Urological Science 26 (2015) 49e50
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Editorial comment
Optimizing pharmacotherapy of overactive bladder e Targeting muscarinic receptor or beta-adrenergic receptor, or both?
Overactive bladder (OAB) symptoms presents in both sexes in a great variety of forms: idiopathic, after bladder infection, and in association with neurologic disorders. One presentation of overactive bladder is persistent storage symptoms after transurethral resection of the prostate (TURP), which happens in approximately 30% of patients. The cause for persistent storage symptoms after TURP is multifactorial. Storage symptoms caused by pre-existing neurological disorders such as stroke are expected to persist after TURP. Irreversible bladder outlet obstruction-induced bladder denervation is another possibility. Aging is also a risk factor.1 Treatment for post-TURP storage symptom should theoretically be similar to the ordinary form of OAB. This is why studies on pharmacotherapy for persistent OAB after TURP are scarce. In this issue of Urological Science, Chughtai et al2 present their results of a pilot study that used fesoterodine to treat persistent OAB symptoms. During 7 months of follow up, they found trends of improvement in the mean number of nocturia episodes, the International Prostate Symptom Score (IPSS) storage subscore, and quality of life score. A limitation of this pilot study is the small number of patients. However, it is very likely that the improvement would be statistically significant if the case number were sufficiently adequate. The withdrawal rate in Chughtai et al's study was notably highdapproximately one-third of patientsdduring a 7-month follow-up period. Intolerable side effects such as constipation, dry mouth and dry eye, which are typical adverse effects of antimuscarinics, were the major reasons patients discontinued fesoterodine. The rate of persistence with antimuscarinics for OAB is low, approximately only 30% at 12 months.3 The leading cause for the low compliance rate of antimuscarinics is their adverse effects. There have been multiple attempts to reduce the adverse effects of antimuscarinics such as searching for compounds that are more bladder selective, changing the route of administration, and changing to an extended-release formulation. However, even with these efforts, the adverse effects of antimuscarinics are sufficient enough to cause a low drug persistence rate. The emergence of b3 adrenergic agonist is timely with regard to improving drug adherence. In this issue of Urological Science, Kuo et al4 report a randomized double-blind, placebo- and activecontrolled trial that compared treatment efficacy between mirabegron, tolterodine, and placebo on OAB symptoms in Taiwanese patients. They demonstrated that mirabegron at a dose of 50 mg once daily for 12 weeks was superior to a placebo in reducing urinary frequency. The study also showed that mirabegron had a good
safety profile with a low incidence of adverse events, which was similar to that in the placebo group. The incidence of dry mouth was as low as 5.9%, which was lower than its incidence with antimuscarinics. The incidence of cardiovascular side effects was also low, particularly for b-adrenergic agonists. Good treatment efficacy on OAB symptoms and satisfactory safety profile of mirabegron demonstrated in this Taiwanese study are similar to those of studies conducted in Japan, the United States of America, and Europe. Because of its low incidence of adverse effects, mirabegron is expected to have a higher drug persistence rate. In this Taiwanese mirabegron study, >75% of patients had previously used drug medications for OAB, primarily antimuscarinics agents, which indicates that OAB that is refractory to antimuscarinics can be well managed with a b3 adrenergic agonist. This finding is in accordance with a report by a post hoc subgroup analysis of a clinical trial, which showed that mirabegron benefits OAB patients who were antimuscarinic treatment-naive and who had received prior antimuscarinic treatment.5 Mirabegron may provide new hope for patients with refractory OAB who have a poor response to antimuscarinics. Could the combination of antimuscarinics and b3 agonists be used to treat OAB that is not responding well to either agent or could the combination be used to reduce adverse effects of either agent? A published Phase 2 study has provided a preliminary answer. Abrams et al6 report that combination therapy with solifenacin and mirabegron significantly improved OAB symptoms, compared to solifenacin (5 mg) monotherapy. They concluded that combination therapy improves OAB symptoms and has similar safety and acceptability.6 Further study may elucidate the most appropriate dose combination of antimuscarinic and b3 agonist. In conclusion, the introduction of a b3 agonist has significantly advanced the care for OAB patients. The definition of refractory OAB should be revised from “refractory” to “only antimuscarinics”, “resistant to monotherapy with antimuscarinics or b3 agonists”, or “combination therapy with both classes of drugs”. Conflicts of interest The author declares that he has no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript. Sources of Funding No funding was received for the work described in the article.
http://dx.doi.org/10.1016/j.urols.2015.01.001 1879-5226/Copyright © 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. Open access under CC BY-NC-ND license.
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Editorial comment / Urological Science 26 (2015) 49e50
References 1. Han HH, Ko WJ, Yoo TK, Oh TH, Kim DY, Kwon DD, et al. Factors associated with continuing medical therapy after transurethral resection of prostate. Urology 2014;84:675e80. 2. Chughtai B, Laudano M, Dunphy C, Lee R, Kaplan SA, Te A. A pilot study of fesoterodine in management of men with refractory overactive bladder symptoms after surgery for bladder outlet obstruction. Urol Sci 2015;26:38e40. 3. Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 2014;191:1003. 4. Kuo HC, Lin HH, Yu HJ, Cheng CL, Hung MJ, Lin AT, and Taiwan Mirabegron Study Team. Results of a randomized, double-blind, placebo-controlled, study of mirabegron in Taiwanese with overactive bladder and comparison with other clinical trials. Urol Sci 2015;26:41e8. 5. Khullar V, Cambronero J, Angulo JC, Wooning M, Blauwet MB, Dorrepaal C, et al. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. BMC Urol 2013;13:45. 6. 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 2014. http://dx. doi.org/10.1016/j.eururo.2014.02.012.
Alex Tong Long Lin* Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan Department of Urology, National Yang-Ming University, School of Medicine, Taipei, Taiwan *
Department of Urology, Taipei Veterans General Hospital, Number 201, Section 2, Shih-Pai Road, Taipei, Taiwan. E-mail address:
[email protected]. 29 December 2014 Available online 7 February 2015
