Venous leg ulcers

Recommendations

Identify and Treat the Cause
1 Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing) Level of Evidence
5
2 Perform a bilateral lower leg physical assessment including an ankle-brachial pressure index (ABPI). Level of Evidence
1a
3 Determine the cause(s) and for possible chronic venous insufficiency based on etiology: abnormal valves (reflux), obstruction, or calf-muscle-pump failure. Level of Evidence
5
4 Treat the cause and implement appropriate compression therapy for venous disease in the absence of arterial predominant disease. Level of Evidence
1a
5 Implement appropriate medical therapy. Level of Evidence
5
6 Consider the addition of medical therapy to increase wound healing and manage problems such as lipodermatosclerosis and superficial phlebitis. Level of Evidence
Not Assessed
7 Address systemic factors that may affect healing, including lifestyle modification. Level of Evidence
Not Assessed
8 Consider surgical management for venous (if significant superficial or perforator vein disease exists in the absence of deep venous disease) or arterial disease (bypass, dilation, or stent). Level of Evidence
1a
9 For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction) Level of Evidence
1a


Address patient-centered Concerns
10 Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences. Level of Evidence
5
11 Educate patients about the need for lifelong compression hose and reinforce adherence frequently. Level of Evidence
5
12 Assess / Control pain and optimize activities of daily living. Level of Evidence
Not Assessed


Provide Local Wound Care
13 Assess and document the wound at regular intervals. Level of Evidence
Not Assessed
14 Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate. Level of Evidence
1a
15 Consider surgery for adherent and medically fit patients who have nonhealing ulcers and superficial or perforator disease without deep valvular disease. Level of Evidence
1a


Provide Organizational Support
16 Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition). Level of Evidence
1a


Background

Chronicity and recurrence of venous leg ulcers have an important effect on patient quality of life and societal costs of management. Evidence-based management has the potential to improve patient quality of life and to reduce these costs substantially.

Compression
Compression therapy is the gold-standard treatment for venous ulcers. High-compression bandaging is optimal, but this approach may require modification in patients with diabetes, arthritis, infection, or mild arterial disease (ankle-brachial index [ABI] 0.6-0.8). Compression is contraindicated in patients with ABI <0.6. No clear differences in effectiveness exist between different multilayer compression systems, but elastic systems may have advantages over inelastic systems. Compression and support bandages differ in their mechanism of action. Compression uses an elastic system that provides high pressure at rest and high (but slightly lower) pressure with muscle contraction. High-compression systems include four-layer systems, the gold standard for compression therapy, and long-stretch systems. Support uses an inelastic (rigid) system that provides low pressure at rest and high pressure against fixed resistance with muscle contraction. High-compression support systems include short-stretch systems and the Duke boot (modified Unna’s boot).

Local wound care
Wound assessment establishes a baseline for developing an individualized wound care plan. Local wound care includes debridement; cleansing; identification and treatment of critical colonization and infection; attention to moisture balance; and appropriate dressings. Debridement and moist wound healing are only appropriate in wounds with an adequate blood supply for healing. Autolytic debridement is most commonly used for venous ulcers. Specific types of dressings have not been shown to improve wound healing or decrease pain. Dressings should be selected based on their characteristics, desired action, patient comfort, and cost effectiveness.

Medical therapy
Pentoxyfilline and micronized purified flavonoid fraction (MPFF) are effective for healing venous ulcers. Stanozolol has been shown significantly to reduce the area affected by chronic lipodermatosclerosis. Acetylsalicylic acid (ASA) or other nonsteroidal antiinflammatory drugs (NSAIDs) can treat acute lipodermatosclerosis. Superficial phlebitis may also respond to an NSAID, and low-dose ASA may speed healing of a venous ulcer. Patients with deep vein thrombosis (DVT) require anticoagulation.

Lifestyle management
Exercise therapy may improve healing. Lifelong use of support hose is usually necessary to prevent recurrence, and lifestyle changes may also be important. Patients should be educated about warning signs of arterial disease and monitored for development of arterial disease.

Effective communication and patient, family and caregiver education (especially incorporating self-management components) are critical in obtaining adherence to therapeutic and preventive strategies and achieving optimal long-term outcomes.

Patient-centred concerns
Venous ulcers are associated with numerous patient-centred concerns, including increased stress; pain; and difficulty coping, both at a psychologic and a functional level. Decreased mobility, sleep disruption and limited social interaction decrease patient quality of life.

Nonhealing ulcers—complementary and advanced therapies, skin substitutes
Evidence indicates that wounds whose size has not decreased by 30% within 4 weeks do not heal by 12 weeks. Attention to initial healing rates may allow earlier identification of nonhealing and prompt changes in the care plan. The following factors have a statistically significant association with nonhealing venous leg ulcers:
♦ ABI <0.8
♦ History of venous ligation or stripping
♦ Hip or knee surgery
♦ Yellow, fibrin-like material >50% of ulcer base
♦ Larger area
♦ Longer duration.

