elastomeric high-compression bandaging significantly increased healing rates compared with non-elastomeric bandaging (77/134 [57%] with elastomeric compression v 52/139 [37%] with non-elastomeric compression; RR 1.54, 95% CI 1.19 to 2.00, NNT for variable periods of treatment 5, 95% CI 3 to 12). The subsequent RCT (112 people) found no significant difference in healing rates between elastomeric and non-elastomeric layered compression (58% with elastomeric compression v 62% with non-elastomeric compression; P = 0.623).

Harms

High levels of compression applied to limbs with insufficient arterial supply, or inexpert application of bandages, can lead to tissue damage and, at worst, amputation. One observational study (194 people) found that four-layer compression bandaging for several months was associated with toe ulceration in 12 (6%) people.

Multilayer elastomeric versus non-elastomeric high-compression bandages:

No adverse effects were reported in the review. The subsequent RCT reported one withdrawal from the elastomeric group because of pretibial skin necrosis.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Single-layer non-elastic system versus multilayer elastic system

Summary

HEALING RATES Compared with multilayer elastic system: Non-elastic systems may be more effective at reducing areas of ulceration, but we don’t know whether they are more effective at increasing the proportion of limbs with complete healing of ulcers at 12 weeks ( very low-quality evidence ). One RCT found that a non-elastic system increased ulcer healing rate compared with a four-layer elastic bandage. However, there was no difference between the non-elastic and the multilayered elastic systems in the proportion of limbs with complete healing of ulcers at 12 weeks.

Benefits

Single-layer non-elastic system versus multilayer elastic system:

We found one RCT (12 people, 24 limbs). The RCT compared a non-elastic compression device versus a four-layer elastic bandage. The RCT found that a similar proportion of limbs had complete healing of ulcers at 12 weeks with both the non-elastic and the multilayered elastic systems in the (4/12 [33%] with non-elastic system v 4/12 [33%] with elastic system; significance not assessed). The RCT found a significantly higher rate of ulcer-area reduction with the non-elastic system compared with the multilayer elastic system (HR 0.56, 95% CI 0.33 to 0.96).

Harms

Single-layer non-elastic system versus multilayer elastic system:

The RCT gave no information on adverse effects for this comparison.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Single-layer non-elastic system versus multilayer non-elastic system

Summary

HEALING RATES Compared with multilayer non-elastic system: We don’t know whether non-elastic legging systems are more effective than Unna’s boot at increasing healing rates ( low-quality evidence ).

Benefits

Single-layer non-elastic system versus multilayer non-elastic system:

We found one RCT (38 people), which compared a single-layer non-elastic system versus Unna's boot (multilayer non-elastic system). The RCT found similar healing rates between the non-elastic legging system and Unna's boot (17/19 [89%] with non-elastic legging system v 11/19 [58%] with Unna's boot; significance not assessed).

Harms

Single-layer non-elastic system versus multilayer non-elastic system:

The RCT reported that five people withdrew from the study in the Unna's Boot (multilayer) arm of the study, because of allergy, weeping dermatitis, and increasing ulcer size, and two people withdrew from the single-layer arm of the study because of the ulcer not healing and the person being referred for surgery.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Peri-ulcer injection of granulocyte-macrophage colony-stimulating factor

Summary

HEALING RATES Compared with placebo: Recombinant human granulocyte-macrophage colony-stimulating factors are more effective at increasing the proportion of people with completely healed ulcers at 13 weeks ( high-quality evidence ).

Benefits

Peri-ulcer injection of granulocyte-macrophage colony-stimulating factor:

One RCT (60 people) found that a 4-week course of injections of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) 200 or 400 micrograms around the ulcer significantly increased the proportion of people whose ulcers had completely healed after 13 weeks' treatment compared with placebo (23/39 [59%] with rHuGM-CSF v 4/21 [19%] with placebo; combined RR for rHuGM-CSF 200 and 400 micrograms 3.21, 95% CI 1.23 to 8.34; NNT for 13 weeks' treatment 2, 95% CI 1 to 7).

Harms

Granulocyte-macrophage colony-stimulating factor contains polyethylene glycol, which may be linked to allergic reactions.

Peri-ulcer injection of granulocyte-macrophage colony-stimulating factor:

Adverse effects were reported in 2/21 (9%) people receiving placebo, 8/21 (38%) people receiving rHuGM-CSF 200 micrograms, and 5/18 (26%) people receiving rHuGM-CSF 400 micrograms. The RCT reported that the most common treatment related adverse events were lumbar pain and malaise (5/21 [24%] people receiving rHuGM-CSF 200 micrograms v 3/19 [17%] people receiving rHuGM-CSF 400 micrograms). None of the adverse effects were considered life threatening; all were graded as mild to moderate.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Compression bandages or stockings versus intermittent pneumatic compression

Summary

We found no clinically important results comparing compression stockings with intermittent pneumatic compression in people with venous leg ulcers.

Benefits

Compression bandages or stockings versus intermittent pneumatic compression:

We found two systematic reviews (search date 2001), which identified the same RCT (16 people). The RCT identified by the reviews found no significant difference in the proportion of people with healed ulcers over 2–3 months between compression bandages and intermittent pneumatic compression (0/6 [0%] with compression bandages v 0/10 [0%] with intermittent pneumatic compression; P value not reported). However, the number of people in this trial is below BMJ Clinical Evidence inclusion criteria, and is too small to draw a reliable conclusion.

Harms

Compression bandages or stockings versus intermittent pneumatic compression:

The RCT identified by the reviews gave no information on adverse effects for this comparison.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Debriding agents

Summary

We found no clinically important results about the effects of debriding agents in people with venous leg ulcers.

Benefits

Debriding agents versus usual care or versus each other:

We found one systematic review (search date 1997, 23 RCTs), which compared debriding agents versus traditional dressing in people with chronic non-healing wounds. The review did not perform a meta-analysis specifically in people with venous leg ulcers. Six RCTs (277 people) identified by the review compared dextranomer polysaccharide bead dressings with traditional dressings, but only two RCTs reported complete ulcer healing. The incomplete reporting of healing rates, and small sample sizes mean we cannot draw any firm conclusions from these trials. Seven RCTs (451 people) identified by the review compared cadexomer iodine versus traditional dressings, but only three RCTs reported complete ulcer healing. The incomplete reporting of healing rates means we cannot draw any firm conclusions from these trials. Two RCTs identified by the review compared enzymatic preparations versus traditional dressings (52 ulcers) and found no evidence of a difference in ulcer healing rates.

Harms

Preparations containing iodine may affect thyroid function if used over large surface areas for extended periods. Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives, perfumes, or dyes.

Debriding agents versus usual topical care or versus each other:

The review reported adverse events such as pain, allergy, bacterial infection, and wound-size increase.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Foam, film, hyaluronic acid-derived dressings, collagen, cellulose, or alginate (semi-occlusive) dressings

Summary

HEALING RATES Semi-occlusive dressings compared with simple low-adherent dressings: Semi-occlusive dressings (foam, film, hyaluronic acid-derived dressings, collagen, cellulose, or alginate) and simple low-adherent dressings (such as paraffin-tulle, or knitted viscose dressings) are equally effective at increasing wound healing rates in the presence of compression ( high-quality evidence ). Alginate dressings compared with zinc oxide dressings: We don't know whether alginate dressings are more effective at increasing ulcer healing ( low-quality evidence ). Different occlusive or semi-occlusive dressing (excluding hydrocollids) compared with each other: Occlusive and semi-occlusive dressings (excluding hydrocolloids) are equally effective at increasing healing rates ( moderate-quality evidence ).

Benefits

Foam, film, hyaluronic acid-derived dressings, collagen, cellulose or alginate (semi-occlusive) dressings versus simple low-adherent dressings, in the presence of compression:

