Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT

Abstract

Background Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking. Objective To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women. Design Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months’ treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year. Setting Eight UK NHS secondary care sites. Participants A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial. Interventions A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted. Main outcome measures The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient’s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction. Results Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months’ data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in Escherichia coli cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew E. coli resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in E. coli isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms. Limitations This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation. Conclusions This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics. Recommendations for research Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics. Trial registration This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.

Methenamine for urinary tract infection prophylaxis: A systematic review

“…34,35 Despite the differences in the number of UTI episodes between the two groups, the absolute difference was within the predefined, non-inferiority limit and thus methenamine was concluded to be non-inferior to antibiotics for UTI prevention. 34,35 Methenamine use as an alternative to antibiotic therapy reduces the risk of antibiotic resistance as well as potential complications associated with antibiotic usage. 35 The ALTAR study demonstrated low adverse event rates in both the methenamine and antibiotic groups.…”

“…These limitations prevented meaningful subgroup analysis to identify variations in the efficacy of individual agents or specific patient subgroups that might marginally benefit from either methenamine or low-dose antibiotics. 34,35 Antibiotic resistance profiles of E. coli isolates were evaluated in the ALTAR study. Isolates were obtained from urine and perineal swabs, and antimicrobial sensitivities were tested in triplicate against a panel of antibiotics.…”

“…At 6-or 12-month follow-up, the number of participants with perineal E. coli isolates demonstrating resistance to at least one antibiotic was found to be higher in the antibiotic group (46/64, 72%) compared to the methenamine group (39/70, 56%; p = 0.05). 34,35 The observed disparities in antibiotic resistance rates suggest that the utilization of continuous low-dose antibiotic prophylaxis plays a significant role in fostering the emergence of antibiotic resistance. 34,35 The ImpresU consortium is conducting a triple-blinded randomized control trial to evaluate whether the use of methenamine can effectively reduce rUTI.…”

“…34,35 The observed disparities in antibiotic resistance rates suggest that the utilization of continuous low-dose antibiotic prophylaxis plays a significant role in fostering the emergence of antibiotic resistance. 34,35 The ImpresU consortium is conducting a triple-blinded randomized control trial to evaluate whether the use of methenamine can effectively reduce rUTI. 36 or a placebo group (one placebo tablet twice a day) for 6 months with a 6-month follow-up period.…”

Evidence-based review of nonantibiotic urinary tract infection prevention strategies for women: a patient-centered approach

“…Newer evidence is emerging that methenamine has a role in rUTI prevention, including in older patients and those who require long-term catheterization, provided they have normal renal function [30]. A recent RCT demonstrated noninferiority of methenamine hippurate to the current standard of low-dose daily prophylaxis with antibiotics over a 12-month period with an equal number of adverse reactions [31], and a complementary study showed that women in the prophylactic antibiotics arm had higher rates of antibiotic resistance than those taking methenamine [32].…”