The Evidence for Antimuscarinic Agents in Female Mixed Urinary Incontinence

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1 european urology supplements 5 (2006) available at journal homepage: The Evidence for Antimuscarinic Agents in Female Mixed Urinary Incontinence Stefano Salvatore * Clinica Ostetrica e Ginecologica, Università dell Insubria, Piazza Biroldi 1, Varese, Italy Article info Keywords: Antimuscarinic agents Overactive bladder syndrome (OAB) Solifenacin Stress incontinence Tolterodine Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Antimuscarinic agents are the most commonly used treatments for overactive bladder (OAB) syndrome where they reduce urgency, frequency, and urge incontinence. Despite few studies investigating the effects of antimuscarinic agents on mixed urinary incontinence (MUI), awareness is increasing about their value as first-line treatments for patients with MUI (combination of OAB wet and stress urinary incontinence). Evidence suggests that they are as effective in patients with urgency-predominant MUI as they are in OAB, resulting in significant reductions in urgency episodes, urinary frequency, and incontinence. # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. * Tel /299397; Fax: address: stefanosalvatore@hotmail.com. 1. Background Antimuscarinic agents are the most commonly used treatments for overactive bladder (OAB) syndrome. They reduce urgency, frequency, and urgency incontinence through antagonistic effects at the muscarinic (M2 and M3) receptors on the detrusor muscle of the bladder [1]. As previously described, mixed urinary incontinence (MUI) is the complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing, or coughing [2]. In effect, it is a combination of OAB wet and stress urinary incontinence (SUI). The treatment of MUI has traditionally focused on the pathophysiology of the predominant symptoms. This has included physiotherapy and surgery for SUI and bladder retraining and pharmacotherapy to address the OAB. Within this latter category, evidence supports the use of antimuscarinic agents in MUI as well as in OAB. To verify this, a search of the medical literature was conducted using PubMed and Embase to access English-language citations contained in Current Contents/All Editions and MEDLINE through August The search terms women and urinary mixed incontinence, pharmacological therapy were used to identify relevant papers from peer-reviewed journals /$ see front matter # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eursup

2 850 european urology supplements 5 (2006) The role of antimuscarinic agents Despite the significant prevalence of MUI and its considerable impact on quality of life, few studies have investigated the effects of antimuscarinic agents specifically on this condition. Most have considered subgroups of patients with MUI within studies of OAB. In 1989, Karram and Bhatia reported data on 52 patients with objective evidence of combined stress and urgency incontinence, 27 of whom were treated primarily with retropubic urethropexy (modified Burch procedure) and 25 medically with oxybutynin, imipramine, and oestrogen [3]. Thirty-two percent of those treated medically were cured and 28% were markedly improved, compared with 59% and 22%, respectively, of those who had surgical treatment. Urodynamic evaluation had no predictive value for cure or improvement. There was no statistically significant difference between the two treatments, and the researchers concluded that patients with combined SUI and detrusor overactivity should initially be managed medically to reduce the incidence of surgical intervention. More recently Dmochowski et al. reported a significant reduction in the number of weekly incontinence episodes using 3.9 mg transdermal oxybutynin compared to placebo (median change 19.0 vs [p = ]) in a group of 520 adults with OAB and urge urinary incontinence (UUI) or MUI [4]. Dmochowski et al. consistently showed a comparable efficacy of 3.9 mg/d transdermal oxybutynin and 4 mg/d long-acting tolterodine in reducing the number of daily incontinence episodes, which was significantly better than placebo ( p < 0.05), in a population of 361 adults with UUI and MUI [5]. 3. Tolterodine In the first study to look specifically at patients with MUI, 60% of 410 women who were treated for 8 wk with slow-release tolterodine had a regression in symptoms [6]. In a subsequent study of 239 patients with urgency-predominant MUI and 755 patients with UUI alone, treated with tolterodine 1 or 2 mg twice daily for 16 wk, the median reduction in incontinence episodes from baseline was 67% in the patients with MUI and 75% in those with UUI [7]. Thirty-nine percent of the patients with MUI and 44% of those with UUI were dry at the end of the study, and neither of the differences in effectiveness between the MUI and UUI groups was statistically significant. The authors concluded that tolterodine was as effective at reducing urinary leakage and other OAB symptoms in patients with MUI as it was in those with UUI. On this basis, antimuscarinic treatment could be considered an effective firstline treatment option for patients with urgencypredominant MUI. The first prospective, randomised trial to look specifically at patients with MUI was the Mixed Incontinence Effectiveness Research: Investigating Tolterodine (MERIT) study, which included 854 women with urgency-predominant MUI [8]. Patients were recruited if they had UUI (five or more episodes per week), urinary frequency (eight or more micturitions on average per 24 h), and urgency (a strong and sudden desire to void) in combination with SUI. Subjects received 4 mg extended-release tolterodine or placebo, once daily for 8 wk. Patients in the two treatment groups were well matched for age and symptom severity. At baseline, patients in the placebo group experienced a mean of 21.4 episodes of UUI per week and 9.7 episodes of SUI. This compared with 20.7 and 9.2 episodes in the tolterodine group. After 8 wk of treatment, mixed incontinence episodes were reduced by a median 50.6% in the placebo group compared with 72.9% in the tolterodine group ( p < 0.01). Urinary frequency was reduced by a median 13.8% and 20%, respectively ( p < 0.01). Urgency episodes were reduced by a median 19.2% in the placebo and by 37.2% in the tolterodine group ( p < 0.001). Outcome was not affected by whether patients had experienced first SUI or first UUI. This was in contrast to a previous study of surgery in MUI that showed that operations were more likely to be successful when SUI rather than UUI had been the first symptom [9]. The reduction in weekly urgency incontinence episodes was comparable to that previously reported with extended-release tolterodine 4 mg/d in a 12-wk study of patients with OAB [10], leading the MERIT authors to conclude that the ability to treat UUI was unaffected by the presence of SUI [8]. They recommended that, because UUI has a greater negative impact on quality of life, treating the urgency component first would seem justified in women in whom urgency and stress incontinence episodes occur with equal frequency. In 2250 patients with OAB symptoms with concomitant SUI treated with 2 mg tolterodine twicedailyfor12wk,micheletal.showedthat severity of SUI (defined as 1 3 degrees according

