Editorial by Giacomo Novara and Jean-Nicolas Cornu on pp. 306–308 of this issue
Efficacy and Tolerability of Mirabegron, a β3-Adrenoceptor Agonist, in Patients with Overactive Bladder: Results from a Randomised European–Australian Phase 3 Trial☆
To assess the efficacy and tolerability of mirabegron versus placebo.
Design, setting, and participants
Multicenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥18 yr of age with symptoms of OAB for ≥3 mo.
Intervention
After a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50 mg, mirabegron 100 mg, or tolterodine extended release 4 mg orally once daily for 12 wk.
Outcome measurements and statistical analysis
Patients completed a micturition diary and quality-of-life (QoL) assessments. Co–primary efficacy end points were change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24 h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo. Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and postvoid residual volume.
Results and limitations
A total of 1978 patients were randomised and received the study drug. Mirabegron 50-mg and 100-mg groups demonstrated statistically significant improvements (adjusted mean change from baseline [95% confidence intervals]) at the final visit in the number of incontinence episodes per 24 h (−1.57 [−1.79 to −1.35] and −1.46 [–1.68 to −1.23], respectively, vs placebo −1.17 [−1.39 to –0.95]) and number of micturitions per 24 h (−1.93 [−2.15 to −1.72] and −1.77 [−1.99 to −1.56], respectively, vs placebo −1.34 [−1.55 to −1.12]; p < 0.05 for all comparisons). Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes. The incidence of treatment-emergent AEs was similar across treatment groups. The main limitation of this study was the short (12-wk) duration of treatment.
Conclusions
Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability.
Trial identification
This study is registered at ClinicalTrials.gov, identifier NCT00689104.
Introduction
Overactive bladder syndrome (OAB) affects >400 million people worldwide [1]. The prevalence of OAB increases with age, affecting 30–40% of the population >75 yr of age [2], [3].
Treatment options for OAB include antimuscarinics as first-line pharmacotherapy [4], [5]; however, OAB patients may have a suboptimal response or find that antimuscarinic therapy is limited by associated adverse events (AEs), with dry mouth the most common and bothersome AE [6], [7]. For these patients there has not been another class of oral therapeutic agents available; therefore, there is a need for a new treatment option for OAB that is effective and well tolerated, with a distinct mechanism of action.
An important role has been proposed for the β3-adrenergic receptor (β3-AR) in promoting urine storage in the bladder by inducing detrusor relaxation [8], [9]. Mirabegron is a β3-AR agonist that has been developed for the treatment of OAB. The effects of mirabegron on the symptoms of OAB have been examined in completed phase 2 (NCT01604928 and NCT00337090) and phase 3 studies (NCT00689104, NCT00662909, NCT00912964, and NCT00688688), and it is the first drug in this class to be approved for the treatment of symptoms of OAB. The results of one of these studies (NCT00689104), a large phase 3 trial conducted in Europe and Australia, are presented here. The purpose of this study was to assess the efficacy, safety, and tolerability of mirabegron 50 mg and 100 mg once daily in a multinational and multicenter randomised double-blind, parallel-group placebo- and tolterodine extended-release (ER)-controlled trial in patients with OAB. The tolterodine ER control served to place the efficacy and safety of mirabegron in context with that of an established antimuscarinic OAB treatment; however, no statistical comparisons were performed for mirabegron versus tolterodine ER.
Section snippets
Study design and participants
This 12-wk multinational and multicenter randomised double-blind, parallel-group placebo- and active-controlled trial was conducted at 189 sites in 27 countries in Europe and Australia. The study population consisted of men and women ≥18 yr of age with symptoms of OAB for ≥3 mo. Patients were selected for randomisation if they met all inclusion criteria including an average micturition frequency of eight or more times per 24-h period and at least three episodes of urgency, with or without
Patient demographics
A total of 2336 patients with symptoms of OAB for ≥3 mo were enrolled, of whom 1987 successfully completed the run-in phase and were randomised into the study (Fig. 2); 1978 randomised patients received the study drug. The number and proportion of patients who discontinued the study was comparable across all treatment groups.