Advanced therapies, including topical negative pressure, hyperbaric oxygen, electrical stimulation, therapeutic ultrasound, biologicals and skin substitutes, may stimulate healing at the edge of nonhealing wounds (edge effect). Cellular and acellular skin substitutes have a role in managing stalled but healable chronic ulcers. Evidence supports the use of Oasis, an acellular skin substitute, in healing venous leg ulcers. The use of composite cellular skin substitutes, such as Apligraf and Dermagraft, is supported by good evidence in healing diabetic foot ulcers. This therapy may be cost effective if ulcers have been present for more than 1 year.

Adjunctive therapy
Identified factors that may affect healing, such as poor nutrition and sedentary lifestyle, can be addressed through an exercise prescription and management of nutritional deficiencies. Physical therapy may improve restricted ankle mobility in patients. Both therapeutic ultrasound and electrical stimulation may accelerate ulcer healing.

Surgery
Significant superficial or perforator vein disease, without extensive deep valvular disease, may be treated surgically, with subfascial endoscopic perforator surgery (SEPS). SEPS is associated with almost 90% ulcer healing rates and low recurrence. This operation may be accompanied by Linton’s procedure, or removal of the long saphenous vein. Longer follow-up of patients treated surgically is necessary to evaluate the effectiveness of surgery fully. Until then, venous surgery should be reserved for medically fit patients who fail to respond to standard therapy and who adhere to medical therapy. Surgery is unlikely to be helpful in patients with deep venous incompetence.

