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Re: 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)
EURURO-6982; No. of Pages 1 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: 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) Drake MJ, Chapple C, Esen AA, et al; BESIDE study investigators Eur Urol 2016;70:136–45 Expert’s summary: BESIDE is a randomised double-blind parallel-group study that enrolled 2401 adults (predominantly female) with an average of three urgency urinary incontinence (UUI) episodes per day. After 4 wk on solifenacin 5 mg, 2176 patients remained incontinent (one or more UUI episode in a 3-d diary) and were randomised to 12 wk of daily double-blind treatment with a combination (solifenacin 5 mg and mirabegron 25 mg increasing to 50 mg after week 4), with solifenacin 10 mg, or with maintenance on solifenacin 5 mg. For the primary end point, combination therapy was superior to solifenacin 5 mg in reducing the number of UUI episodes per day from baseline. Among the several secondary outcomes, the most exciting one was the demonstration that combination therapy was not inferior to solifenacin 10 mg in UUI improvement. Interestingly, a higher proportion of patients were dry after combination therapy (46%) than after solifenacin 10 mg (40.2%). Expert’s comments: Dry rates achieved with low-dose antimuscarinics, the most common first-line pharmacotherapy for UUI, are generally disappointing [1], as confirmed once more by the BESIDE study. Almost all patients exposed to solifenacin 5 mg during the initial 4 wk maintained significant incontinence. Insufficient efficacy is the main reason for the rapid discontinuation of antimuscarinic treatment among UUI patients, exceeding 50% in the first 3 mo [2]. The two treatment options available to improve UUI control and to avoid early treatment discontinuation are dose escalation of the antimuscarinic drug or addition of the b3-adrenoceptor agonist mirabegron to the antimuscarinic drug at low dose. Combination is justifiable because the two drug classes address detrusor relaxation through independent pathways [3]. Escalation of antimuscarinic dose, although effective in improving UUI cure rates, is frequently hampered
by worsening of characteristic antimuscarinic adverse events like dry mouth [1]. In addition, chronic antimuscarinic medication in cognitively normal older adults was recently associated with cognitive impairment and brain atrophy [4], despite the fact that cognitive changes had not been detected during short periods of administration of the most recent antimuscarinic drugs approved for UUI treatment [2]. Therefore, all opportunities to reduce antimuscarinic load in long-term treatment of UUI should be used, particularly among elderly patients. The BESIDE study showed that high antimuscarinic doses are unneeded in most cases of UUI refractory to initial low-dose antimuscarinic medication. The combination of a low-dose antimuscarinic and mirabegron has effects that are equivalent to, if not better than, antimuscarinics alone at high dose, as noted by Drake et al. Hopefully, combination therapy will become the preferred option for the pharmacologic treatment of refractory UUI. Conflicts of interest: Francisco Cruz has been an investigator, consultant, and speaker for Astellas.
References [1] Buser N, Ivic S, Kessler TM, Kessels AG, Bachmann LM. Efficacy and adverse events of antimuscarinics for treating overactive bladder: network meta-analyses. Eur Urol 2012;62:1040–60. http://dx.doi. org/10.1016/j.eururo.2012.08.060. [2] Lucas MG, Bosch RJ, Burkhard FC, et al. European Association of Urology. EAU guidelines on assessment and nonsurgical management of urinary incontinence [published correction appears in Eur Urol 2013;64:e20]. Eur Urol 2012;62:1130–42. http://dx.doi.org/ 10.1016/j.eururo.2012.08.047. [3] Ochodnicky P, Uvelius B, Andersson KE, Michel MC. Autonomic nervous control of the urinary bladder. Acta Physiol (Oxf) 2013;207:16–33. http://dx.doi.org/10.1111/apha.12010. [4] Risacher SL, McDonald BC, Tallman EF, et al. Alzheimer’s Disease Neuroimaging Initiative. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol 2016;73:721–32. http://dx.doi.org/10.1001/jamaneurol.2016.0580. Francisco Cruz Hospital Sa˜o Joa˜o and Faculty of Medicine of Porto and Instituto de Investigac¸a˜o e Inovac¸a˜o em Sau´de (I3S), Porto, Portugal
http://dx.doi.org/10.1016/j.eururo.2016.08.027 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
E-mail address: [email protected].