We found three systematic reviews (search date 1997, 6 RCTs, search date 2003, 7 RCTs, and search date April 2006, 4 RCTs ). The first review identified six RCTs comparing semi-occlusive dressings (foam, film, alginates) versus simple (traditional) low-adherent dressings (such as paraffin-tulle or knitted viscose dressings) in the presence of compression. The second review identified these six RCTs plus one other RCT, which compared a collagen dressing versus a non-adherent dressing. The first RCT (71 people) identified by the reviews compared film versus saline-soaked gauze. It found no significant difference between dressings in wound healing (11/36 [31%] with film v 8/35 [23%] with gauze; OR 1.48, 95% CI 0.5 to 4.3). The second RCT (11 people, 12 ulcers) compared film versus Unna's boot. It found that film significantly reduced the wound area compared with Unna's boot (mean reduction in wound area: 39% with film v 7% with Unna's boot; mean difference 32%, 95% CI 10% to 54%). The third RCT (132 people) identified by the review compared foam versus a knitted viscose dressing. It found no significant difference between dressings in wound healing (31/66 [47%] with foam v 23/66 [35%] with knitted viscose; OR 1.67, 95% CI 0.80 to 3.30). The fourth RCT (48 people) compared foam compress versus a sterile gauze compress. It found that foam significantly reduced the wound area compared with the sterile gauze (mean change in wound area: –66% with foam compress v +78% with sterile gauze compress; mean difference between treatments: 144%, 95% CI 49% to 239%). The fifth RCT (60 people) compared an alginate dressing versus a knitted viscose dressing. It found no significant difference between dressings in wound healing (26/30 [87%] with alginate v 24/30 [80%] with knitted viscose; OR 1.62, 95% CI 0.40 to 6.50). The sixth RCT (113 people with 133 ulcerated limbs) compared alginate dressings versus zinc oxide paste applied as a bandage or stocking. It found a significant increase in the proportion of ulcers healed with the zinc oxide-impregnated bandage compared with alginate (25/43 [58%] with zinc oxide bandage v 16/46 [35%] with alginate; OR 2.6, 95% CI 1.1 to 6.1). However, the RCT found no significant difference in ulcers healed between the zinc oxide-impregnated stocking and alginate (19/44 [43%] with zinc oxide stocking v 16/46 [35%] with alginate; OR 1.42, 95% CI 0.61 to 3.34). The RCT (75 people) identified by the second review compared a collagen dressing versus a non-adherent dressing. It found no significant difference between the collagen dressing and the non-adherent dressing in the proportion of ulcers healed (RR 1.33, 95% CI 0.71 to 2.49).The third review identified two RCTs. The first RCT included in the review (17 people) compared hyaluronic dressings versus paraffin gauze. It found no significant difference in rates of ulcer healing between hyaluronic dressings and paraffin gauze (2/12 [17%] with hyaluronic dressing v 1/12 [8%] with paraffin gauze, no significance test performed). The second RCT included in the review (73 people) compared a collagen-plus-cellulose dressing versus a modern low-adherent dressing. It found no significant difference between treatments in healing rates at 12 weeks (18/37 [49%] with collagen-plus-cellulose dressing v 12/36 [33%] with modern low-adherent dressing; risk difference +0.16, 95% CI –0.07 to +0.38).However, the RCTs identified by the reviews may have been too small to detect anything but a large difference in effectiveness.

Comparisons between different occlusive or semi-occlusive dressings:

See benefits of hydrocolloid (occlusive) dressings in the presence of compression.

Harms

It is unlikely that low-adherent primary wound dressings cause harm, although dressings containing iodine may affect thyroid function if used over large surface areas for extended periods. Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives, perfumes, or dyes.

Foam, film, hyaluronic acid-derived dressings, collagen, cellulose, or alginate (semi-occlusive) dressings versus simple low-adherent dressings, in the presence of compression:

The reviews reported adverse effects such as pain, infection, allergy, leakage, eczema, and odour. Frequent changes of adhesive dressings may also damage the skin.

Comparisons between different occlusive or semi-occlusive dressings:

See harms of hydrocolloid (occlusive) dressings in the presence of compression.

Comment

Simple primary dressings maintain a moist environment beneath compression bandages by preventing loss of moisture from the wound.

Substantive changes

Foam or semi occlusive dressings: One systematic review added evaluating the effectiveness of wound dressings to treat venous leg ulcers. The review included two RCTs not previously reported. The first RCT found similar rates of ulcer healing between hyaluronic dressings and paraffin gauze.The second RCT compared a collagen-plus-cellulose dressing versus a modern low-adherent dressing. It found similar healing rates at 12 weeks with both treatments. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1902.
Published online 2008 September 15.

Intermittent pneumatic compression

Summary

HEALING RATES Intermittent pneumatic compression plus compression stockings compared with compression stockings or bandages alone: We don’t know whether pneumatic compression plus compression stockings are more effective at increasing healing rates ( low-quality evidence ).

Benefits

Intermittent pneumatic compression versus compression bandages:

See benefits of compression bandages versus intermittent compression.

Intermittent pneumatic compression plus compression stockings versus compression stockings or bandages alone:

We found two systematic reviews (search date 2001, 3 RCTs, 115 people; search date 2001, 2 RCTS, 99 people). Two RCTs were included in both systematic reviews. The reviews did not perform a meta-analysis because of clinical and methodological differences among the trials. The first RCT identified by the reviews (45 people) found that intermittent pneumatic compression plus graduated compression stockings significantly increased the proportion of people with healed ulcers at 3 months compared with graduated compression stockings alone (10/21 [48%] with intermittent pneumatic compression plus graduated compression stockings v 1/24 [4%] with graduated compression stockings alone; RR 11.4, 95% CI 1.6 to 82.0). The second RCT (53 people) found no significant difference in the proportion of people healed at 6 months between intermittent pneumatic compression plus elastic stockings and Unna's boot (20/28 [71%] with intermittent pneumatic compression plus elastic stockings v 15/20 [75%] with Unna's boot; RR 0.95, 95% CI 0.67 to 1.34). The third RCT included in the first systematic review (22 people) found no significant difference in healing at 6 months between intermittent pneumatic compression plus Unna's boot and Unna's boot alone (12/12 [100%] with intermittent pneumatic compression plus Unna's boot v 8/10 [80%] with Unna's boot alone; RR 1.25, 95% CI 0.92 to 1.70).

Harms

Intermittent pneumatic compression versus compression bandages:

See harms of compression bandages versus intermittent compression.

Intermittent pneumatic compression plus compression stockings versus compression stockings or bandages alone:

One RCT identified by the review reported an adverse reaction to Unna's boot. Peroneal neuropathy and compartment syndrome have been associated with the use of intermittent pneumatic compression to prevent deep vein thrombosis during surgery.

Comment

Availability may vary widely in different healthcare settings. Treatment can be delivered in the home, in outpatient clinics, or in the hospital ward. RCTs have evaluated the use of intermittent pneumatic pressure for 1 hour twice weekly and 3–4 hours daily. Treatment requires resting for 1–4 hours daily, which may reduce quality of life.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Antimicrobial agents (topical)

Summary

HEALING RATES Compared with placebo or usual care: Topical antimicrobial agents may be no more effective at increasing the proportion of people with completely healed ulcers ( low-quality evidence ).

Benefits

Topical antimicrobial agents versus placebo or usual care:

We found two systematic reviews (search date 1997, 14 RCTs;and search date 2006, 9 RCTS), and two additional RCTs, which compared antimicrobial agents versus either placebo or usual care. The RCTs identified by the first review were small (25–153 people), and of poor quality, making it impossible to draw firm conclusions. The second review (9 RCTs, 6 included in the first review) compared dressings impregnated with silver versus dressings not containing silver for venous ulcers. It found no significant difference between groups in the proportion of ulcers completely healed (2 RCTs, 147 people, RR 1.66, 95% CI 0.68 to 4.05; P = 0.27). The first subsequent RCT (251 people) compared topical ethacridin lactate (0.1% solution) applied twice daily versus placebo. The authors defined responders as people with a greater than 20% reduction in ulcer area at 28 days. The RCT found a significantly higher proportion of responders with ethacridin lactate compared with placebo (104/129 [81%] with ethacridin lactate v 69/122 [57%] with placebo; P less than 0.0001). Ulcer healing was not reported. The second subsequent RCT (119 people) compared daily application of 10% pale sulfonated shale oil (has antiseptic and anti-inflammatory properties) versus vehicle (non-ionic gel). The RCT found no significant difference in the proportion of people with completely healed ulcers between pale sulfonated shale oil and vehicle (21/62 [34%] with pale sulfonated shale oil v 13/57 [23%] with vehicle; P = 0.177). However, the RCT found that pale sulfonated shale oil significantly reduced ulcer area compared with vehicle (72% with pale sulfonated shale oil v 19% with vehicle; P less than 0.001).

Harms

Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives, perfumes, or dyes.

Topical antimicrobial agents versus placebo or usual care:

The review reported adverse events such as erythema, pruritus, and severe irritation.The second systematic review gave no information on adverse effects. The first additional RCT gave no information on adverse effects of ethacridin lactate. The second RCT found no difference in adverse effects between 10% pale sulfonated shale oil and vehicle (12% with pale sulfonated shale oil v 11% with vehicle). Two people in each group had eczema and pruritus.

Comment

Daily or twice-daily application of topical antiseptics requires considerable investment in nursing time, or involvement of patients/carer, because of the need to remove and reapply compression bandages.

Substantive changes

Antimicrobial agents (topical) One systematic review added comparing dressings impregnated with silver versus dressings not containing silver for venous ulcers. It found no significant difference between groups in proportion of ulcers completely healed. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1902.
Published online 2008 September 15.

Calcitonin gene-related peptide (topical)

Summary

HEALING RATES Compared with placebo: Calcitonin gene-related peptide plus vasoactive intestinal polypeptide is no more effective at increasing the proportion of people with healed ulcers at 12 weeks ( moderate-quality evidence ).

Benefits

Topical calcitonin gene-related peptide plus vasoactive intestinal polypeptide versus placebo:

We found one RCT (66 people) which compared calcitonin (salcatonin) gene-related peptide plus vasoactive intestinal polypeptide given by iontophoresis versus placebo iontophoresis. It found no significant difference between treatments in the proportion of people with healed ulcers after 12 weeks (11/33 [33%] with calcitonin (salcatonin) gene-related peptide plus vasoactive intestinal polypeptide v 6/33 [18%] with placebo; RR 1.83, 95% CI 0.77 to 4.38). However, the RCT may have been too small to detect a clinically important difference.