Demographic and baseline characteristics were consistent across treatment groups for patients in the SAF (n = 1978; Table 1), FAS (n = 1906), and FAS-I (n = 1165) populations.
Discussion
Antimuscarinic therapy is the current standard first-line pharmacotherapy for OAB. However, although these agents are generally effective, some patients experience a suboptimal response to treatment or experience frequent, bothersome AEs, the most common of which is dry mouth. Patients with suboptimal responses to antimuscarinic treatment or who are unwilling to continue treatment due to the associated AEs have no other oral drug available as a treatment option.
With the β3-AR implicated in
Conclusions
Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability. It offers promise as an effective oral agent for the treatment of OAB with a distinct efficacy/tolerability balance.
To determine how a patient’s demographics, including insurance type, race/ethnicity, gender, and age, may impact the choice of medication prescribed for overactive bladder (OAB).
We queried the AUA Quality Registry for adults between 2014 and 2020 with a diagnosis of OAB for >1 year, excluding neurogenic causes. Variables included age, race/ethnicity, gender, insurance type, medication first prescribed, year of prescription, provider metropolitan status, and provider practice type. Primary outcome was which factors were associated with increased odds of beta-3 prescription as first medication choice.
We found 1,453,566 patients with OAB, 641,122 (44.1%) with complete data. Of these, 112,021 (17.5%) were prescribed medication. On multivariate analysis, patients with Medicaid, Medicare, and other/self-pay insurance were less likely to receive a beta-3 vs an anticholinergic compared to private or military insurance. Compared to white patients, Asian, Black, and other races were less likely to receive a beta-3, as were patients outside of metropolitan areas. Age >50, prescriptions after 2014, and nonacademic settings were associated with increased odds of beta-3 prescription. There was no difference between genders.
Many nonclinical factors, including insurance type and race, may affect which medication is first prescribed for OAB. This is useful for practicing urologists and may help lower barriers to beta-3 prescription through policy change and advocacy.
Many patients discontinue overactive bladder (OAB) treatment because of unmet treatment expectations and/or tolerability issues.
To develop a model for predicting the individual treatment response to mirabegron using patient baseline characteristics.
This was a post hoc analysis of data from eight global phase 2/3, double-blind, randomized, placebo- or active-controlled trials of mirabegron in adult patients with OAB.
Mirabegron 50 mg once-daily monotherapy for ≥12 wk.
Primary efficacy outcomes were the change in the mean number of micturitions and the number of incontinence episodes/24 h after 12 wk of treatment. Secondary efficacy outcomes were the change in the mean number of urgency episodes/24 h and the change in Symptom Bother score after 12 wk of treatment. Baseline demographic characteristics, OAB-related characteristics, and intrinsic and extrinsic factor variables were used to create multivariable linear regression models to predict the primary and secondary outcomes.
Data for 3627 patients were included. The predicted effect of mirabegron 50 mg was an average of 2.5 fewer micturition episodes/24 h (95% confidence interval −2.85 to −2.14) and 0.81 fewer incontinence episodes/24 h (95% confidence interval −1.15 to −0.46) from baseline to week 12. A higher number of urgency episodes was predictive of a larger reduction in micturition episodes; body mass index (BMI) ≥30 kg/m2, OAB symptoms for ≥12 mo, and incontinence at baseline were predictive of a smaller reduction. Mixed stress/urgency incontinence and more than five urgency episodes per day were predictive of greater reductions in incontinence episodes. Reductions in urgency episodes and Symptom Bother score were also predicted with mirabegron. Limitations include the exclusion of placebo groups from the analysis and the use of clinical trial rather than real-world data.
Data from the predictive models provide new insights into the effects of modifiable factors (such as BMI) and nonmodifiable factors on treatment outcomes with mirabegron 50 mg.
This study aimed to identify factors that could predict how patients with overactive bladder respond to mirabegron treatment to help doctors effectively treat this condition. Mirabegron treatment was associated with a lower number of urinations and occurrences of urinary incontinence per day. Factors associated with worse responses to the medication included being obese.
