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Rev Mex Urol. 2017 July;77(4):223-226. DOI: https://doi.org/10.24245/revmexurol.v77i4.1434
Antonio Alcántara Montero
Centro de Salud José María Álvarez, Don Benito (Badajoz), Spain. Member of the Working Group of Urology (Nephrology and Urinary Tract) of the Sociedad Española de Médicos de Atención Primaria (SEMERGEN)
In 2002, the International Continence Society (ICS) defined overactive bladder syndrome as the presence of urinary urgency, alone, or combined with other symptoms, such as urge incontinence, generally associated with increased daytime urinary frequency and nocturia, in the absence of any other demonstrable disease. Men and women with symptoms of overactive bladder complain of a low level of quality of life related to health and to work productivity, as well as high levels of anxiety and depression, compared with individuals that have mild symptoms or none at all.1
First-line pharmacologic treatment for overactive bladder is with antimuscarinic agents and mirabegron, a β3-adrenergic receptor agonist. Both drug classes are similarly efficacious, but mirabegron is not associated with anticholinergic adverse events (the incidence of dry mouth is comparable to that with placebo). In current clinical practice, the treatment of these patients often begins with antimuscarinic drugs. However, symptom improvement is frequently insufficient, resulting in patient dissatisfaction, especially if incontinence persists. Increasing the dose of the muscarinic agent often exacerbates the anticholinergic adverse events, which can lead to treatment abandonment. If oral drug treatment fails, intravesical onabotulinum toxin A can be used to treat overactive bladder symptoms, but it is sometimes associated with urinary infections, a varying response, and can require intermittent self-catheterization. Other invasive alternatives include the neuromodulation techniques of percutaneous tibial nerve stimulation and sacral nerve stimulation, but their usefulness in clinical practice is limited.1
Two phase III clinical trials on the combination treatment with solifenacin (an antimuscarinic agent) and mirabegron have recently been published. The initial experience with that combination, based on the results of a Japanese open study, after the commercialization of mirabegron in Japan, suggested good efficacy and tolerability of 25 or 50 mg of mirabegron plus 2.5 or 5 mg of solifenacin versus solifenacin as monotherapy.2 In addition, a phase II European study (SYMPHONY) evaluated six combinations of mirabegron and solifenacin doses versus mirabegron and solifenacin as monotherapies or placebo, and found that the combination therapy had greater efficacy in relation to mean voiding/micturition volume, urinary frequency/24 h, and urgency episodes, than 5 mg of solifenacin alone, in the change that occurred from the baseline to end-of-treatment (EoT). All the combinations were well-tolerated, compared with the monotherapies or placebo.3 The combination of 5 mg of solifenacin with 25 mg or 50 mg of mirabegron appeared to be optimum in terms of the benefit/risk profile in that study.4
The BESIDE study is a multicenter, double-blind, randomized clinical trial that evaluated the efficacy, safety, and tolerability of the combination treatment of solifenacin (5 mg) with mirabegron (50 mg) versus monotherapy treatment with 5 or 10 mg of solifenacin for 12 weeks in patients presenting with incontinence after 4 weeks of treatment with 5 mg of solifenacin. Patients that had overactive bladder with incontinence, despite daily treatment with 5 mg of solifenacin for 4 weeks (single-blind period) were randomized 1: 1: 1 to the combination treatment (mirabegron plus solifenacin) or 5 or 10 mg of solifenacin for 12 weeks (double-blind period). The patients that received the combination treatment began with 25 mg of mirabegron and increased the dose to 50 mg after week 4. The primary aim of that trial was to evaluate combination therapy efficacy versus 5 mg of solifenacin. The secondary aims were to assess the safety/tolerability of the combination treatment versus 5 o 10 mg of solifenacin, and the non-inferiority (and potential superiority) of the combination therapy versus 10 mg of solifenacin.5
A total of 2,174 patients were randomly assigned to the combination treatment (n=727), 5 mg of solifenacin (n=728), or 10 mg of solifenacin (n=719). From the baseline until end-of-treatment, the combination therapy was superior to 5 mg of solifenacin, with significant improvement in the number of incontinence episodes in 24 hours (p = 0.001), daily micturitions (p < 0.001), and the number of incontinence episodes registered in a 3-day micturition diary (p = 0.014). The combination treatment was not inferior to 10 mg of solifenacin in relation to the secondary aim criteria and was superior to 10 mg of solifenacin for reducing daily micturitions. All the treatments were well-tolerated. The incidence of adverse events was greater with 10 mg of solifenacin, especially dry mouth, whereas no differences were observed in the 5 mg of solifenacin or combination treatments.5