Harms

Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives.

Topical calcitonin gene-related peptide plus vasoactive intestinal polypeptide versus placebo:

The RCT gave no information on adverse effects for this comparison.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Mesoglycan (topical)

Summary

HEALING RATES Compared with plant-based extract: We don’t know whether topical mesoglycan (a profibrinolytic agent) is more effective at increasing ulcer healing at 2 months ( low-quality evidence ).

Benefits

Topical mesoglycan versus a plant-based extract:

We found one RCT (40 people) which found similar cure rates at 2 months between topically applied mesoglycan, a profibrinolytic agent, and a plant-based extract (19/20 [95%] with topical mesoglycan v 16/20 [85%] with plant extract; CI not reported, significance assessment not performed).

Harms

Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives.

Topical mesoglycan versus a plant based extract:

The RCT gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Topical negative pressure

Summary

TIME TO HEALING Compared with usual care: Topical negative pressure (vacuum-assisted closure [VAC]) may be more effective than conventional wound care techniques at reducing time to complete healing in people with venous or arterio-venous ulcers of at least 6 months' duration ( very low-quality evidence ). RECURRENCE RATES Compared with usual care: Topical negative pressure (VAC) may be no more effective at reducing median time to recurrence of ulcers in people with venous or arteriovenous ulcers of at least 6 months' duration (very low-quality evidence).

Benefits

Topical negative pressure versus usual care:

We found two systematic reviews (search date 2002 and search date 2004) and one subsquent RCT. Both reviews identified one RCT (24 people), which compared topical negative pressure versus simple dressings. The single RCT identified by the reviews was carried out in people with any type of chronic wound, but included some people with venous leg ulcers. However, it may have been too small to detect a clinically important difference in outcomes between topical negative pressure and simple dressings. The subsequent RCT (60 people with venous or arterio-venous ulcers of at least 6 months' duration) compared topical negative pressure (vacuum-assisted closure [VAC]) versus control (conventional wound care techniques). The RCT found that VAC significantly reduced time to complete healing compared with control (29 days with VAC v 45 days with control, P = 0.001). However, there was no significant difference between groups for median length of time to recurrence (4 months with VAC v 2 months with control, P = 0.47).

Harms

Topical negative pressure versus usual care:

Two RCTs reported by the first review reported adverse events for topical negative pressure. The first RCT reported that 3/18 (17%) wounds with topical negative pressure had osteomyelitis, calcaneal features, or both. Two people suffered calcaneal features while ambulating on the topical negative pressure dressing (against medical advice). Both people eventually required amputation. The second RCT reported pain in some people with topical negative pressure with initial collapse, foam dressing removal, or both. The second review gave no information on adverse effects. The subsequent RCT reported no significant differences for adverse effects for erysipelas, pain, wound infection, postoperative bleeding at donor site, and non-healing ulcers (erysipelas: 1 with VAC v 0 with control; pain: 3 with VAC v 1 with control; wound infection: 0 with VAC v 1 with control; postoperative bleeding at donor site: 0 with VAC v 2 with control; non-healing ulcers: 1 with VAC v 1 with control; all reported as non significant, no P values reported). However, the RCT reported that VAC significantly increased the risk of cutaneous damage secondary to treatment compared with control (7 with VAC v 2 with control, P less than 0.05).

Comment

One review reported that one of the 10 RCTs of topical negative therapy underway includes venous leg ulcers.In the subsequent RCT, all the included people had chronic ulcers (more than 6 months' duration) and were hospitalised throughout. This limits the applicability of this evidence, as most ulcers are treated outside hospital, which reduces cost.

Substantive changes

Topical negative pressure One RCT added comparing vacuum-assisted closure (VAC) versus conventional wound care techniques. It found that VAC reduced time to complete healing compared with conventional therapy, but did not lengthen time to recurrence. The RCT reported no significant difference in adverse effects between groups, apart from an increased risk of cutaneous damage secondary to therapy in the VAC group. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1902.
Published online 2008 September 15.

Recombinant keratinocyte growth factor 2 (topical)

Summary

HEALING RATES Compared with placebo: Topical recombinant human keratinocyte growth factor 2 plus compression is no more effective at increasing complete ulcer healing rates at 12 weeks ( moderate-quality evidence ).

Benefits

Topical recombinant human keratinocyte growth factor 2 plus compression versus placebo plus compression:

We found one RCT (94 people) which compared topically applied recombinant human keratinocyte growth factor 2 (repifermin 20 or 60 micrograms/cm2) plus compression versus placebo plus compression). It found no significant difference in the rate of complete ulcer healing after 12 weeks between human keratinocyte growth factor 2 and placebo (32% with repifermin 20 micrograms/cm2 v 38% with repifermin 60 micrograms/cm2 v 29% with placebo; for all doses of human keratinocyte growth factor 2 v placebo, P = 0.57).

Harms

Topical recombinant human keratinocyte growth factor 2 plus compression versus placebo plus compression:

The RCT found no significant difference in adverse effects (leg pain, pruritus, skin ulcer, rash abrasion, and reopening of venous ulcer) between repifermin and placebo. However, this study may have lacked power to detect a clinically important difference between groups.

Comment

Clinical guide:

Growth factors may be expensive: for them to be cost effective in clinical practice, their use would need to reduce the time to healing, and therefore nursing costs.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Platelet-derived growth factor (topically applied)

Summary

HEALING RATES Compared with placebo: We don’t know whether platelet-derived growth factors are more effective at increasing ulcer healing rates ( low-quality evidence ).

Benefits

Platelet-derived growth factor versus placebo:

We found two RCTs (135 people) in one publication, which found similar healing rates between platelet-derived growth factor and placebo gel (first RCT: 12/35 [36%] healed with growth factor v 12/36 [34%] healed with placebo; second RCT: 18/32 [56%] healed with growth factor v 14/32 [44%] healed with placebo; CI not reported, significance assessment not performed).

Harms

Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives.

Platelet-derived growth factor versus placebo:

In the first RCT, 11/35 (31%) people receiving becaplermin gel and 14/36 (39%) people receiving placebo had at least one treatment related, wound-related adverse event. In the second RCT, 17/32 (53%) people receiving becaplermin gel and 11/32 (34%) people receiving placebo had at least one such event.

Drug safety alert

FDA issues drug safety alert on increased risk of cancer mortality associated with use of three or more tubes of becaplermin (09 June 2008).

A drug safety alert has been issued on the increased risk of cancer mortality associated with use of three or more tubes of becaplermin (http://www.fda.gov/bbs/topics/NEWS/2008/NEW01845.html).

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Hydrocolloid (occlusive) dressings in the presence of compression

Summary

HEALING RATES Compared with simple dressings: Hydrocolloid dressings and simple low-adherent dressings in the presence of compression are equally effective at increasing ulcer healing rates ( high-quality evidence ). Hydrocolloids compared with other occlusive or semi-occlusive dressings: Hydrocolloids and other occlusive or semi-occlusive dressings are equally effective at increasing proportion of ulcers healed at 12–16 weeks (high-quality evidence). Different occlusive or semi-occlusive dressing (excluding hydrocolloids) compared with each other: Occlusive and semi-occlusive dressings (excluding hydrocolloids) are equally effective at increasing healing rates ( moderate-quality evidence ).

Benefits

We found three systematic reviews (search date 1997, 16 RCTs; search date 2003, 15 RCTs; and search date 2006, 27 RCTs ) comparing hydrocolloid dressings in the presence of compression.

Hydrocolloid (occlusive) dressings versus simple dressings in the presence of compression:

The first systematic review identified nine RCTs, the second review identified eight RCTs, and the third review identified nine RCTs comparing hydrocolloid dressings versus simple dressings in the presence of compression. Five RCTs were included in both the first and second reviews. A random-effects meta-analysis of seven of the nine studies identified by the first review (714 people) found no significant difference in rates of ulcer healing between hydrocolloid dressings and simple low-adherent dressings in the presence of compression (158/358 [44%] with hydrocolloid dressing v 140/356 [39%] with simple dressing; OR 1.45, 95% CI 0.83 to 2.54). A meta-analysis of the eight RCTs (782 people) identified by the second review found no significant difference in ulcer healing between hydrocolloid dressings and simple low-adherent dressings in the presence of compression (172/397 [43.3%] with hydrocolloid dressing v 168/385 [43.6%] with simple dressing; RR 0.99, 0.85 to 1.15).The third review found no significant difference in ulcer healing for hydrocolloid dressings compared with simple low-adherent dressings in the presence of compression (8 RCTs: 190/397 [48%] with hydrocolloid dressing v 170/395 [45%] with simple dressing; RR 1.09, 0.89 to 1.34).

