Effectiveness of methenamine hippurate in preventing urinary tract infections: an updated systematic review, meta-analysis and trial sequential analysis of randomized controlled trials

Urinary Tract Infections (UTIs) are a significant health problem worldwide, especially among women. methenamine hippurate has been proposed as a preventive measure against recurrent UTIs. This updated systematic review and meta-analysis aimed to evaluate the effectiveness of methenamine hippurate in preventing UTIs, incorporating the latest research findings and employing trial sequential analysis to assess the robustness of the evidence. A systematic review was conducted across MEDLINE, Embase, Scopus, Cochrane, and Google Scholar up to March 2024 for randomized controlled trials comparing methenamine hippurate with placebo or antibiotic in adult women with a history of recurrent, confirmed UTIs. Key outcomes included symptomatic UTIs as primary outcome and positive urine culture, asymptomatic bacteriuria and adverse effects as secondary outcomes. It is important to state that asymptomatic UTIs with negative urine cultures were not adequately accounted for in the studies; therefore, this outcome was excluded from our meta-analysis. Additionally, adverse effects related to antibiotic resistance were not described in the studies, so only the adverse effects of the medications themselves were considered. The risk of bias was evaluated using the Cochrane Risk of Bias 2, and statistical analysis was conducted using RStudio software. We retrieved 5 articles, encompassing 216 patients in the methenamine group and 205 patients in the control group (Antibiotic). Our analysis revealed non-inferiority in the rate of symptomatic UTI episodes between the two groups (RR 1.15; 95%CI 0.96,1.38; p = 0.41; I2 = 0%). Similarly, there were no notable distinctions in the rate of positive urine cultures (RR 1.20; 95CI 0.91, 1.57; p = 0.25; I2 = 28%), and the rate of adverse effects (RR 0.98; 95CI 0.86, 1.12; p = 0.35; I2 = 9%). However, we observed a decreased frequency of asymptomatic bacteriuria in the control group (RR 1.91; 95CI 1.29, 2.81; p = 0.0001; I2 = 0%). In trial sequential analysis, existing studies were not able to achieve the futility boundaries. Overall, our meta-analysis provides evidence supporting methenamine hippurate as an effective, non-inferior and safe prophylactic option for preventing recurrent UTIs in adult women, as demonstrated by the current evidence base. Nevertheless, more RCTs are necessary to achieve the futility boundaries in trial sequential analysis.