References

Essential Publications
1 Compression Therapy Quality Indicator
 Type: Systematic review
Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000265. DOI: 10.1002/14651858.CD000265.
This well designed systematic review indicates that compression is more effective in treating venous leg ulcers than no compression, high compression is more effective than low compression, elastic is more effective than non-elastic, multi-layered high compression is more effective than single-layered compression.
2 Compression Therapy for prevention of recurrence of venous leg ulcers Quality Indicator
 Type: Systematic review
Nelson EA, Bell-Syer SEM, Cullum NA. Compression for preventing recurrence of venous ulcers. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD002303. DOI: 10.1002/14651858.CD002303.
This review that is quite old is important because a gap was identified – that there was no evidence to show if compression prevents venous leg ulcers. This led to the development of a RCT on this topic.
3 Compression for the prevention of recurrence of venous leg ulcers Quality Indicator
 Type: RCT
Nelson EA, Harper, DR, Prescott RJ, Gibson B, Brown D and Ruckley V. Prevention of recurrence of venous ulceration: Randomized controlled trial of class 2 and class 3 elastic compression. J Vasc Surg 2006;44:803-8.
This paper is important because it illustrates the trade-off between clinical effectiveness and reduced compliance in patients assigned to high compression. Thirty-six percent (107/300) of patients had recurrent leg ulceration by 5 years. Recurrence occurred in 59 (39%) of 151 class 2 elastic compression cases and in 48 (32%) of class 3 compression cases. there was no statistically significant difference in recurrence rates, but fewer people experienced recurrence with high compression, although not at the conventional levels of statistical significance. It is important to note that this trial does not demonstrate equivalence in recurrence rates in moderate and high compression. In addition, the two factors most important to leg ulcer recurrence were multiple previous episodes of leg ulceration and less than full ankle range of motion.
4 Compression therapy in venous insufficiency and venous ulcers Quality Indicator
 Type: Systematic review
Berliner et al, A systematic review of pneumatic compression for treatment of chronic venous insufficiency and venous ulcers, 2003, Agency for Healthcare Research and Quality, 1-12.
In this well-designed systematic review of RCTs and cohort studies it was found that compression therapy is an important part of treatment for chronic venous insufficiency (CVI) and venous leg ulcers. Long-term use of pneumatic compression devices in the home environment may be used in addition to or as an alternative to other compression therapies for patients who are unable or refuse to comply with other methods.
5 Compression Therapy - Post-thrombotic Syndrome Quality Indicator
 Type: Systematic review
KolbachDN, SandbrinkMWC, NeumannHAM, PrinsMH.Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004177. DOI: 10.1002/14651858.CD004177.
This systematic review of RCTs was conducted to determine the relative effectiveness of compression therapy in people with stage I and II post-thrombotic syndrome according to the classification of Widmer. There is some evidence of a beneficial effect of intermittent pneumatic compression units.
6 Dressings - venous and mixed etiology leg ulcers Quality Indicator
 Type: Systematic review
Bouza C, Munoz A, Amate JM. Efficacy of modern dressings in the treatment of leg ulcers: A systematic review. Wound Repair and Regeneration 2005;13:218-229.
This is well-conducted systematic review to determine the benefit of using modern dressings to treat patients with leg ulcers of venous, mixed or poorly differentiated etiology. There were no differences in the proportion of healed ulcers or in the reduction of wound size between modern and conventional dressings or between different dressings. This review illustrates the need for further research on this topic.
7 Dressings - venous leg ulcers Quality Indicator
 Type: Systematic review
Palfreyman SJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001103. DOI: 10.1002/14651858.CD001103.pub2
This is a well-conducted Cochrane systematic review that included 42 RCTs and 3001 subjects indicated that when hydrocolloid was compared with foam dressings, alginate dressings, hydrocolloid and low-adherent dressings, there were no evidence of a statistically significant difference in healing rates. Similarly hydrocolloids are no more effective for healing than low adherent dressings used beneath compression (RR=1.09, 95%CI 0.89 to 1.34). Decisions regarding which dressing to apply should be based on local costs of dressings and patient preferences. More research in this area is required.
8 Dressings - venous leg ulcers Quality Indicator
 Type: Systematic review
Palfreyman SJ, Nelson EA, Michaels JA. Dressings for venous leg ulcers: systematic review and meta-analysis. BMJ 2007;335:244.
This systematic review is a condensed version (12 pages) of the Cochrane review published in 2006 (62 pages) by the same authors. In addition to providing the information in fewer pages, it contains Forest plots that provide a visual illustration that no differences were detected.
9 Silver dressing - venous leg ulcers Quality Indicator
 Type: Systematic review
Chambers H, Dumville JC, Cullum N.Silver treatments for leg ulcers: a systematic review. Wound Repair and Regeneration 2007;15:165-173.
This is a well-conducted systematic review of four RCTs that were included in the meta-analyses. It is important for illustrating lack of evidence to support the use of silver products, as studies provided inconsistent evidence regarding the effects of silver-based dressings and topical agents on leg ulcer healing.
10 Electromagnetic therapy - venous leg ulcers Quality Indicator
 Type: Systematic review
Ravaghi H, Flemming K, Cullum N, Olyaee Manesh A. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 2, 1-15.
