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Randomized Controlled Trial
. 2022 May;26(23):1-172.
doi: 10.3310/QOIZ6538.

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

Chris Harding  1   2 , Thomas Chadwick  3 , Tara Homer  3 , Jan Lecouturier  3 , Helen Mossop  3 , Sonya Carnell  4 , Will King  3 , Alaa Abouhajar  4 , Luke Vale  3 , Gillian Watson  4 , Rebecca Forbes  4 , Stephanie Currer  4 , Robert Pickard  5 , Ian Eardley  6 , Ian Pearce  7 , Nikesh Thiruchelvam  8 , Karen Guerrero  9 , Katherine Walton  10 , Zahid Hussain  11 , Henry Lazarowicz  12 , Ased Ali  13
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Free article
Randomized Controlled Trial

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

Chris Harding et al. Health Technol Assess. 2022 May.
Free article

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.

Keywords: ANTI-BACTERIAL AGENTS; ANTIBIOTIC PROPHYLAXIS; COST-EFFECTIVENESS ANALYSIS; ESCHERICHIA COLI; METHENAMINE HIPPURATE; RANDOMISED CONTROLLED TRIAL; RECURRENT URINARY TRACT INFECTION.

Plain language summary

Women with recurrent urine infections often require preventative treatment to reduce the frequency of infection episodes. Daily low-dose antibiotic medication is a guideline-recommended treatment option for these women. There is increasing concern globally regarding antibiotic-resistant infections, which has led researchers to look at alternative treatments. This trial was conducted to find out whether or not taking an alternative treatment that is not an antibiotic [i.e. methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA)] was as effective as the standard daily low-dose antibiotics. A total of 240 women from across the UK took part in the trial. They were divided equally into two groups; half of the women were given methenamine hippurate and the other half were given standard low-dose antibiotics. Both treatments were prescribed to be taken every day for 1 year. To make a fair comparison, people were put into the two groups at random using a computer program. Aspects of the trial that could be improved were identified through telephone interviews with patients and recruiting staff. Feedback from these telephone interviews helped to ensure the successful conduct of the trial. Patients were followed up for 18 months, comprising the 12 months when they were taking treatment and a 6-month follow-up phase after they had finished treatment. We found that the non-antibiotic option of methenamine hippurate was no worse than the current standard treatment of daily antibiotics in preventing urinary tract infection episodes in adult women. For both treatments, patients expressed high levels of satisfaction. One advantage of the methenamine hippurate treatment was that infecting bacteria were slightly less likely to develop resistance to antibiotics. We also evaluated health-care costs of both treatments and found that methenamine hippurate seemed worthwhile to the NHS in the short term, but there was uncertainty over longer-term costs and benefits. These results will help patients with repeated urinary tract infections to decide on treatment options, particularly if they want to avoid prolonged courses of preventative antibiotics.

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