Compression therapies for venous leg ulcers: The VENous Ulcer Study 6 (VenUS 6), an open, multicentre, randomised clinical trial

BACKGROUND: Strong compression is a recommended first line venous leg ulcer treatment. With limited research comparing the clinical effectiveness of compression wraps (CW) and two-layer compression bandage treatments with evidence-based compression (EBC) (four-layer compression bandages and two-layer compression hosiery), this study aimed to evaluate their clinical effectiveness on time to venous leg ulcer healing. METHODS AND FINDINGS: A pragmatic, three-arm, randomised controlled trial in 33 United Kingdom primary, community and hospital sites between 03.02.2021 and 31.08.2024. Adults with a venous leg ulcer appropriate for compression therapy were randomised 1:1:1 to be offered CW, two-layer bandage, or EBC (two-layer hosiery or four-layer bandage). Participants and clinical staff were not blinded. The primary outcome was time to blind assessed ulcer healing (date of ulcer healing: date of earliest photograph showing healing). Analyses included a noninferiority comparison of two-layer bandage and EBC (handling key intercurrent events under hypothetical and treatment policy strategies), and superiority comparisons of CW with both EBC and two-layer bandage (handling key intercurrent events under a treatment policy strategy). Healing times were analysed using Cox proportional hazards regression adjusted for fixed effects (treatment allocation, baseline ulcer area and duration, participant age, and mobility status), and shared frailties (recruitment site). The trial was pre-registered: ISRCTN67321719. 637 participants were randomised to be offered CW (n = 213), two-layer bandage (n = 211) or EBC (n = 213). Mean age was 70.3 (range 24.6 to 97.0) years, 55% (n = 351) were male, and the majority (n = 606, 95%) were white. 633 participants contributed time at risk of healing and were included in the analysis. Using a treatment policy strategy to handle key intercurrent events (modified intention-to-treat analysis), the estimated hazard ratio (HR) for the noninferiority comparison (EBC and two-layer bandage) was 1.01 (95% CI [0.79, 1.28]), meeting the pre-specified noninferiority margin of 1.33. The corresponding hypothetical strategy analysis gave a HR of 1.16 (95% CI [0.86, 1.58]), which did not demonstrate noninferiority. For the superiority comparisons, healing was slower in the CW group than in the EBC group (HR 0.78, 95% CI [0.61, 1.00]; p = 0.046). Results were similar for the two-layer bandage group (HR 0.79, 95% CI [0.61, 1.01]; p = 0.056), although this did not reach statistical significance. Both comparisons showed considerable statistical uncertainty, with confidence intervals ranging from a 39% reduction in the hazard of healing to little or no difference between groups. Nine serious adverse events occurred; one potentially related to treatment (cause of death could not be ascertained). Departures from allocated compression treatment were common, which limits generalisability to settings with different adherence patterns. These departures, lower than expected ulcer healing incidence rates and slight under-recruitment, resulted in the number of healing events being smaller than the number required for 80% power. CONCLUSION: CW is unlikely to reduce the time to venous leg ulcer healing compared to two-layer bandage or EBC, although confidence intervals included treatment effects indicating little or no difference between groups. Despite remaining uncertainty, these findings may not support CW as a first line strong compression treatment for venous leg ulcers. TRIAL REGISTRATION: ISRCTN - reference 67321719.