This is a well-conducted update of a Cochrane review (2005); no new RCTs were found comparing electromagnetic therapy with sham or other therapies. No significant difference was found in the three RCTs in the original review. This study illustrates the need for more individual studies of electromagnetic therapy.
11 Skin grafting - venous leg ulcers Quality Indicator
 Type: Systematic review
Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD001737. DOI: 10.1002/14651858.CD001737.pub3.
Grafts were compared with standard care, with other grafts, and with other agents. Pooling of five trials of fresh or frozen allografts compared with standard care of low-adherent dressing or hydrocolloid showed there were significantly higher healing rates with allografts than dressings (RR 2.00, 95% CI 1.04 to 3.84). Since there were methodological problems, this result should be accepted with some caution and confirmed by large, well-designed and conducted trials. Pooled results of two trials of bilayered human skin equivalent compared with standard care of foam or placebo dressing yielded a relative risk of healing with the artificial skin compared with simple dressings of 1.51 (95%CI 1.22 to 1.88). The increase in healing rate from approximately 40% to 60% represents an NNT of 5 for six months' treatment, indicating that five people would need to be treated with artificial skin, rather than a simple dressing, in order for one additional ulcer to heal at six months. These two trials provide reasonable evidence that a greater proportion of venous ulcers heal with artificial skin than a simple dressing.
12 Oral treatment with Daflon – venous leg ulcers Quality Indicator
 Type: Systematic review
Coleridge Smith P, Daflon 500 mg and Venous Leg Ulcer: New Results From a Meta-Analysis, 2005, Angiology, S33-S39.
This is a well-conducted systematic review of RCTs to assess the effect of oral treatment with micronized purified flavonoid fraction (MPFF, Daflon 500 mg) on leg ulcer healing. At 6 months based on 616 subjects irrespective of study conditions, 61.3% were completely healed in the Daflon 500 mg group versus 47.7% in the control group. The relative hazard of healing was 38% higher in the Daflon 500 mg group compared with the control group (CI, 11% to 70%). The time to complete healing of ulcers was shorter in the Daflon group (16 weeks vs 21 weeks; hazard ratio = 1.33). A strong trend in favor of Daflon 500 mg began to emerge by week 8 of treatment. Daflon 500 mg might be a useful adjunct to conventional therapy in large and longstanding ulcers that might be expected to heal slowly.
13 Adjunctive therapy - Micronized Purified Flavonoid Fraction (MPFF) – Venous leg ulcers Quality Indicator
 Type: Systematic review
Coleridge-Smith P, Lok C, Ramelet A-A, Venous leg Ulcer: A Meta-analysis of Adjunctive Therapy with Micronized Purified Flavonoid Fraction, 2005, European Journal of Vascular and Endovascular Surgery 30, 198-208.
This well-conducted review of 5 RCTs was undertaken to assess the effect of oral treatment with micronized purified flavonoid fraction (MPFF) on leg ulcer healing. After 6 months, 61.3% of these patients were completely healed in the MPFF group versus 47.7% in the control group (RRR 32% 95%CI 3-70%). At 2 months, the chance for ulcer healing in the MPFF group compared to the controls (N=723) was 44% (CI, 7–94%; P=0.015). The effect was seen particularly in ulcers between 5 and 10 cm2 and present for 6-12 months duration. This review suggests that MPFF may be effective in accelerating venous leg ulcer healing in large ulcers of long duration.
14 Topical agents versus dressings for pain – Venous leg ulcers Quality Indicator
 Type: Systematic review
Briggs M, Nelson EA. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database of Systematic Reviews 2003, Issue 1.Art. No.: CD001177. DOI: 10.1002/14651858.CD001177.
This is a well-conducted systematic review assessing the effectiveness of dressings, local anaesthetics or topical analgesia for pain relief in people with venous leg ulcers. There are six trials indicating that a eutectic mixture of local anaesthetic (EMLA) (5%) provides pain reduction of 20.6 mm (95% CI 29.1 to 12.2) during venous leg ulcer debridement. Further research is required to determine whether debridement of venous leg ulcers aids healing and what impact local anaesthetic has on leg ulcer healing. This review indicates the lack of evidence to answer several of the questions about pain in people with leg ulcers.
15 Ultrasound treatment of venous leg ulcers Quality Indicator
 Type: Systematic review
Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001180. DOI: 10.1002/14651858.CD001180.
This well-conducted systematic review of RCTs was undertaken to determine if therapeutic ultrasound stimulates venous leg ulcer healing, and specific details of the optimum treatment regimen. The study methods and outcomes were not homogeneous and the results were not combined. Although no statistical differences in healing rates between any of the therapies were found the direction of effect was consistently in favour of ultrasound. This review illustrates the need for well-designed trials of ultrasound.
16 Laser therapy for venous leg ulcers Quality Indicator
 Type: Systematic review
Flemming K, Cullum N. Laser therapy for venous leg ulcers. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001182. DOI: 10.1002/14651858.CD001182.
This well-conducted systematic review of RCTs was undertaken to determine if low level laser therapy stimulates venous leg ulcer healing, and specific details of the optimum treatment regimen. The four studies included do not demonstrate a statistically significant improvement in venous leg ulcer healing with the use of low level laser therapy. The only suggestion of therapeutic benefit is shown in one small RCT where a combination of laser and infrared light led to an improvement in the healing rates of venous ulcers. This review illustrates the need for well-designed trials of laser therapy.
17 Pentoxifylline for venous leg ulcers Quality Indicator
 Type: Systematic review
Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD001733. DOI: 10.1002/14651858.CD001733.
