Efficacy of Ramelteon, Suvorexant, and Lemborexant for Delirium Prevention in Hospitalized Patients: A Systematic Review and Meta-Analysis

OBJECTIVES: Delirium is a prevalent complication among hospitalized patients, particularly in older adults and ICU populations, and it is associated with poor prognosis. Pharmacologic interventions targeting sleep-wake regulation and neurobiologic pathways, such as orexin receptor antagonists and melatonin receptor agonists, offer promising strategies for delirium prevention. Our objective was to evaluate the preventive efficacy of suvorexant, lemborexant, and ramelteon in reducing delirium prevalence and associated clinical outcomes. DATA SOURCES: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, clinical trial registries, and gray literature databases through November 2024. STUDY SELECTION: Randomized controlled trials or observational studies involving hospitalized adults assessing the use of suvorexant, lemborexant, or ramelteon for delirium prevention were included. DATA EXTRACTION: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines, two reviewers extracted data independently. Quality was assessed using the Grading of Recommendations Assessment, Development, and Evaluation; Risk of Bias in Randomized Studies; and Risk of Bias in Nonrandomized Studies-of Interventions tools. Random-effects meta-analysis pooled risk ratios (RRs) and median differences with 95% CIs. DATA SYNTHESIS: Twenty-four studies involving 4489 patients were analyzed, of whom 1752 (39%) received one of the evaluated pharmacotherapies. Pooled analyses showed a significant reduction in delirium prevalence in both randomized trials (RR, 0.60; 95% CI, 0.38-0.97; low certainty) and observational studies (RR, 0.54; 95% CI, 0.43-0.68; low certainty). Exploratory analyses by individual agent did not identify credible subgroup effects (interaction p > 0.1), and medication-specific findings should be interpreted with caution. No significant effects were observed for ventilator days, mortality, or length of hospital or ICU stay (very low certainty). CONCLUSIONS: Sleep-wake regulating pharmacologic agents were associated with 40%-46% relative risk reductions in delirium prevalence, based on low-certainty evidence. Although these findings are promising, the absence of credible subgroup effects limits conclusions about the comparative efficacy of individual agents. Further, high-quality, prospective trials are needed to confirm these results and to clarify the role of specific pharmacologic strategies in delirium prevention.