The authors of that trial concluded that the addition of 50 mg of mirabegron to the treatment of patients with overactive bladder with insufficient response to 5 mg of solifenacin as monotherapy for 12 weeks provided greater improvement in overactive bladder symptoms, compared with 5 or 10 mg of solifenacin as monotherapy, and was a well-tolerated treatment.5
The SYNERGY study evaluated the response of 5 mg of solifenacin (the recommended initial daily dose and the most widely used in clinical practice) in combination with 25 mg or 50 mg of mirabegron to demonstrate whether it provided greater efficacy than individual monotherapies, with acceptable tolerance, in a general population with overactive bladder and urinary incontinence. It is a multinational, multicenter, double-blind, phase III randomized trial on parallel groups, with placebo and active control. The study lasted 18 weeks and had a 4-week single-blind preinclusion period with placebo, a double-blind period of 12 weeks of treatment, and a final 2-week single-blind washout period with placebo. It included patients 18 years of age or older that had experienced wet overactive bladder symptoms (urgency, urinary frequency, incontinence) for at least 3 months. The patients that registered a mean of micturitions equal to or above 8 /24 h, urgency episodes equal to or above 1/24 h, (grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale [PPIUS] / 24h), and 3 or more incontinence episodes during the recording of a 7-day micturition diary, were eligible for randomization into the 2: 2: 1: 1: 1: 1 double-blind daily treatment: 5 mg of solifenacin plus 25 mg of mirabegron (5 + 25 mg combination), 5 mg of solifenacin plus 50 mg of mirabegron (5 + 50 mg combination), placebo, 25 mg of mirabegron, 50 mg of mirabegron, and 5 mg of solifenacin. The primary efficacy variables were the change in the mean number of incontinence episodes/24 h and micturition episodes/24 h from treatment onset to end-of-treatment and evaluated through a 7-day micturition diary. The main secondary efficacy variables were the change from the baseline to end-of-treatment in the mean voiding/micturition volumes and the patient-reported outcomes (PROs).6
A total of 3,527 patients were randomized and 3,494 (99%) received double-blind treatment. The combination therapies of 5 mg of solifenacin + 25 mg of mirabegron and 5 mg of solifenacin + 50 mg of mirabegron improved efficacy, compared with the respective monotherapies, with effect sizes that appeared to be additive. Even though the primary aim was not achieved, by a small margin, statistical significance for the primary criteria evaluation (incontinence episodes/24 h, p = 0.052 and micturitions/24h, p < 0.05) was approximated. Regarding safety, there was a slightly greater frequency of adverse events related to the combination therapy groups versus monotherapies and placebo. The incidence of adverse events was lower in the 25 mg of mirabegron group (32%) and higher in the 5 + 25 mg combination group (40%). The majority of the adverse events in all the treatment groups were mild or moderate, mainly dry mouth, constipation, and dyspepsia. There were no significant differences between treatment groups in the incidence of adverse events leading to treatment interruption.6
Therefore, in that study on patients with wet overactive bladder, under previous anticholinergic treatment, and on patients that were not under previous treatment, efficacy improved with the combination therapies of 5 mg of solifenacin + 25 mg of mirabegron and 5 mg of solifenacin + 50 mg of mirabegron, compared with the respective monotherapies, with effect sizes that appeared to be additive. In general, the effect size of the 5 + 50 mg combination was higher and more pronounced than that of the 5 + 25 mg combination, with hardly any differences in the safety profile.6
In conclusion, combination therapy with solifenacin and mirabegron needs to be evaluated in clinical practice as a possible alternative to the current focus of overactive bladder pharmacologic treatment that includes increasing the conventional doses of antimuscarinic drugs or progressing to third-line treatment with more invasive therapies, such as intravesical botulinum toxin or neuromodulation.
1. Alcántara-Montero A. Novedades en el tratamiento médico de la vejiga hiperactiva SEMERGEN-Medicina de Familia. 2016;42:557-65.
2. Yamaguchi O, Kakizaki H, Homma Y, Igawa Y, et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int. 2015;116:612-22.
3. Abrams P, Kelleher C, Staskin D, Rechberger T, Kay R, Martina R, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study(Symphony). Eur Urol. 2015;67:577-88.
4. de Greef-van der Sandt I, Newgreen D, Schaddelee M, Dorrepaal C, et al. A quantitative benefit-risk assessment approach to improve decision making in drug development: Application of a multicriteria decision analysis model in the development of combination therapy for overactive bladder. Clin Pharmacol Ther. 2016;99:442-51.
5. Drake MJ, Chapple C, Esen AA, Athanasiou S, Cambronero J, Mitcheson D, et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). Eur Urol. 2016;70:136-45.
6. Herschorn S, Chapple CR, Abrams P, Arlandis S, Mitcheson D, Lee KS, et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int. 2017. doi: 10.1111/bju.13882.
Antonio Alcántara Montero