Hydrocolloids versus other occlusive or semi-occlusive dressings:

We found three systematic reviews (search date 1997, 6 RCTs; search date 2003, 6 RCTs;and search date 2006, 9 RCTs), which compared hydrocolloids with other modern dressings and reported complete ulcer healing. The third review supersedes the first two reviews, so we only report the most recent data here. The review found no significant difference between the two treatments in the proportion of ulcers healed between 12 and 16 weeks (4 RCTs; 311 people, 85/171 [50%] with hydrocolloid v 69/140 [49%] with foam; RR 0.98, 95% CI 0.79 to 1.22, P = 0.9).

Different occlusive or semi-occlusive dressings (excluding hydrocolloids) versus each other:

We found two systematic reviews (search date 1997, 1 small RCT;and search date 2006, 8 RCTs), and three subsequent RCTs comparing different occlusive or semi-occlusive dressings. The reviews found no significant difference in healing rates between dressings, or insufficient data were reported to calculate their significance. The first subsequent RCT (107 people) compared a foam dressing with a foam composite. It found no difference between treatments in healing rates at 12 weeks (healed: 39% with foam dressing v 36% with foam composite; CI not reported, significance assessment not performed).The second subsequent RCT (159 people with chronic venous leg ulcers) compared a foam dressing versus a silicione foam dressing (both under compression) over 24 weeks. The RCT found no significant difference between groups for complete ulcer healing (50/81 [62%] with foam dressing v 50/75 [67%] with silicone foam dressing; HR for healing 1.48, 0.87 to 2.54, P = 0.15). The third subsequent crossover RCT (122 people with chronic venous leg ulcers of more than 8 weeks' duration) compared a foam dressing containing ibuprofen versus a similar foam dressing with no ibuprofen. People were randomised to the ibuprofen group (62) and non-ibuprofen group (60). The groups were assessed in one treatment on days 1–5, and then subsequently crossed over to the other treatment and were assessed at days 43–47. The people included in the RCT were allowed to take concomitant pain medication during the trial as long as it was constant at days 1–5 and 43–47 when pain was assessed. The RCT assessed chronic (persistent) and dressing change-related (temporary) pain on days 1–5 and on days 43–47. Chronic pain was rated on a pain-relief 5-point verbal rating scale (VRS) (0 = no relief to 4 = complete relief). Pain intensity was measured on an 11-point numeric box scale (NBS 0 to 10, 0 = no pain, 10 = worst pain imaginable). The RCT found that ibuprofen dressings significantly reduced chronic pain on days 1–5 compared with non-ibuprofen dressings (46/62 [74%] with ibuprofen v 35/60 [58%] with non-ibuprofen dressings, P = 0.0003). The RCT found no significant difference between groups for ulcer healing at 24 weeks (11.2 cm² to 7.9 cm² with ibuprofen v 7.2 cm² to 3.8 cm² with non-ibuprofen, reported as non significant, RR, CI, and P value not reported).

Harms

It is unlikely that low-adherent primary wound dressings cause harm, although dressings containing iodine may affect thyroid function if used over large surface areas for extended periods. Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives, perfumes, or dyes.

Hydrocolloid (occlusive) dressings versus simple dressings, in the presence of compression:

The reviews reported adverse effects such as wound infection, cellulitis, increase in ulcer size, and dermatitis of peri-ulcer skin.

Hydrocolloids versus other occlusive or semi-occlusive dressings:

The reviews reported adverse events such as pain, wound infection, allergy, dressing leakage, peri-wound eczema, injury/intolerance of peri-ulcer skin, and extensive exudates and odour leakage.

Different occlusive or semi-occlusive dressings (excluding hydrocolloids) versus each other:

The two reviews gave no information on adverse effects. The first subsequent RCT reported that the most common adverse event in the foam-compress group was new wound development in different anatomical locations (6 people). In the foam-dressing group, the most common adverse event was maceration, which also affected six people.The second subsequent RCT reported no difference between groups for adverse effects related to the dressings, with 11 events in each group definitely related to the dressing. The third subsequent RCT reported 31 adverse effects in 19 people (12 people with ibuprofen [21 adverse effects] v 7 people with no ibuprofen [10 adverse effects], P value not reported). Frequent changes of adhesive dressings may damage the skin on removal.

Comment

Simple primary dressings maintain a moist environment beneath compression bandages as the layers of dressings and bandages prevent loss of moisture from the wound.A foam dressing containing ibuprofen reduced pain intensity from 6.8 to 4.1, while a similar foam reduced pain from 6.6 to 4.6 (pain intensity measured on a 10-point scale), but required dressings to be changed every 48 hours.

Substantive changes

Occlusive dressings One review and two subsequent RCTs added comparing occlusive dressings with simple dressing in the presence of compression, and other occlusive or semi-occlusive dressings. The review found no significant difference in ulcer healing between hydrocolloid dressings compared with simple low-adherent dressings in the presence of compression, hydrocolloids compared with other modern dressings, or occlusive dressings compared with semi-occlusive dressings. The first subsequent RCT compared a foam dressing with a silicione foam dressing (both under compression) over 24 weeks. It found no significant difference between treatments for complete ulcer healing. The second subsequent crossover RCT compared a foam dressing containing ibuprofen with a similar foam dressing with no ibuprofen. It found that ibuprofen dressings reduced chronic pain on days 1–5 compared with non-ibuprofen dressings, but found no significant difference between groups for ulcer healing at 24 weeks. Categorisation unchanged (Unlikely to be beneficial).

2008; 2008: 1902.
Published online 2008 September 15.

Autologous platelet lysate (topically applied)

Summary

HEALING RATES Compared with placebo: Topically applied autologous platelet lysate is no more effective at increasing the proportion of people with healed ulcers at 9 months ( moderate-quality evidence ).

Benefits

Topically applied autologous platelet lysate versus placebo:

We found one RCT (86 people), which found no significant difference in the proportion of people healed at 9 months between topical autologous platelet lysate and placebo (33/42 [78%] with topical autologous platelet lysate v 34/44 [77%] with placebo; RR 1.05, 95% CI 0.80 to 1.30).

Harms

Many people (50–85%) with venous leg ulcers have contact sensitivity to preservatives.

Topically applied autologous platelet lysate versus placebo:

The RCT reported that there was no evidence of any adverse effects specifically related to the application of the lysate solution.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Freeze-dried keratinocyte lysate (topically applied)

Summary

HEALING RATES Compared with placebo/usual care: Topically applied freeze-dried keratinocyte lysate is no more effective at increasing healing rates at 24 weeks ( moderate-quality evidence ).

Benefits

Topically applied freeze-dried keratinocyte lysate versus vehicle or usual care:

We found one RCT (200 people) which compared three interventions: keratinocyte lysate plus usual care, placebo (vehicle) plus usual care, and usual care alone. It found no significant difference between treatments in healing (37% with lysate v 27% with vehicle or usual care; P = 0.14).

Harms

Topically applied freeze-dried keratinocyte lysate versus vehicle or usual care:

In total, 47 (24%) people had at least one general adverse effect during the treatment phase (25% with usual care plus lysate v 25% with usual care plus vehicle v 22% with usual care alone) and 27 (15%) people during the follow-up period (16% with usual care plus lysatev 17% with usual care plus vehicle v 12% with usual care alone). No significant differences were noted between the three treatment arms.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Pentoxifylline (oral)

Summary

HEALING RATES Compared with placebo: Oral pentoxifylline plus compression is more effective at increasing the proportion of people with healed ulcers at 8–24 weeks ( high-quality evidence ).

Benefits

Oral pentoxifylline versus placebo:

We found one systematic review (search date 2007, 12 RCTs, 864 people). The systematic review compared pentoxifylline (oxpentifylline) 1200 or 2400 mg daily versus placebo or versus other treatments, with or without compression. It found that, in the presence of compression, pentoxifylline significantly increased the proportion of people with healed ulcers over 8–24 weeks compared with placebo (7 RCTs: 221/348 [64%] with pentoxifylline v 126/311 [40%] with placebo; RR 1.51; 95% CI 1.3 to 1.76). One RCT identified by the review found no significant difference in healing rates at 3 months in people receiving compression between pentoxifylline and defibrotide (11/12 [92%] with pentoxifylline v 9/11 [82%] with defibrotide; RR 1.12, 95% CI 0.81 to 1.55).

Harms

Oral pentoxifylline versus placebo:

The review of oral pentoxifylline versus placebo found that people taking pentoxifylline had more adverse effects, although the difference was not significant (55/297 [18%] with pentoxifylline v 33/252 [13%] with placebo; RR 1.27, 95% CI 0.89 to 1.83). Nearly half of the adverse effects were gastrointestinal (dyspepsia, vomiting, or diarrhoea).

Comment

None.

Substantive changes

Pentoxifylline (oral) One systematic review updated comparing pentoxifylline (oxpentifylline) 1200 or 2400 mg daily versus placebo or versus other treatments, with or without compression. It found that, in the presence of compression, pentoxifylline increased the proportion of people with healed ulcers over 8–24 weeks compared with placebo. Categorisation unchanged (Beneficial).

2008; 2008: 1902.
Published online 2008 September 15.

