An Evidence-Based Algorithm for Treating Venous Leg Ulcers Utilizing the Cochrane Database of Systematic Reviews

Howard M. Kimmel, DPM, MBA, FACFAS; Angela L. Robin, DPM

Disclosures

Wounds. 2013;25(9):242-250. 

In This Article

Treatment Response

The "4-week" Model

The initial healing rate of VLUs and the percentage change in the ulcer area after treatment initiation have been shown to predict ulcer healing.[48] The use of a valid surrogate marker for complete VLU healing may allow for the identification of patients who are not likely to heal by standard methods early in the course of treatment, thereby allowing for expedited referral to specialty centers or the earlier initiation of advanced wound healing therapies.

The VLU treatment algorithm recommends > 40% wound closure after 4 weeks of conventional therapy as a surrogate marker for the identification of patients who are likely to achieve complete wound closure with continued conservative treatment. Patients with < 40% closure at 4 weeks are unlikely to achieve complete wound healing and may benefit from alternative or advanced interventions.[49]

The algorithm recommendation is based on an analysis of wound characteristics and healing rates in 29,189 patients with 56,488 VLUs.[49] The median wound size was 189 mm2 and the median wound duration was 3 months. By the 12th week of care, 45.2% of patients had healed. Those that healed had smaller wounds at baseline and wounds of shorter duration as compared with those that did not heal (all P values < 0.001). The continuous surrogates percent change in wound area, log healing rate, and log area ratio at weeks 2, 4, and 6 were shown to discriminate between a wound that healed by 12 weeks of care and one that did not. The 4-week surrogate maximized accuracy and minimized the time to surrogate endpoint. Dichotomization of the surrogate markers at week 4 demonstrated that a wound's healing status at 24 weeks can be correctly classified at a rate of 66%-69% depending on the marker utilized. These surrogates were further validated by demonstrating that established risk factors for not healing, such as wound size and wound duration, are also important risk factors for not achieving the surrogate endpoint.

Skin Autografts, Allografts, and Xenografts

A Cochrane Review was conducted to assess the effect of various skin grafts for treating VLUs.[50] The types of skin grafts examined in this review included autografts (from the patient's own skin), fresh or frozen allografts (from other human sources), and xenografts (from pigs).

The review found that the randomized controlled trials were of generally poor methodological quality, characterized by flaws including lack of reported inclusion criteria, unclear descriptions of randomization methods, lack of baseline comparability, and lack of blinded outcome assessments. The authors concluded there was not enough evidence to recommend any of these types of grafts for the treatment of VLUs. It was recommended that further research be conducted to improve methods for identifying patients amenable to treatment with skin grafts and to assess whether skin grafts increase healing for VLU patients.

Bilayered and Single-layered Bioengineered Cellular Technologies

The Cochran Review of skin grafting for VLUs also examined the available evidence for bioengineered cellular technologies.[50] These advanced technologies feature living human cells and differ from traditional skin grafts in that they do not engraft or persist long-term, but instead delivery a cascade of growth factors and cytokines that stimulate healing in the recipient.

The single layer technology (Dermagraft, Shire Regenerative Medicine, Inc, San Diego, CA) contains only the dermal component and is comprised of human fibroblasts seeded onto a vicryl mesh.

The Cochrane Review analyzed data from 2 single-layer technology VLU trials which employed different dosage regimes (1 piece, 4 pieces, and 12 pieces) and found there was no evidence of benefit associated with any of these dosage protocols.

The bilayered living cellular construct (Apligraf, Organogenesis, Inc, Canton, MA) contains 2 layers of living human cells—an epidermal layer of differentiated keratinocytes and a dermal layer of fibroblasts in a collagen matrix. The safety and efficacy of this bilayered living cellular product in treating VLUs was evaluated in a large prospective randomized controlled trial where patients were eligible to receive up to 5 applications.[51] The results showed a significantly higher proportion of ulcers healed in the Apligraf treatment group, and also reported a shorter time to complete healing. Based on these findings, the authors of the Cochrane Review concluded that applying a bilayered living cellular construct with compression increases the chance of healing a venous ulcer compared to compression alone. Based on these Cochrane conclusions, the algorithm recommends applying bilayered living cellular constructs to VLUs that failed to reduce in size > 40% following 4 weeks of conventional care.

Surgical Therapy

Direct surgical intervention may be helpful in patients with VLUs not responding to conservative management, but is generally performed to decrease the likelihood of VLU recurrence. In patients with first-time VLUs, healing rates with surgery are comparable to those achieved with conservative treatment. The benefits of surgical treatment may outweigh those of conservative treatment in patients with recurrent VLUs. Other factors favoring surgical intervention include medial ulceration, older age, and larger VLU size. Direct surgical intervention on the deep venous system is generally reserved for patients who do not respond to treatment of the superficial system or are not candidates for superficial venous intervention.

Surgical correction of superficial venous reflux does not increase healing rates in patients with VLUs receiving compression therapy. In 500 patients with open or recently healed VLUs and superficial venous reflux, healing rates at 3 years were 89% for the compression group and 93% for the compression plus surgery group (P = 0.73).[52] Rates of ulcer recurrence at 4 years were 56% for the compression group and 31% for the compression plus surgery group (P < 0.01). Patients receiving compression plus surgery experienced significantly longer absolute (100 weeks vs 85 weeks, P = 0.013) and proportional (78% vs 71%,P = 0.007) ulcer-free time up to 3 years compared to those receiving compression alone. These findings support the role of surgery and compression therapy in patients with chronic wounds. Surgical correction of superficial venous reflux in addition to compression bandaging reduces the recurrence of VLUs at 4 years and results in a greater proportion of ulcer-free time.

Maintenance Therapy

Appropriate maintenance therapy following healing of VLUs may help prevent the occurrence of new VLUs and reduce the incidence of ulcer recurrence. Well-designed randomized controlled trials of maintenance strategies following VLU healing are rare. Maintenance treatment with compressive stockings and appropriate skin care should be considered in all patients with healed VLUs. The identification of patients who are likely to benefit from posthealing VLU surgery is difficult. It is unclear which type of compression stocking may be most suitable for maintenance therapy, and the choice may be based on cost issues and patient and provider preferences. Further studies, including economic evaluations, are needed to help determine the optimal maintenance strategies in patients with VLUs.

Functional Restoration

Patients with VLUs experience significant functional impairment including loss of mobility, decreased work capacity, limitations in leisure activities, and challenges with activities of daily living. In addition to ulcer healing and prevention of recurrence, functional restoration, defined as a return to pre-VLU levels of activity, may be an appropriate endpoint in VLU clinical trials and a useful marker of VLU treatment success. From the patient's perspective, pain relief and restoration of functional capacity may be the most important outcomes of VLU treatment. Providers should monitor changes in functional capacity during VLU treatment and consider lack of functional restoration as a possible marker of inadequate treatment.

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