This well-conducted systematic review was undertaken to determine if pentoxifylline improves healing of venous leg ulcers, when compared with placebo, both with or without compression therapy. The relative risk of healing with pentoxifylline versus placebo, with compression, in trials of eight to 12 weeks, pooled using a fixed effects model, was significant (RR 2.36, 95% CI 1.74 to 3.19). Comparison of pentoxifylline with placebo, without compression, also favoured pentoxifylline (RR 2.25, 95% CI 1.49 to 3.39). However, comparison of pentoxifylline versus defibrotide indicated no significant difference in healing at three months. Pentoxifylline appears to be an effective adjunct to compression bandaging for treating venous ulcers and may be effective for treating venous leg ulcers even without compression.
18 Pentoxifylline, compression, dressings – Venous leg ulcers Quality Indicator
 Type: RCT
Nelson EA, Prescott RJ, Harper DR, Gibson B, Brown D, Ruckley CV. A factorial, randomized trial of pentoxifylline or placebo, four-layer or single-layer compression, and knitted viscose or hydrocolloid dressings for venous ulcers. J Vasc Surg 2007;45:134-41.
In this excellent recent factorial design RCT involving 245 patients, the effectiveness of pentoxifylline (1200 mg daily) was compared with placebo, knitted viscose with hydrocolloid dressings, and single-layer with four-layer bandaging for venous ulceration. In unadjusted analyses, only four-layer bandages were associated with significantly higher healing rates than single-layer bandages (67% vs. 49%; P=0.009). In adjusted analysis, the significance of the pentoxifylline effect increased just to significance (relative risk of healing, 1.4; 95% confidence interval, 1.0 to 2.0). This study further indicates the important effect of high-compression bandaging on healing rate, irrespective of dressing, and less strongly suggests that pentoxifylline may increase the chance of healing.
19 Topical pale sulfonated shale oil – Venous leg ulcers Quality Indicator
 Type: RCT
Beckert S, Warnecke J, Zelenkova H, Kovnerystyy O, Cholcha W, Konigsrainer A and Coerper S. 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.
This is a well-designed multi-center observer-blind RCT, conducted to determine if Pale Sulfonated Shale Oils (PSSO) are more effective at facilitating venous healing than simple compression therapy in patients with venous leg ulcers. The cumulative wound area was significantly more reduced in the PSSO group compared with the vehicle group (P<0.0001). PSSO was judged successful both by physicians and patients and there were no important adverse events. The study suggests an enhancement of venous ulcer healing by a topical agent in addition to standard care consisting of compression therapy.
20 Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency Quality Indicator
 Type: RCT
Cesarone MR, Belcaro G, Rohdewald P, Pellegrini L, Ledda A, Vinciguerra G, Ricci A, Gizzi G, Ippolito E, Fano F, Dugall M, Acerbi B, Cacchio M, Di Renzo A, Hosoi M, Stuard S and Corsi M. Comparison of Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency: A Prospective, Controlled Study. Clin Appl Thrombosis/Hemostasis 12(2):205–212, 2006.
This RCT was conducted to investigate the clinical effectiveness of two doses of Pycnogenol compared to Daflon in a group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling and previous history of venous ulcerations. All microcirculatory parameters indicated a significantly larger (p < .05) improvement of CVI produced by Pycnogenol in comparison with the Daflon treatment group both in the lower dose and in the higher dose groups. Edema formation, resting flux, and rate of ankle swelling were reduced about twice as much by Pycnogenol in comparison with Daflon (P<0.05). Treatments were well tolerated in all groups and no side effects due to treatment were reported. This study suggests that oral treatment with Pycnogenol is very effective and fast in improving the microcirculation, signs, and symptoms in patients with CVI and venous microangiopathy.
21 Prevalence of venous leg ulcers Quality Indicator
 Type: Systematic review
Graham ID, Harrison MB, Nelson A, Lorimer K, Fisher A. Prevalence of Lower-Limb Ulceration: A Systematic Review of Prevalence Studies, 2003, Advances in Skin & Wound Care, 305-16.
This well-conducted systematic review of cohort studies was undertaken to determine the prevalence of leg ulcers reported in the literature. In the population-based prevalence studies that used clinical validation, the prevalence rate of ulceration was 1.8% with a range of 0.12% to 1.1%. Good quality prevalence studies with large numbers, description of case identification, and definition of ulcers with clinical confirmation, are required. This study provides an estimate of venous leg ulcer prevalence.
22 Ketansein - patients with diabetes with venous insufficiency Quality Indicator
 Type: RCT
Quatresooz P, Kharfi M, Paquet P, Vroome V, Cauwenbergh G and Pierard GE. Healing effect of ketanserin on chronic leg ulcers in patients with diabetes. JEADV 2006, 20, 277–281.
This double blind study suggests that application of topical 2% ketanserin ointment affects the healing rate of chronic leg ulcers present in patients with diabetes with venous insufficiency. Twelve patients with diabetes and at least 2 difficult-to-treat leg ulcers that were randomly allocated to treatment served as their own control. Within subjects, there was significant relative wound area reduction at week 4 (P=0.010) at week 6 (P=0.010) and at week 8 (P=0.004). Weekly reduction was 10.25% for the ketanserin-treated ulcers and 2.5% for the placebo-treated ulcers.
23 Mimosa tenuiflora cortex extract - Venous leg ulcers Quality Indicator
 Type: RCT
Rivera-Arce E, Chavez-Soto MA, Herrera-Arellano A, Arzate S, Aguero J, Feria-Romero IA, Cruz-Guzman A and Lozoya X. Therapeutic effectiveness of a Mimosa tenuiflora cortex extract in venous leg ulceration treatment. Journal of Ethnopharmacology 2007;109:523–528.