Cultured allogenic bilayer skin replacement

Summary

HEALING RATES Compared with non-adherent dressing: Cultured allogenic bilayer skin replacement (containing both epidermal and dermal components) is more effective at increasing the proportion of healed ulcers at 6 months ( moderate-quality evidence ).

Benefits

Cultured allogenic bilayer skin replacement versus non-adherent dressing:

We found one systematic review (2 RCTs, 345 people, search date 2006). It found that a cultured allogenic bilayer skin replacement, containing both epidermal and dermal components, significantly increased the proportion of ulcers healed completely in 6 months compared with a simple non-adherent dressing (pooling 2 trials using a fixed-effect model: RR 1.51, 95% CI 1.22 to 1.88).

Harms

Cultured allogenic bilayer skin replacement versus non-adherent dressing:

Taking a skin graft leaves a wound that itself requires management, and may cause pain. We found no evidence of harm from tissue-engineered skin.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Flavonoids (oral)

Summary

HEALING RATES Flavonoids plus compression compared with compression alone: We don’t know whether flavanoids plus compession is more effective at increasing ulcer healing rates ( moderate-quality evidence ).

Benefits

Flavonoids plus compression versus compression alone:

We found one systematic review (search date 2003, 5 RCTs, 723 people). Two RCTs included in the review compared micronised purified flavonoid fraction 1 g daily plus compression versus compression with or without placebo. The first RCT (107 people) found no significant difference in cure rates at 2 months between adding flavonoids to compression and adding placebo, although cure rates were higher with flavonoids (14/53 [26%] with flavonoids v 6/52 [11%] with placebo; RR 2.29, 95% CI 0.99 to 5.43). It found that flavonoids significantly reduced time to healing of ulcers less than 10 cm2 compared with placebo (P = 0.037). The second RCT (202 people; previously unpublished) found similar cure rates at 2 months with flavonoid plus compression compared with compression plus placebo (21/103 [20%] with flavonoids v 25/99 [25%] with placebo; significance not assessed). Three RCTs identified by the review compared flavonoids plus compression versus compression alone. The first RCT (140 people) found that flavonoids plus compression significantly increased cure rates at 6 months compared with compression alone (33/71 [47%] with adding flavonoids v 19/69 [28%] with compression alone; OR 2.3, 95% CI 1.1 to 4.6). The second RCT (150 people) found similar cure rates at 2 months with flavonoids plus compression and compression alone (10/71 [14%] with flavonoids v 6/69 [9%] with compression alone; significance not assessed). The third RCT (124 people, previously unpublished) reported a higher proportion of people healing at 2 months with flavonoids plus compression compared with compression alone (25/62 [40%] with flavonoids v 13/62 [21%] with compression alone; significance not assessed). The systematic review performed a meta-analysis of healing rates at 2 months (follow-up was to 6 months in 4 of the trials), and the findings were dependent on the model used. Using a random-effects model, flavonoids increased ulcer healing by 54% (95% CI 0% to 137%), whereas, with a fixed-effect model, flavonoids increased ulcer healing by 44% (95% CI 7% to 94%). The review found that flavonoids significantly increased ulcer healing compared with compression plus placebo or compression alone (HR 1.38, 95% CI 1.11 to 1.70). However, the systematic review excluded two unpublished RCTs (271 people) from the meta-analysis because of missing data at baseline or intermediate time points, or study incompletion, and it is not clear what impact these RCTs might have on the meta-analysis.

Harms

Flavonoids plus compression versus compression alone:

The review reported adverse effects of flavonoids, such as gastrointestinal disturbance, in 10% of people.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Sulodexide (oral)

Summary

HEALING RATES Oral sulodexide plus compression compared with compression alone: Oral sulodexide plus compression is more effective at increasing healing rates at 2–3 months ( high-quality evidence ).

Benefits

Oral sulodexide plus compression versus compression alone:

We found four RCTs (488 people). The first RCT (235 people) found that adding sulodexide to compression significantly increased cure rates at 3 months compared with adding placebo (63/121 [52%] with adding sulodexide v 36/114 [32%] with adding placebo; RR 1.65, 95% CI 1.28 to 18.54). The second RCT (95 people) also found that adding sulodexide to compression significantly increased cure rates at 2 months compared with compression alone (30/52 [58%] with adding sulodexide v 15/43 [35%] with adding placebo; RR 1.65, 95% CI 1.06 to 2.7; NNT for 3 months' treatment 4, 95% CI 3 to 9). The third RCT (44 people) found that adding intramuscular and then oral sulodexide to a compression regimen significantly increased healing rates at 7 weeks (16/23 [70%] with sulodexide v 7/21 [35%] with control; P less than 0.05).The fourth RCT (114 people) found that oral sulodexide significantly increased healing at 30 days compared with compression alone (32/61 [52%] with sulodexide v 17/53 [32%] with compression alone; P less than 0.05) .

Harms

Oral sulodexide plus compression versus compression alone:

One RCT reported 37 people with a total of 40 adverse events, 23 (19%) in the sulodexide group and 17 (15%) in the placebo group. Of these, four adverse events in the treatment group (1 cutaneous rash, 1 diarrhoea, 1 epigastric pain, and 1 headache) were considered treatment related. Two RCTs gave no information on adverse effects. The fourth RCT found no severe adverse effects in the people included in the RCT

Comment

Sulodexide is not widely available, and daily injections may be unacceptable to some people.

Substantive changes

Sulodexide (oral) One RCT added comparing sulodexide versus compression alone. It found that sulodexide increased healing at 30 days compared with compression alone. Categorisation unchanged (Likely to be beneficial).

2008; 2008: 1902.
Published online 2008 September 15.

Mesoglycan (systemic)

Summary

HEALING RATES Systemic mesoglycan plus compression compared with placebo plus compression: Systemic mesoglycan plus compression is more effective at increasing the proportion of people with healed ulcers at 24 weeks ( moderate-quality evidence ).

Benefits

Systemic mesoglycan plus compression versus placebo plus compression:

We found one RCT (183 people) comparing systemic mesoglycan (daily im for 21 days and then orally for 21 weeks) plus compression versus placebo plus compression. It found that systemic mesoglycan significantly increased the proportion of people with healed ulcers after 24 weeks' treatment compared with placebo (82/92 [89%] with mesoglycan v 69/91 [76%] with placebo; RR 1.17, 95% CI 1.03 to 1.35).

Harms

Systemic mesoglycan plus compression versus placebo plus compression:

The RCT reported that total adverse-event incidence was 7/92 (8%) with mesoglycan and 6/91 (7%) with placebo. There were two serious (non-fatal) events in each group, and two people withdrew from mesoclycan treatment (road accident trauma and congestive heart failure), and four with placebo (skin rash, cerebral stroke, ischaemia, and rectal bleeding). Most of the events were considered unrelated to treatment.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Cultured allogenic single-layer dermal replacement

Summary

HEALING RATES Compared with usual care: We don’t know whether human dermal skin replacements (12-, 4-, or 1-piece dermagrafts) are more effective at increasing ulcer healing rates at 8–11 weeks ( low-quality evidence ).

Benefits

Cultured allogenic single-layer dermal replacement versus usual care:

We found one systematic review (search date 2006, 2 RCTs, 71 people), which compared single layered dermal replacement with standard care. The first RCT included in the review compared three different regimens versus usual care (12 pieces, 4 pieces and 1 piece of dermagraft) and the second RCT compared the four-piece regimen versus usual care. The first RCT found no significant difference in rates of healing at 11 weeks for 12 pieces of dermal skin replacement, or for one piece of dermal skin replacement at baseline compared with usual care (12 pieces: 1 RCT, 26 people, RR 2.5, 95% CI 0.59 to 10.64, P = 0.2; 1 piece: 1 RCT, 26 people, RR 0.46, 95% CI 0.05 to 4.53, P = 0.5). The review found no significant difference in rates of healing for the four-piece dermal skin replacement at baseline, or at 1, 4, and 8 weeks (2 RCTs, 44 people, RR 3.04, 95% CI 0.95 to 9.68, P = 0.06).

Harms

Taking a skin graft leaves a wound that itself requires management and may cause pain. We found no evidence of harm from tissue-engineered skin.

Cultured allogenic single-layer dermal replacement versus usual care:

The review gave no information on adverse effects.

Comment

None.

Substantive changes

Allogenic single-layer skin replacement One systematic review added comparing single-layer dermal replacement versus usual care. The review found similar rates of healing between 12-piece, 4-piece or 1-piece dermal skin replacement and usual care.

2008; 2008: 1902.
Published online 2008 September 15.

Prostaglandin E1 (intravenous)

Summary

HEALING RATES Compared with placebo: Intravenous prostaglandin E1 may be more effective at improving the number of healed ulcers at 120 days ( low-quality evidence ).

Benefits

Intravenous prostaglandin E1 versus placebo:

We found one RCT (87 people), which compared intravenous prostaglandin E1 (PGE1) 60 mg daily (infused over 2 hours) for 20 days versus a placebo infusion. Participants received infusions as outpatients and stayed in hospital for 6 hours. Both groups were also treated with elastic bandaging and local treatment. The RCT found that intravenous PGE1 significantly improved the proportion of ulcers healed at 120 days compared with placebo (40/44 [91%] with PGE1 v 32/43 [74%] with placebo; P less than 0.05). However, the RCT did not include an analysis that was adjusted for effects of bandages and local treatment.

