The Efficacy and Safety of Intravenous Difelikefalin for the Treatment of Pruritus in Patients Undergoing Hemodialysis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) is one of the most prevalent and distressing symptoms experienced by patients with end-stage renal disease (ESRD), significantly impacting their quality of life and the sustainability of hemodialysis (HD) treatment. This systematic review aimed to evaluate the efficacy and safety of difelikefalin (DFK) in treating patients with chronic kidney disease (CKD). METHODS: Electronic databases, including PubMed, Embase, The Cochrane Library, Web of Science, and Scopus, were systematically searched for randomized controlled trials (RCTs) that reported on the efficacy and safety of DFK in patients with ESRD undergoing HD. The search was conducted up to November 19, 2024. The risk of bias in the included studies was assessed using the Cochrane risk of bias tool. Data analysis was performed using Stata version 15.1. Results were reported as RR and MD with 95% confidence interval (CI). RESULTS: This meta-analysis included five randomized controlled trials with a total of 937 participants, all of whom were undergoing MHD. The results indicated that, in comparison to the control group, DFK significantly reduced the weekly average WI-NRS score (MD: -0.41 [-0.51, -0.31], p = 0.671). Specifically, DFK demonstrated a significant reduction in the weekly mean WI-NRS scores compared with placebo at week 4 (MD: -0.48 [-0.61, -0.35], p = 0.965) and at week 8 (MD: -0.32 [-0.46, -0.17], p = 0.473). Additionally, DFK significantly reduced the total score on the 5-D itch scale (MD: -0.42 [-0.53, -0.31], p = 0.262), the total score on Skindex-10 (MD: -0.42 [-0.58, -0.26], p = 0.221), and the total score on Skindex-16 (MD: -0.16 [-0.23, -0.00], p = 0.287). Furthermore, DFK significantly increased the proportion of participants achieving a weekly average WI-NRS score improvement of ≥3 points (RR: 1.29 [1.04, 1.50], p = 0.034) and ≥4 points (RR: 1.45 [1.10, 1.92], p = 0.047), as well as PGIG (RR: 1.44 [1.15, 1.80], p = 0.007). Additionally, it significantly improved adverse events (RR: 1.26 [1.08, 1.45], p < 0.001). However, no significant differences were observed between the two groups regarding serious adverse events (RR: 1.33, 95% CI [0.94, 1.88], p = 0.134), discontinuation (RR: 1.50, 95% CI [0.90, 2.28], p = 0.108), and mortality (RR: 0.92, 95% CI [0.35, 2.46], p = 0.949). CONCLUSION: DFK is an effective medication for the treatment of moderate-to-severe pruritus associated with CKD, in patients with ESRD undergoing HD. However, the use of DFK may also lead to an increase in adverse reactions. This systematic review still acknowledges its limitations and recognizes the need for more comprehensive evidence. Therefore, it is imperative to conduct multicenter, large-scale randomized controlled trials to further validate the efficacy and safety of DFK in alleviating pruritus among HD patients.