This is a well-designed randomized, double-blind clinical trial. For 13 weeks, the treatment group (n=20) received a hydrogel containing 5% of a crude extract standardized in its tannin concentration initially followed by topical application of the corresponding hydrogel and dressing while the control group received placebo hydrogel (n=20). Reduction in wound size was noted in all patients in the extract group with mean reduction by 8 weeks of 92%, while wound size reduced in only in one patient in the control group (p=0.0001). This study shows that the extract obtained from Mimosa tenuiflora bark facilitated skin-ulcer cicatrization when used as a coadjuvant in conventional VLU treatment in ambulatory patients.
24 Larval Therapy – Venous leg ulcers Quality Indicator
 Type: RCT
Petherick ES, O'Meara S, Spilsbury K, Iglesias CP, Nelson EA, Torgerson DJ. Patient acceptability of larval therapy for leg ulcer treatment: a randomised survey to inform the sample size calculation of a randomised trial. BMC Medical Research Methodology 2006;6:43 doi:10.1186/1471-2288-6-43
This randomized survey was undertaken as a precursor to RCT to evaluate patient aversion to larval therapy and preference for loose versus bagged larvae to debride and heal sloughy and necrotic venous leg ulcers. In addition, acceptable time to healing for this method was determined. People aged 18 years and above (n=35) with at least one leg ulcer of venous or mixed (venous and arterial) aetiology completed a survey comparing Loose Larvae and hydrogel, and a survey comparing bagged larvae and hydrogel. 77% of participants would consider the use of larval therapy as an acceptable treatment option, regardless of the method of containment. Half the respondents would be willing to use this therapy even if they were equally able to achieve healing using hydrogel by 20 weeks. Regarding the use of loose larvae, complete healing would have to occur over 17 weeks for patients to choose larvae rather than hydrogel. Patient acceptance of this therapy may be of value to clinicians; specific details will inform research.
25 Vacuum-assisted closure – chronic leg ulcers Quality Indicator
 Type: RCT
Vuerstaek JDD, Vainas T, Wuite J, Nelemans P, Neumann MHA and Veraart JCJM. 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;44:1029-38.
This well-designed RCT was conducted to determine the efficacy of V.A.C. in wound healing compared with standard wound dressings in hospitalized patients with chronic venous, combined venous and arterial, or microangiopathic leg ulcers with durations greater than six months. Median total healing time in the V.A.C. group was 29 days (95% CI 25.5-32.5) compared with 45 days (95% CI 36.2-56.8) in the control group (P=0.0001). Median wound bed preparation time (time from surgical debridement to application of punch skin grafts) was less in the V.A.C. group 7 days (95% CI 5.7-8.3) than in the control group 17 days (95% CI 10-24). There were non-significant differences in recurrence rates, relapse rates, and complications. This study indicates that there may be advantages to using V.A.C. to reduce healing time in these patients.
26 Surgical treatment versus conservative – Venous leg ulcers Quality Indicator
 Type: RCT
Van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM,. Wittens CH. Conservative versus surgical treatment of venous leg ulcers: A prospective, randomized, multicenter trial. Journal of Vascular Surgery. 2006; 44:563-71.
This multicentre RCT was conducted to determine if ambulatory compression therapy with venous surgery is better than just ambulatory compression in leg ulcer patients. Subfascial endoscopic perforating vein surgery (SEPS) was provided to patints with 94 ulcers; standard ambulatory compression therapy 102 patients. There was no difference between the groups in the length of the ulcer free period following treatment (P=0.11). Only patients with recurrent ulceration or medially located ulcers remained ulcer-free longer following surgery than patients treated conservatively (P=0.02). Although the findings of this study are biased by the inclusion of 200 ulcers in 170 patients, the findings suggest that patients with recurrent and or/ medial ulceration might benefit from SEPS in addition to compression.
27 Amelogenins (XelmaTM) - Venous leg ulcers Quality Indicator
 Type: RCT
Vowden P, Romanelli M, Peter R, Bostrom A, Josefsson A, Stege H. The effect of amelogenins (XelmaTM) on hard-to-heal venous leg ulcers. Wound Repair and Regeneration 2006; 14: 240-246
This single-blind randomized multicenter study was conductd to examine wound size reduction using amlogenin proteins in patients with hard to heal venous ulcers. Patients were randomly allocated to receive treatment with XelmaTM cream (n=62) or to the control group that received propylene glycol alginate 7% (n=61) for 12 weeks. The group treated with amelogenins experienced greatest healing, especially in large or hard-to-heal wounds.
28 Autologous keratinocytes in fibrin sealant – Recalcitrant venous leg ulcers Quality Indicator
 Type: RCT
Vanscheidt W, Ukat A, Horak V, Bruning H, Hunyadi J, Pavlicek R, Emter M, Hartmann A, Bende J, Zwingers T, Ermuth T, and Eberhardt R. Treatment of recalcitrant venous leg ulcers with autologous keratinocytes in fibrin sealant: A multinational randomized controlled clinical trial. Wound Rep Reg (2007) 15 308–315.
This is a very well-described open-label multicntre RCT to compare wound healing using BioSeed®-S and compression therapy (n=116) with standard care (nonadherent gauze and compression therapy) (n=109) in patients with chronic venous leg ulcers of at least 3 month duration, with areas between 2 and 500 cm^2. Time to healing was less in the BioSeed®-S group than in the standard care group, 176 days versus more than 201 days (P<0.0001). Similarly, complete healing occurred in 38.3% of patients who received BioSeed®-S treatment compared with 22.4% of patients who received standard treatment. (P=0.0106). This study illustrates a treatment option that improved the healing rate and time to healing in patients with recalcitrant legs ulcers.
29 Outcome measures and comparison of hydrogels – Venous leg ulcers Quality Indicator
 Type: RCT