Harms

Intravenous prostaglandin E1 versus placebo:

Adverse effects reported in the RCT included headache, nausea, hypotension, diarrhoea, and vomiting (5/44 [11%] with PGE1 v 2/43 [5%] with placebo; significance not assessed).

Comment

PGE1 improves local ischaemia, and so could be effective in the treatment of venous leg ulcers.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Larval therapy

Summary

We found no direct information about larval therapy in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs on larval therapy in the healing of venous leg ulcers.

Harms

We found no RCTs.

Comment

Larval therapy is available either “free range”, and subsequently isolated in the wound using dressings and netting, or supplied already placed in a net bag. Larval therapy is acceptable to about three quarters of people with leg ulcer.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Laser treatment (low-level)

Summary

HEALING RATES Compared with sham treatment: We don’t know whether low-level laser treatment is more effective at increasing ulcer healing rates at 4 weeks to 9 months ( very low-quality evidence ).

Benefits

Low-level laser treatment versus sham treatment:

We found two systematic reviews and three subsequent RCTs (4 publications). Two RCTs identified by the first review (search date 1998, 4 RCTs, 139 people) compared low-level laser treatment versus sham treatment, and found no significant difference in healing rates over 12 weeks (17/44 [39%] with laser treatment v 14/44 [32%] with sham treatment; RR 1.21, 95% CI 0.73 to 2.03). The third RCT (30 people) included in the first review compared three interventions: low-level laser treatment, low-level laser treatment plus infrared light, and non-coherent, unpolarised red light. It found a significantly higher proportion of ulcers healed completely after 9 months' treatment with a combination of laser plus infrared light compared with non-coherent, unpolarised red light (12/15 [80%] with laser plus infrared light v 5/15 [33%] with non-coherent, unpolarised red light; RR 2.40, 95% CI 1.12 to 5.13). The fourth RCT included in the first review compared laser versus ultraviolet light, and found no significant difference in healing over 4 weeks (reported as not significant; P value not reported). The second review (search date 1999, 5 RCTs, 148 people) identified, but did not describe fully, the four RCTs identified by the first review, and did not perform a meta-analysis. The fifth RCT identified by the second review (9 people, 12 venous leg ulcers) compared low-level laser treatment versus sham treatment, and found limited evidence that ulcer-area reduction was greater with laser over 10 weeks (ulcer area remaining unhealed: 25% with laser treatment v 85% with sham treatment; CI not reported, significance assessment not performed). The RCT did not assess complete ulcer healing. The first subsequent RCT (15 people) compared low-level laser treatment plus phototherapy once-weekly for 4 weeks versus sham treatment. It found no significant difference in ulcer area at 12 weeks between laser and sham (P = 0.14). The second subsequent RCT (65 people receiving compression and drug treatment) compared three interventions: low-level laser, sham laser, and “no additional treatment” (although it is unclear if the “no additional treatment” was established by randomisation). It found no significant difference between treatments in the change in area of ulceration (reduction in area: 4.25 cm2 [27%] with laser v 5.21 cm2 [39%] with sham laser v 2.98 cm2 [18%] with no treatment; reported as not significant, P value not reported). The third subsequent RCT (44 people) compared compression plus low-level laser, compression plus placebo laser, and compression alone. The RCT found no significant difference between the treatment groups in reduction in ulcer size (reported as not significant; P value not reported).

Harms

Low-level laser treatment versus sham treatment:

The two reviews gave no information on adverse effects. The first subsequent RCT reported an increase in pain levels during the treatment period for both groups. The second subsequent RCT gave no information on adverse effects. The third subsequent RCT reported increases in ulcer area in 28% of people receiving laser treatment compared with 11% of people in the compression-alone group. Eye protection is required when using some types of laser, as the high-energy beam may damage the retina.

Comment

The laser power, wavelength, frequency, duration, and follow-up of treatment were different for all of the studies. The subsequent RCTs may have lacked power to detect clinically important differences between laser and sham treatment. The third subsequent RCT reported within-group rather than between-group differences.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Aspirin (oral)

Summary

HEALING RATES Compared with placebo: Aspirin may be more effective at increasing ulcer healing rates ( very low-quality evidence ).

Benefits

Oral aspirin versus placebo:

We found one small RCT comparing aspirin (300 mg daily, enteric coated) versus placebo. It found that aspirin significantly increased ulcer healing rates compared with placebo (38% with aspirin v 0% with placebo; P less than 0.007). However, the RCT had several methodological weaknesses, so the result should be treated with caution.

Harms

Oral aspirin versus placebo:

The RCT gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Rutosides (oral)

Summary

HEALING RATES Compared with placebo: We don’t know whether oral rutosides alone or with compression are more effective at increasing ulcer healing rates at 6–12 weeks ( low-quality evidence ).

Benefits

Oral rutosides versus placebo:

We found two reports of three RCTs. The two RCTs (119 people) reported in one publication compared two different doses of oral hydroxyethyl rutosides (500 and 1000 mg twice daily) with placebo. The RCTs found no significant difference in rates of complete ulcer healing at 12 weeks between either dose of rutosides and placebo (1 RCT, 55 people, 48 analysed: 12/23 [52%] with rutoside 1 g/day v 7/25 [28%] with placebo; P = 0.087; results for the second RCT not reported). The third RCT (107 people) compared oral rutosides 500 mg twice daily plus compression versus compression alone. The RCT found no difference in healing rates at 6 weeks between oral rutoside plus compression and compression alone (10/55 [18%] with rutoside plus compression v 12/52 [23%] with compression alone; significance not assessed). The RCTs may have been too small to detect a clinically important difference.

Harms

Oral rutosides versus placebo:

One report of two RCTs (119 people) found no significant difference in adverse effects between oral rutosides and placebo (no details reported). The third RCT gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Thromboxane alpha2 antagonists (oral)

Summary

HEALING RATES Compared with placebo: We don’t know whether oral thromboxane alpha 2 antagonists are more effective at increasing ulcer healing rates ( low-quality evidence ).

Benefits

Oral thromboxane alpha2 antagonists versus placebo:

We found one RCT (165 people) comparing an oral thromboxane alpha2 antagonist versus placebo. It found no significant difference in the proportion of ulcers healed (55% with thromboxane alpha2 antagonist v 54% with placebo; CI not reported).

Harms

Oral thromboxane alpha2 antagonists versus placebo:

The RCT gave no information on any adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Zinc (oral)

Summary

We found no clinically important results about the effects of oral zinc in people with venous leg ulcers.

Benefits

Oral zinc versus placebo:

We found one systematic review (search date 1997, 5 RCTs, 151 people) comparing daily doses of oral zinc sulphate 440–660 mg versus placebo. The review found no evidence of benefit for oral zinc in people with venous leg ulcers (significance not assessed).

Harms

Oral zinc versus placebo:

The review gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Skin grafting

Summary

HEALING RATES Compared with other treatments for leg ulcers: We don’t know whether different types of skin grafts are more effective at increasing healing of venous ulcers ( low-quality evidence ).

Benefits

Different types of skin grafts versus other treatments for leg ulcers:

We found one systematic review (search date 2006, 11 RCTs, 768 people) of skin grafts (autografts, allografts, or xerografts) for venous leg ulcers, and one subsequent RCT. In 11 RCTs identified by the review, people also received compression bandaging; one RCT (31 people) compared an autograft with a dressing, three RCTs (45 people) compared fresh allografts with dressings, three RCTs (80 people) compared frozen allografts with dressings, one RCT (92 people) compared an autograft with a frozen allograft, one RCT (51 people) compared a pinch autograft with a xenograft, one RCT (7 people) compared tissue-engineered skin with a split-thickness graft, and one RCT (50 people) compared a fresh allograft with a frozen allograft. The review found insufficient evidence to determine whether skin grafting increased healing rates for venous ulcers, because studies were small and generally of poor quality.In the additional RCT (120 people), a porcine extracellular matrix graft was compared with usual care (both groups received compression). There was a significantly higher proportion of people healed at 12 weeks with the matrix graft than with usual care (55% with matrix graft v 34% with usual care; RR for healing with matrix 1.59, 95% CI 1.06 to 2.42).

Harms

Different types of skin grafts versus other treatments for leg ulcers:

Taking a skin graft leaves a wound that itself requires management and may cause pain. We found no evidence of harm from tissue-engineered skin. The subsequent RCT gave no information on adverse effects.

Comment

Porcine derived products may not be acceptable to some patient groups.

Substantive changes

Skin grafting One systematic review updated, comparing different types of skin grafts. It found insufficient evidence to determine whether skin grafting increased the healing of venous ulcers. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1902.
Published online 2008 September 15.