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: 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) Drake MJ, Chapple C, Esen AA, et al; BESIDE study investigators Eur Urol 2016;70:136–45 Expert’s summary: BESIDE is a randomised double-blind parallel-group study that enrolled 2401 adults (predominantly female) with an average of three urgency urinary incontinence (UUI) episodes per day. After 4 wk on solifenacin 5 mg, 2176 patients remained incontinent (one or more UUI episode in a 3-d diary) and were randomised to 12 wk of daily double-blind treatment with a combination (solifenacin 5 mg and mirabegron 25 mg increasing to 50 mg after week 4), with solifenacin 10 mg, or with maintenance on solifenacin 5 mg. For the primary end point, combination therapy was superior to solifenacin 5 mg in reducing the number of UUI episodes per day from baseline. Among the several secondary outcomes, the most exciting one was the demonstration that combination therapy was not inferior to solifenacin 10 mg in UUI improvement. Interestingly, a higher proportion of patients were dry after combination therapy (46%) than after solifenacin 10 mg (40.2%). Expert’s comments: Dry rates achieved with low-dose antimuscarinics, the most common first-line pharmacotherapy for UUI, are generally disappointing [1], as confirmed once more by the BESIDE study. Almost all patients exposed to solifenacin 5 mg during the initial 4 wk maintained significant incontinence. Insufficient efficacy is the main reason for the rapid discontinuation of antimuscarinic treatment among UUI patients, exceeding 50% in the first 3 mo [2]. The two treatment options available to improve UUI control and to avoid early treatment discontinuation are dose escalation of the antimuscarinic drug or addition of the b3-adrenoceptor agonist mirabegron to the antimuscarinic drug at low dose. Combination is justifiable because the two drug classes address detrusor relaxation through independent pathways [3]. Escalation of antimuscarinic dose, although effective in improving UUI cure rates, is frequently hampered
by worsening of characteristic antimuscarinic adverse events like dry mouth [1]. In addition, chronic antimuscarinic medication in cognitively normal older adults was recently associated with cognitive impairment and brain atrophy [4], despite the fact that cognitive changes had not been detected during short periods of administration of the most recent antimuscarinic drugs approved for UUI treatment [2]. Therefore, all opportunities to reduce antimuscarinic load in long-term treatment of UUI should be used, particularly among elderly patients. The BESIDE study showed that high antimuscarinic doses are unneeded in most cases of UUI refractory to initial low-dose antimuscarinic medication. The combination of a low-dose antimuscarinic and mirabegron has effects that are equivalent to, if not better than, antimuscarinics alone at high dose, as noted by Drake et al. Hopefully, combination therapy will become the preferred option for the pharmacologic treatment of refractory UUI. Conflicts of interest: Francisco Cruz has been an investigator, consultant, and speaker for Astellas.
References [1] Buser N, Ivic S, Kessler TM, Kessels AG, Bachmann LM. Efficacy and adverse events of antimuscarinics for treating overactive bladder: network meta-analyses. Eur Urol 2012;62:1040–60. http://dx.doi. org/10.1016/j.eururo.2012.08.060. [2] Lucas MG, Bosch RJ, Burkhard FC, et al. European Association of Urology. EAU guidelines on assessment and nonsurgical management of urinary incontinence [published correction appears in Eur Urol 2013;64:e20]. Eur Urol 2012;62:1130–42. http://dx.doi.org/ 10.1016/j.eururo.2012.08.047. [3] Ochodnicky P, Uvelius B, Andersson KE, Michel MC. Autonomic nervous control of the urinary bladder. Acta Physiol (Oxf) 2013;207:16–33. http://dx.doi.org/10.1111/apha.12010. [4] Risacher SL, McDonald BC, Tallman EF, et al. Alzheimer’s Disease Neuroimaging Initiative. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol 2016;73:721–32. http://dx.doi.org/10.1001/jamaneurol.2016.0580. Francisco Cruz Hospital Sa˜o Joa˜o and Faculty of Medicine of Porto and Instituto de Investigac¸a˜o e Inovac¸a˜o em Sau´de (I3S), Porto, Portugal
http://dx.doi.org/10.1016/j.eururo.2016.08.027 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
E-mail address: [email protected].