De la Brassinne, M., Thirion, L., Horvat, L. A novel method of comparing the healing properties of two hydrogels in chronic leg ulcers (2005). JEADV, 20, 131-135.
This pilot study was conducted to compare alginate gel Flaminal® (n=10) and hydrocolloid gel Intrasite® as the control (n=10) on the healing of leg ulcers and to describe the use of volume and surface area reduction as outcome measures in trials. Significant difference in wound volume reduction after treatment with Flaminal® was detected at 7 days, while surface area reduction was detected only by 28 days. In this pilot study volume reduction detected greater effect with Flaminol® than Intrasite® at 7, 14, and 28 days. This study suggests that reduction in volume may be a good outcome measure for comparing and measuring different treatment effects.
30 Comparison of two foam dressings – Venous leg ulcers Quality Indicator
 Type: RCT
Franks PJ, Moody M, Moffatt CJ, Hiskett G, Gatto P, Davies C, Furlong WT, Barrow E, Thomas H on behalf of the Wound Healing Nursing Research Group. Randomized trial of two foam dressings in the management of chronic venous ulceration. Wound Rep Reg 2007;15:197-202.
This multicentre RCT was undertaken to compare two foam dressings, Allevyn Hydrocellular (n=81) and Mepilex (n=75) in the management of chronic venous leg ulcers. Propotion of wound closure: Allevyn 61.7%, Mepilex 66.7% closure. The hazard ratio for healing after adjustment for bandage type and trial centre was not significant at 1.48 (95% CI 0.87 to 2.54, P=0.15). The groups had similar Pain scores and similar proportions of bandage related withdrawls. This study is important because it illustrates that the effect of using these two foam dressings is similar. It also illustrates the need for statistically powered studies on this topic.
31 Biatain-Ibu versus Biatain dressings – Venous leg ulcers Quality Indicator
 Type: RCT
Gottrup F, Jorgensen B, Karlsmark T, Sibbald RG, Rimdeika R, Harding K, Price P, Venning v, Vowden P, Junger M, Wortmann S, Sulcaite R, Vilkevicius G, Ahokas T-L, Ettler K, Arenbergerova M. Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers. International Wound Journal 2007; 4 (Suppl. 1):24-34.
This is a very well-designed multinational, multicenter, parallel group, double-blind RCT to compare a non adhesive foam dressing with ibuprofen with a non adhesive foam without ibuprofen in 122 patients with painful chronic venous leg ulcer of more than 8-week duration. 74% of 62 patients treated with the Biatain-Ibu non adhesiveexperineced persistent (chronic) pain relief on days 1-5 versus 58% of 60 patients treated with the comparator foam dressing, Biatain non-adhesive (P=0.0003). Persistent pain intensity was reduced in 40% versus 30% of subjects respectively (P=0.0003). Non-significant differences in the adverse events were detected. The study is well described and effectively demonstrates that ibuprofen-foam dressing is beneficial for persistent pain relief and reducing persistent and temporary wound pain intensity. The potential for adverse events related to dressings should be observed.
32 Ibuprofen-foam versus local best practice – Venous leg ulcers Quality Indicator
 Type: RCT
Sibbald RG, Coutts P Fierheller M, Woo K. A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (Ibuprofen-foam versus local best practice). International Wound Journal, 2007, 4, SUPPL.1, 16-23.
This is a well-conducted pilot RCT to compare a foam dressing with continuous low-level release of Ibuprofen (Biatain-ibu) with local best care involving a variety of dressings. Persons with chronic painful exudating leg ulcers were randomly allocated to receive continuous low-level release of Ibuprofen (Biatain-ibu) (n=12) or local best care (n=12) for one week. Pain intensity (pooled morning and evening scores) was less in the Ibuprofen group (P=0.0217) and ulcer area was significantly reduced (P=0.05). This is a good short-term pilot study that provides numbers to inform a RCT and suggests that Biatain-Ibu may control pain in patients with venous leg ulcers.
34 Dressings - Venous Leg Ulcers Quality Indicator
 Type: RCT
Jørgensen B, Price P, Andersen KE, Gottrup F, Bech-Thomsen N, Scanlon E, Kirsner R, Rheinen H, Roed-Petersen J, Romanelli M, Jemec G, Leaper DJ, Neumann MH, Veraart J, Coerper S, Agerslev RH, Bendz SH, Larsen JR, Sibbald RG. The silver-releasing foam dressing, Contreet Foam, promotes faster healing of critically colonised venous leg ulcers: a randomised, controlled trial. Int Wound J. 2005 Mar; 2(1):64-73.
The RCT provides evidence of the superior performance of the silver-releasing dressing, Contreet Foam, compared with a traditional moist foam wound healing dressing. After 4 weeks of treatment, the median relative reduction in ulcer area are significantly higher in the Contreet Foam group than in the Allevyn Hydrocellular group (P=0.034). The overall estimated wear time for the silver-containing dressing (mean of 5.1 days) was significantly higher than for the foam dressing without added silver (mean of 3.9 days) (P=0.023). These results suggest an important role of sustained silver-releasing dressings in the treatment of critically colonised chronic wounds.
35 Outcomes After Surgical Management of Venous Disease - Subfascial Endoscopic Perforator Surgery Quality Indicator
 Type: Systematic review
TenBrook JA, Iafrati MD, O'Donnell TF, Wolf MP, Hoffman SN, Pauker SG, Lau J, Wong JB. Systematic review of outcomes after surgical management of venous disease incorporating subfascial endoscopic perforator surgery, 2004, Journal of Vascular Surgery, 39:583-9.
The purpose of the systematic review is to quantify the overall rates of surgical outcomes for patients with severe chronic venous insufficiency treated with surgical management that incorporated subfascial endoscopic perforator surgery (SEPS). Surgical management of venous ulcer including SEPS, with or without saphenous ablation, leads to an 88% chance of ulcer healing and a 13% chance of ulcer recurrence over the short term. RCTs are needed to clarify the contributions of compression therapy, superficial venous surgery, and SEPS in the treatment of venous ulcer disease.