Superficial vein surgery to treat venous leg ulcers

Summary

HEALING RATES Perforator ligation compared with no surgery or surgery plus skin grafting: We don’t know whether perforator ligation is more effective at increasing the proportion of ulcers healed at 1 year or at reducing time to ulcer healing ( very low-quality evidence ). Minimally invasive surgery compared with compression bandages or usual care: We don’t know whether minimally invasive surgery may be more effective at reducing time to complete healing, or whether it is more effective at increasing ulcer healing rates ( low-quality evidence ). Venous surgery (based on duplex scan) plus compression compared with compression alone: Venous surgery (based on duplex scan) plus compression and compression alone are equally effective at increasing healing rates at 24 weeks and at 3 years ( high-quality evidence ). Open perforator surgery compared with subfascial endoscopic perforator surgery: We don’t know whether open perforator surgery is more effective at increasing ulcer healing rates at 4 months ( low-quality evidence ). ADVERSE EFFECTS Open perforator surgery compared with subfascial endoscopic perforator surgery: Open perforator surgery is associated with higher wound infection rates compared with subfascial endoscopic perforator surgery ( moderate-quality evidence ).

Benefits

Perforator ligation versus no surgery or versus surgery plus skin grafting:

We found one RCT (47 people) which compared perforator ligation versus no surgery or surgery plus skin grafting. All participants were also treated with a compression bandage. The RCT found no significant difference in the proportion of ulcers healed after 1 year or in the time to complete ulcer healing (reported as P greater than 0.05 for both outcomes). The RCT did not perform an intention-to-treat analysis, and 7/47 (15%) people withdrew from the trial. It is likely to have been underpowered to detect a clinically important difference among groups.

Minimally invasive surgery versus compression bandages or usual care:

We found two RCTs (215 people), which compared minimally invasive surgery versus compression bandages. In the first RCT, people randomised to surgery were treated with a compression bandage before surgery, while in the second RCT they wore compression until ulcer healing. The first RCT found high healing rates in both groups (100% with surgery v 96% with compression); it randomised legs rather than people.. It found that surgery significantly reduced time to complete healing compared with compression bandages (median: 31 days with surgery v 63 days with compression; P less than 0.005). The second RCT (170 people with venous leg ulcers) compared subfascial endoscopic perforator surgery (SEPS) plus superficial venous surgery as required versus compression alone. It found no significant difference in the proportion of ulcers healed between groups (83% with surgery v 73% with conservative care: P = 0.24, absolute figures not reported).

Venous surgery (based on duplex scan) plus compression versus compression alone:

We found one RCT (341 people), which compared venous surgery (type of surgery based on duplex scan) plus compression versus compression alone. The RCT found no significant difference in healing rates between treatments at 24 weeks (ulcer healing rates: 65% in both arms; HR for healing: 0.84, 95% CI 0.77 to 1.24).Long-term follow-up of this RCT also found no significant difference in healing rates between groups at 3 years (93% for surgery plus compression v 89% for compression alone, P = 0.73).

Open perforator surgery versus subfascial endoscopic perforator surgery:

We found one systematic review (search date 2003, 1 RCT, 39 people). The RCT identified by the review found no significant difference between treatments in healing rates at 4 months (17/20 [85%] with subfascial endoscopic perforator surgery v 17/19 [89%] with open surgery; CI not reported).

Harms

Vein surgery carries the usual risks of surgery and anaesthesia.

Perforator ligation:

The first RCT found no postoperative complications, but may have been too small to detect clinically important adverse effects.

Minimally invasive surgery:

The RCTs gave no information on adverse effects.

Venous surgery (based on duplex scan):

The RCT reported that adverse events were minimal and about equal in each group; no further information was given.The long-term follow-up gave no information on adverse effects.

Open perforator surgery versus subfascial endoscopic perforator surgery:

One RCT (39 people) identified by a systematic review found higher wound infection rates with open surgery compared with subfascial endoscopic perforator surgery (0% with subfascial endoscopic perforator surgery v 53% with open surgery; P less than 0.001). The review reported that deep vein thrombosis occurred in 1%, wound infection in 6%, neuralgia in 7%, and haematoma in 9% of all people with venous ulcers having surgical treatment involving subfascial endoscopic perforator surgery.

Comment

Several operative approaches are commonly used, including perforator ligation, saphenous vein stripping, and a combination of both procedures. The RCT comparing open perforator surgery versus subfascial endoscopic perforator surgery found that hospital stay was shorter with subfascial endoscopic perforator surgery (4 days with subfascial endoscopic perforator surgery v 7 days with open surgery). About 25% of people who were offered venous surgery in one study refused it.

Substantive changes

Superficial vein surgery One RCT and one follow-up study added. The RCT compared subfascial endoscopic perforator surgery (SEPS) plus superficial venous surgery as required versus compression alone. It found no significant difference between groups in the number of ulcers healed. The follow-up study compared venous surgery (type of surgery based on duplex scan) plus compression versus compression alone, and found no difference in healing rates between groups at 3 years. Categorisation unchanged (Unknown effectiveness).

2008; 2008: 1902.
Published online 2008 September 15.

Therapeutic ultrasound

Summary

We found no clinically important results about the effects of therapeutic ultrasound in people with venous leg ulcers.

Benefits

Therapeutic ultrasound versus no or sham ultrasound:

We found one systematic review (search date 1999, 7 RCTs, 470 people) comparing therapeutic ultrasound with no ultrasound or sham ultrasound for venous leg ulcers. Ultrasound improved ulcer healing in all studies, but a significant difference was found in only four of the seven RCTs, and heterogeneity precluded pooling the seven RCTs.

Harms

Therapeutic ultrasound versus no or sham ultrasound:

Mild and severe erythema, local pain, and small areas of bleeding were reported in RCTs identified by the review.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Leg ulcer clinics

Summary

HEALING RATES Compared with usual care: We don’t know whether leg ulcer clinics are more effective at increasing ulcer healing rates ( very low-quality evidence ). NOTE Leg ulcer clinics and leg clubs may only be suitable for mobile people.

Benefits

Leg ulcer clinics versus usual care:

We found one systematic review (search date 2001, 1 RCT) and one additional RCT. The RCT identified by the review randomised people with leg ulcers to usual care at home or high-compression bandaging in a leg ulcer clinic. The review found that attending a leg ulcer clinic significantly increased the probability of ulcer healing compared with usual care at home (Cox model, ulcers 1.65 times more likely to heal when attending a leg ulcer clinic, 95% CI 1.15 to 2.35). However, all people attending the leg ulcer clinic were treated with high-compression bandaging, whereas only half the people receiving usual care at home were treated with some type of compression bandaging. Compression bandaging is known to be beneficial in the treatment of leg ulcers, and so increased improvement rates in those attending the leg clinic would be expected. One additional RCT (33 people) compared community-based “Leg Clubs” versus usual care. The RCT found a significantly greater reduction in ulcer area in the “Leg Club” group compared with the usual-care group (P = 0.004). However, the RCT found no significant difference in the proportion of people healed at 12 weeks (7/16 [44%] with “Leg Club” v 4/17 [24%] with usual care; reported as not significant; P value not reported).

Harms

Leg ulcer clinics versus usual care:

The review and RCT gave no information on adverse effects.

Comment

Clinical guide:

Leg ulcer clinics and “Leg Clubs” may only be suitable for mobile people.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Advice to elevate leg

Summary

We found no direct information about the effects of leg elevation in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

We found no RCT evidence to support the elevation of the leg, although this intervention makes sense as venous insufficiency is corrected if the leg is elevated above the heart. The advantages of leg elevation — such as reduced oedema and increasing venous return — must be weighed against the potential for harm if the cardiovascular system cannot cope with a sudden increase in circulating volume. Many people with venous disease have joint or other mobility problems which mitigate against their being able to elevate their legs for long periods.

Substantive changes

Advice to elevate leg New option for which we found no RCT evidence in people with venous leg ulcers. Categorised as Unknown effectiveness.

2008; 2008: 1902.
Published online 2008 September 15.

Advice to keep leg active

Summary

We found no direct information about the effects of keeping the leg active in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

We found no RCT evidence about the effects of advice to keep the leg active, although this intervention makes sense, as venous insufficiency can be reduced by activation of the calf muscle pump. Potential advantages of activity may include reduced leg oedema, and increasing venous return. Many people with venous disease have joint or other mobility problems which may mitigate against increasing their activity levels.

Substantive changes

Advice to keep leg active New option for which we found no RCT evidence in people with venous leg ulcers; categorised as Unknown effectiveness.

2008; 2008: 1902.
Published online 2008 September 15.

Advice to modify diet

Summary

We found no direct information about the effects of diet modification in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

We found no RCT evidence on the impact of dietary modification on venous ulcer prevention or healing. A healthy diet is important for preventing arterial disease, which could, in turn, affect ulcer healing. It is not clear if people with venous ulceration have specific dietary needs, but a diet high in fruit and vegetables, and low in salt, fat, alcohol, and sugar, is likely to maintain vascular supply to support healing.

Substantive changes

Advice to modify diet New option for which we found no RCT evidence in people with venous leg ulcers; categorised as Unknown effectiveness.