Lower urinary tract symptoms (LUTS) are common, often bothersome, and have multifactorial aetiology.
To present a summary of the 2023 version of the European Association of Urology guidelines on the management of male LUTS.
A structured literature search from 1966 to 2021 selected the articles with the highest certainty evidence. The Delphi technique consensus approach was used to develop the recommendations.
The assessment of men with LUTS should be practical. A careful medical history and physical examination are essential. Validated symptom scores, urine test, uroflowmetry, and postvoid urine residual, as well as frequency-volume charts for patients with nocturia or predominately storage symptoms should be used. Prostate-specific antigen should be ordered if a diagnosis of prostate cancer changes the treatment plan. Urodynamics should be performed for selected patients. Men with mild symptoms are candidates for watchful waiting. Behavioural modification should be offered to men with LUTS prior to, or concurrent with, treatment. The choice of medical treatment depends on the assessment findings, predominant type of symptoms, ability of the treatment to change the findings, and the expectations to be met in terms of the speed of onset, efficacy, side effects, and disease progression. Surgery is reserved for men with absolute indications, and for patients who fail or prefer not to receive medical therapy. Surgical management has been divided into five sections: resection, enucleation, vaporisation, and alternative ablative and nonablative techniques. The choice of surgical technique depends on patient’s characteristics, expectations, and preferences; surgeon’s expertise; and availability of modalities.
The guidelines provide an evidence-based approach for the management of male LUTS.
A clinical assessment should identify the cause(s) of symptoms and define the clinical profile and patient’s expectations. The treatment should aim to ameliorate symptoms and reduce the risk of complications.
Idiopathic overactive bladder (OAB) is defined as an urgency symptom with or without urge incontinence, which is not due to known neurological abnormalities. Since children present with variable symptoms, pediatric nonneurogenic idiopathic OAB is a condition that is difficult to diagnose and treat. Although there are few reports on bladder function in pediatric patients compared to adult patients, it can be useful for diagnosis. Antimuscarinic therapy is the pharmacological mainstay of OAB management. However, antimuscarinic use is limited by side effects and Insufficient effects. Vibegron, a new drug with a different mechanism of action (β3-adrenoreceptor agonist), was recently introduced for treating OAB in adults but has not been studied in the pediatric population.
This study aimed to determine the efficacy and tolerability of vibegron in children and adolescents with idiopathic OAB.
We conducted a retrospective study enrolling pediatric patients with OAB whose symptoms did not improve with behavioral therapy or pharmaceutical therapy. Efficacy and tolerability were assessed via a question, and patients underwent video-urodynamic testing before and during treatment with once-daily 50 mg vibegron. Statistical differences were evaluated using Wilcoxon matched-pairs signed-rank tests.
Out of the 17 patients that were recruited, full study with two urodynamic studies were confirmed by 11 patients. OAB symptoms improved in 14 (82.4%) patients, and 3 patients discontinued treatment because of ineffectiveness. No patients discontinued treatment because of intolerance to vibegron. The median (IQR) first desire to void (133 [82–185]–161 [123–227] mL), bladder capacity (158 [136–238]–204 [150–257] mL), and bladder compliance (18.1 [9.1–76.7]–34.0 [30.0–82.3] mL/cm H2O) improved significantly post treatment compared to before treatment. Detrusor overactivity disappeared in one of the eight patients with this condition. The parameters of voiding function did not change significantly after the administration of vibegron.
Treatment with vibegron significantly improved clinical and urodynamic parameters of pediatric OAB with no adverse effects. Little information is available regarding the feasibility of switching drugs when patients discontinue prior pharmacological therapy because of insufficient efficacy or poor tolerability in children. Vibegron may be a promising OAB treatment option with a better balance of efficacy and tolerability.
Vibegron is an alternative agent for pediatric patients with idiopathic OAB for improving both subjective symptoms and lower urinary tract function. Future prospective randomized studies with larger sample sizes must be conducted to validate the results of the present study.
