Treatments for leg ulcers in people with sickle cell disease

Review question

We reviewed the evidence for the effectiveness and harms of interventions for treating leg ulcers in people with sickle cell disease. This is an update of a previously published Cochrane Review.

Background

Leg ulcers are a chronic complication for people living with sickle cell disease. Ulcers tend to be difficult to treat successfully, healing slowly over months or years. They can severely disrupt quality of life, increase disability, require extended absence from the workplace, and place a high burden of care on healthcare systems. We looked at whether treatments for leg ulcers in people with sickle cell disease were effective and safe.

Search date

The evidence is current to: 13 January 2020.

Study characteristics

In this updated Cochrane Review we have included six randomised controlled trials including 198 participants with 250 ulcers. Four of the randomised controlled trials were conducted in Jamaica and two in the USA. These trials included medications or dressings applied directly to the ulcer (topical medications) and medications given orally or intravenously (systemic medications). Given the very different modes of action of these two groups, we treated them separately throughout the review. The topical agents included Solcoseryl® cream, RGD peptide matrix dressing and topical antibiotics. Socoseryl aims to improve the use of oxygen by the skin tissue and so promote wound healing. Topical antibiotics are also used to prevent infection. The RGD peptide matrix is a gel that promotes cell growth. The systemic interventions included arginine butyrate, L-cartinine, and isoxsuprine. Aginine butyrate, given intravenously, is thought to accelerate wound healing, L-carnitine, given orally, is thought to improve tissue hypoxia, and isoxsuprine, given orally as isoxsuprine hydrochloride, is thought to widen blood vessels, so increasing blood flow to an affected wound.

Key results

Given the very low quality of the evidence we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure. None of the included trials reported on our other outcomes of interest: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; incidence of amputation; or harms.

Quality of the evidence

There is very limited evidence available on the use of interventions to treat people with sickle cell disease and chronic leg ulceration. All randomised clinical trials that we included in this review were associated with an unclear or high risk of bias, providing very low-quality evidence. This systematic review has shown the need for well-designed, high-quality randomised trials to assess the benefits and harms of interventions to improve the healing of leg ulcers in people with sickle cell disease.

Authors' conclusions: 

Given the very low quality of the evidence identified in this updated Cochrane Review we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure in treated participants compared to controls. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having an unclear or high risk of bias. The harm profile of the all interventions remains inconclusive.

Read the full abstract...
Background: 

The frequency of skin ulceration makes an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease. This is an update of a previously published Cochrane Review.

Objectives: 

To assess the clinical effectiveness and harms of interventions for treating leg ulcers in people with sickle cell disease.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.

We searched LILACS (1982 to January 2020), ISI Web of Knowledge (1985 to January 2020), and the Clinical Trials Search Portal of the World Health Organization (January 2020). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area.

Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 13 January 2020; date of the last search of the Cochrane Wounds Group Trials Register: 17 February 2017.

Selection criteria: 

Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment.

Data collection and analysis: 

Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data. We used GRADE to assess the quality of the evidence.

Main results: 

Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, arginine-glycine-aspartic acid (RGD) peptide dressing and topical antibiotics). No trials on non-pharmaceutical interventions were included in the review. All trials had an overall unclear or high risk of bias, and drug companies sponsored four of them. We were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the units of randomisation and analysis.

Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, only arginine butyrate showed a reduction of ulcer size compared with a control group, mean reduction -5.10 cm² (95% CI -9.65 to -0.55), but we are uncertain whether this reduces ulcer size compared to standard care alone as the certainty of the evidence has been assessed as very low. Three trials reported on complete leg ulcer closure (isoxsuprine, arginine butyrate, RGD peptide matrix; very low quality of evidence). None reported a clinical benefit. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; incidence of amputation or harms.

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