2008; 2008: 1902.
Published online 2008 September 15.

Advice to stop smoking

Summary

We found no direct information about the effects of smoking cessation in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

We found no RCT evidence on the impact of smoking-cessation advice on venous ulcer prevention or healing. A healthy lifestyle, including avoidance of smoking, is important for preventing arterial disease, which could, in turn, affect ulcer healing.

Substantive changes

Advice to stop smoking New option for which we found no RCT evidence in people with venous leg ulcers; categorised as Unknown effectiveness.

2008; 2008: 1902.
Published online 2008 September 15.

Advice to reduce weight

Summary

We found no direct information about the effects of weight reduction in people with venous leg ulcers.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

We found no RCT evidence on the impact of advice for weight loss on venous ulcer prevention or healing. A healthy lifestyle is important for preventing arterial disease, and increasing activity while maintaining a healthy diet could, in turn, affect ulcer healing.

Substantive changes

Advice to reduce weight New option for which we found no RCT evidence in people with venous leg ulcers; categorised as Unknown effectiveness.

2008; 2008: 1902.
Published online 2008 September 15.

Compression bandages and stockings

Summary

RECURRENCE RATES Compared with no compression: Compression stockings are more effective at reducing ulcer recurrence rates at 6 months ( high-quality evidence ). Compression stockings compared with other forms of compression: High-compression stockings (UK class 3), and moderate compression stockings (UK class 2) seem equally effective at reducing recurrence at 5 years ( moderate-quality evidence ).

Benefits

Compression stockings versus no compression:

We found one systematic review (search date 2000), which found no RCTs comparing compression stockings versus no compression, and one subsequent RCT. The RCT (153 people) found that wearing compression stockings significantly reduced recurrence at 6 months compared with not wearing compression stockings (21% with compression stockings v 46% with no compression stockings; RR 0.46, 95% CI 0.28 to 0.76; NNT for 6 months' treatment 2, 95% CI 2 to 5).

Compression stockings versus other forms of compression:

We found one systematic review (search date 2000, 2 RCTs). The first RCT identified by the review (166 people) compared two brands of UK Class 2 stockings (see comment below) and found no significant difference in recurrence after 18 months (22/92 [24%] with Medi v 27/74 [36%] with Scholl; RR 0.82, 95% CI 0.61 to 1.12). The second RCT identified by the review (300 people) compared Class 2 and Class 3 stockings (see comment below). With intention-to-treat analysis, the RCT found no significant difference in recurrence after 5 years with high-compression stockings (UK Class 3) compared with moderate-compression stockings (recurrence: 59/151 [39%] with Class 2 elastic compression v 48/149 [32%] with Class 3 compression cases; RR 0.74, 95% CI 0.45 to 1.20). This analysis may underestimate the effectiveness of the Class 3 stockings because a significant proportion of people changed from Class 3 to Class 2. Both RCTs found that non-compliance with compression stockings was associated with recurrence.

Harms

The application of high compression to limbs with reduced arterial supply may result in ischaemic tissue damage and, at worst, amputation.

Compression stockings versus no compression:

The review and subsequent RCT gave no information on adverse effects.

Compression stockings versus other forms of compression:

The review gave no information on adverse effects.

Comment

Compression hosiery is classified according to the magnitude of pressure exerted at the ankle; the UK classification states that Class 2 stockings are capable of applying 18–24 mm Hg pressure and Class 3 are capable of applying 25–35 mm Hg pressure at the ankle. Other countries use different classification systems. Stockings reduce venous reflux by locally increasing venous pressure in the legs relative to the rest of the body. This effect only takes place while hosiery is worn. The association between non-compliance with compression and recurrence of venous ulceration provides some indirect evidence of the benefit of compression in prevention. People are advised to wear compression stockings for life, and may be at risk of pressure necrosis from their compression stockings if they subsequently develop arterial disease. Regular reassessment of the arterial supply is considered good practice, but we found no evidence about the optimal frequency of assessment. Other measures designed to reduce leg oedema, such as resting with the leg elevated, may be useful (see comment on advice to elevate legs).

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Superficial vein surgery to prevent recurrence

Summary

RECURRENCE RATES Surgery plus compression compared with compression alone: Superficial vein surgery plus compression is more effective at reducing ulcer recurrence rates at 12 months to 3 years ( moderate-quality evidence ). Open compared with endoscopic surgery: Open surgery is less effective at reducing ulcer recurrences at 12 months, and is associated with higher wound infection rates (moderate-quality evidence).

Benefits

Surgery plus compression versus compression alone:

We found one systematic review (search date 1997, 1 RCT) and three subsequent RCTs. The RCT (30 people) identified by the review compared surgery plus compression stockings versus compression stockings alone for prevention of recurrence (see comment below). It found that surgery plus compression stockings significantly reduced recurrence rates compared with compression stockings alone (5% with surgery plus compression stockings v 24% with compression stockings alone; RR 0.21, 95% CI 0.03 to 0.80). The first subsequent RCT (45 people) compared minimally invasive surgery versus compression bandages. People randomised to surgery wore compression stockings immediately after surgery, and people randomised to compression wore compression stockings after ulcer healing was achieved. The RCT found that surgery significantly reduced recurrence rates over 3 years compared with compression (2/21 [10%] with surgery v 9/24 [38%] with compression bandages; P less than 0.05). The second subsequent RCT (428 people), which compared superficial vein surgery plus compression versus compression alone, found significantly lower recurrence rates after 12 months with surgery plus compression compared with compression alone (12% with surgery plus compression v 28% with compression alone; HR –2.76, 95% CI –1.78 to –4.27).Long-term follow-up of this RCT found that this difference was sustained at 3 years (31% recurrence in surgery group v 56% recurrence in compression group, P less than 0.01). The third subsequent RCT (170 people), which compared subfascial endoscopic perforating vein surgery (SEPS) plus compression versus compression alone, found no significant difference in recurrence rates between groups at 27 months (22% with surgery and compression v 23% with compression alone, reported as non-significant, all other data presented graphically).

Open versus endoscopic surgery:

We found one systematic review (search date 2003, 1 RCT, 39 people), which compared open surgery versus SEPS, and a subsequent long-term follow-up report of the RCT identified by the review. The RCT found four (22%) recurrences at 12 months in the open surgery group, and two (12%) in the SEPS group (reported as P = 0.044).

Harms

One RCT gave information on adverse effects. It found significantly higher wound infection rates with open surgery compared with subfascial endoscopic perforator surgery (SEPS) (53% with open surgery v 0% with SEPS; P less than 0.001). Vein surgery has the usual risks of surgery and anaesthesia.

Surgery plus compression versus compression alone:

The review, three subsequent RCTs, and the long-term follow-up RCT gave no information on adverse effects.

Open versus endoscopic surgery:

The review found that deep vein thrombosis was reported in 1%, wound infection in 6%, neuralgia in 7%, and haematoma in 9% of people having surgical treatment involving SEPS.

Comment

The small RCT identified by the review, which compared surgery plus compression versus compression alone, was poorly controlled, and its results should be interpreted with caution. The subsequent small RCT randomised legs rather than people.

Substantive changes

Superficial vein surgery One long-term follow-up study and one RCT added. The long-term follow-up compared superficial vein surgery plus compression versus compression alone, and found that, after 3 years, recurrence rates were lower with surgery plus compression compared with compression alone. One RCT comparing subfascial endoscopic perforating vein surgery (SEPS) plus compression versus compression alone found no significant difference in recurrence rates between groups.Categorisation unchanged (Likely to be beneficial)

2008; 2008: 1902.
Published online 2008 September 15.

Rutoside (oral)

Summary

RECURRENCE RATES Compared with placebo: Oral rutosides are no more effective at reducing ulcer recurrence at 18 months ( moderate-quality evidence ).

Benefits

Oral rutoside versus placebo:

We found one systematic review (search date 1997, 1 RCT, 139 people). The RCT found no significant difference in recurrence at 18 months between rutoside and placebo (32% with rutoside v 34% with placebo; P = 0.93).

Harms

Oral rutoside versus placebo:

One RCT (31 people with obstructive arm lymphoedema) found that rutoside was associated with headache, flushing, rashes, and mild gastrointestinal disturbances. The review gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 1902.
Published online 2008 September 15.

Stanozolol (oral)

Summary

RECURRENCE RATES Compared with placebo: Stanozolol may be no more effective at reducing ulcer recurrence at 18 months ( low-quality evidence ).

Benefits

Oral stanozolol versus placebo:

We found one systematic review (search date 1997, 1 RCT, 60 people). The RCT found no significant difference in ulcer recurrence between 6 months' treatment with stanozolol and placebo (length of follow-up not reported; recurrence: 7/25 [28%] legs with stanozolol v 4/23 [17%] legs with placebo; RR 1.61, 95% CI 0.54 to 4.79).

Harms

Oral stanozolol versus placebo:

Stanozolol is an anabolic steroid; adverse effects include acne, hirsutism, amenorrhoea, oedema, headache, dyspepsia, rash, hair loss, depression, jaundice, and changes in liver enzymes. The review gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence


Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group