36 Comparison of Two Periwound Skin Protectants - Venous Leg Ulcers Quality Indicator
 Type: RCT
Cameron J, Hofman D, Wilson J, Cherry G. Comparison of two periwound skin protectants in venous leg ulcers: a randomised controlled trial. J Wound Care 2005; 14(5): 233-6.
This study was conducted to compare the efficacy and cost-effectiveness of two skin protectants. No Sting Barrier Film (NSBF) is preferred over zinc paste for effective barrier preparations because it is easy to apply and transparent. The benefits of NSBF include reduced treatment time (p<0.0001) and patient comfort (p=0.005). The mean total costs over the study duration were significantly higher (p<0.0001) for the zinc oxide group (£31.6) than the NSBF group (£20.6). These are important factors to be considered when managing the peri-ulcer skin.
37 Antibiotics and Antiseptics - Venous Leg Ulcers Quality Indicator
 Type: Systematic review
O’Meara S, Al-Kurdi D, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD003557. DOI: 10.1002/14651858.CD003557.
The objective of the review is to determine the effects of systemic antibiotics, topical antibiotics and antiseptics on the healing of venous ulcers. In terms of topical preparations, there is some evidence to support the use of cadexomer iodine. Due to the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should only be used in cases of defined infection and not for bacterial colonisation. Further research is required to support the routine use of systemic antibiotics to promote healing in venous leg ulcers.
38 Protein Extracts Quality Indicator
 Type: RCT
Varelias A, Cowin AJ, Harries RHC, Cooter RD, Belford DA, Fitridge RA, Rayner TE. Mitogenic bovine whey extract modulates matrix matalloproteinase-2, - 9 and tissue inhibitor of matrix metalloproteinase-2 levels in chronic leg ulcers. Wound Repair and Regeneration. 2006; 14: 28-37.
In this study, a mitogenic bovine whey extract (MBWE) enriched with growth factors was investigated to determine if it modulated the expression and activity of MMP-2 and -9 and the tissue inhibitor of MMP-2 in chronic leg ulcers. MBWE significantly decreased active MMP-2 levels over all time points compared with placebo (p=0.007) at the 2.5 and 10mg/mL doses but not at the 20 mg/mL dose. Fibroblasts expressing MMP-2 were reduced at biopsy in days 15 and 29 (p<0.05). There is a deficiency of literature in this field, and targeting of problem proteins may enhance our understanding of healing greatly.
39 Debridement Quality Indicator
 Type: RCT
König M, Vanscheidt W, Augustin M, Kapp H. Enzymatic versus autolytic debridement of chronic leg ulcers: a prospective randomised trial. J Wound Care 2005;14(7):320-3
The efficacy of two debriding approaches for chronic leg ulcers were compared in this study. The two approaches were TenderWet 24, an autolytic degradation treatment (n=15), and Iruxol N (Santyl), an enzymatic approach (n=27). The authors were unable to recruit 29 subjects per group, the sample size required to detect 30% superiority. Therefore, the difference between the two products was not statistically significant. This article illustrates some of the difficulties researchers face in trying to compare the effectiveness of wound care products.
40 Causes for onset of chronic wounds Quality Indicator
 Type: Narrative Review
Chen WY, Rogers AA. Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds. Wound Repair Regen. 2007 Jul-Aug;15(4):434-49.
This publication provides an exemplary summary of the cause-effect relationship between venous insufficiency and chronic wounds. It then proceeds to examine the correlation between this relationship and other types of chronic wounds. It is an effective publication in examining the causes of onset of chronic wounds.
41 Surgery in the treatment of venous leg ulceration Quality Indicator
 Type: RCT
Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, Taylor M, Usher J, Wakely C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004; 363(9424):1854-9.
The purpose of this study was to compare surgical and non-surgical treatment strategies, based on the ability to promote ulcer healing and prevent recurrence. Based on the results, healing rates were not affected by the implementation of surgical treatment. Recurrence rates, however, decrease significantly if surgical treatment is employed (p<0.0001). This suggests that venous ulcer treatment should generally include venous surgery.
42 Surgery in the treatment of venous leg ulceration Quality Indicator
 Type: RCT
Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ. 2007; 335(7610):83.
The purpose of this study was to compare surgical and non-surgical treatment strategies, based on their ability to prevent recurrence of leg ulcers. Through a comparison of compression alone versus compression and saphenous surgery, it was demonstrated that the surgical approach decreases recurrence of leg ulcers and increases ulcer-free time. Therefore, the study suggests that venous surgery can be implemented in most treatment approaches for venous ulcers.
43 Electrical Stimulation Quality Indicator
 Type: RCT
Houghton PE, Kincaid CB, Lovell M, Campbell KE, Keast DH, Woodbury MG, Harris KA. Effect of electrical stimulation on chronic leg ulcer size and appearance. Physical Therapy 2003;83(1):17-28.
High-Voltage Pulsed Current (HVPC) applied to chronic leg ulcers reduced the wound surface area over the 4-week treatment period to approximately one half the initial wound size, which was over 2 times greater than that observed in wounds treated with sham units. The rate of wound closure was appropriately twice that observed in wounds treated identically with sham HVPC.
44 Therapeutic Ultrasound Quality Indicator
 Type: Systematic review
Al-Kurdi D, Bell-Syer SEM, Flemming K. Therapeutic ultrasound for venous leg ulcers. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001180. DOI: 10.1002/14651858.CD001180.pub2.
Ultrasound may increase healing of venous leg ulcers, however due to the poor quality of the studies included in the review these results need to be interpreted with caution.


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