Abstract: 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, RGD peptide dressing, topical antibiotics). Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, RGD peptide matrix significantly reduced ulcer size compared with a control group, mean reduction 6.60cm2 (95% CI 5.51 to 7.69; very low quality of evidence). Three trials reported on the incidence of complete closure (isoxsuprine, arginine butyrate, RGD peptide matrix; ranging between low and very low quality of evidence). None reported a significant effect. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; or incidence of amputation. There was no reported information on the safety of these interventions. There is evidence that a topical intervention (RGD peptide matrix) reduced ulcer size in treated participants compared to controls. This evidence of efficacy is limited by the generally high risk of bias associated with these reports. We planned to analyse results according to general groups: pharmaceutical interventions (systemic and topical); and non-pharmaceutical interventions (surgical and non-surgical). However, we were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the unit of randomisation and the unit of analysis. This heterogeneity, along with a paucity of identified trials, prevented us performing any meta-analyses. This Cochrane review provides some evidence for the effectiveness of one topical intervention - RGD peptide matrix. 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 a high risk of bias. We recommend that readers interpret the trial results with caution. The safety profile of the all interventions was inconclusive.

Plain-language summary: In this Cochrane review we found 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. One medication, a topical intervention (RGD peptide matrix) reduced ulcer size in treated participants compared to controls. However, this effect should be interpreted with caution given the high risk of bias due to the inadequacies associated with this trial report. The evidence for the use of interventions to treat people with sickle cell disease and chronic leg ulceration is not strong. All randomised clinical trials that we included in this review were associated with a high risk of bias. 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.