3 european urology supplements 5 (2006) to the Stamey grading scale) affects tolterodine efficacy. On multiple linear regression analysis 1- and 2-degree SUI had a minor effect on OAB symptom improvement, whereas 3-degree SUI was statistically associated with a smaller decrease in frequency (by micturitions daily [p = ]) and incontinence (by episodes daily [p < ]) [11]. 4. Solifenacin A subgroup analysis of efficacy data from the European trial programme of the bladder on the selective antimuscarinic agent, solifenacin, lends further support to the conclusion that patients with MUI are likely to benefit from antimuscarinic treatment [12]. A total of 3032 patients were randomised to treatment or placebo for 12 wk, across the four phase 3 studies evaluating the short-term efficacy, safety, and tolerability of 5 and 10 mg solifenacin [12]. Patients were required to have a mean of eight or more micturitions per 24 h in addition to a mean of one or more incontinence episodes per 24 h or a mean of one or more urgency episodes per 24 h during the baseline 3-d micturition diary period. Subjects with SUI as the most bothersome component of their MUI condition were excluded from the studies. This was determined by the investigator based on voiding diary data, medical history, and a physical examination. Of the 2689 who had incontinence at baseline, 61% (n = 1648) had UUI only and 39% (n = 1041) had urgency-predominant MUI. In both the UUI and MUI patients, greater baseline to end point reductions in incontinence, micturition frequency, and urgency were seen in both solifenacin treatment groups compared with placebo. Mean reductions in all key symptoms were statistically significantly greater with both doses of solifenacin compared with placebo (Fig. 1). In patients with MUI, solifenacin treatment resulted in median reductions in incontinence episodes of 82% and 94% (5 mg and 10 mg, respectively) compared with a 64% reduction for patients receiving placebo. Micturition frequency was reduced by 21% and 22% (5 mg and 10 mg solifenacin, respectively) compared with a 12% reduction in the placebo group. Urgency episodes were reduced by 73% and 69% on 5 mg and 10 mg solifenacin, respectively, compared with a 42% reduction in patients receiving placebo (Fig. 2). Nearly half of those in the MUI group were continent at the end of the study (43% and 49% on 5 mg and 10 mg solifenacin, respectively) compared Fig. 1 Median baseline to end point percent changes in patients with urge urinary incontinence. Reproduced with permission from Kelleher et al. [12].

4 852 european urology supplements 5 (2006) Fig. 2 Median baseline to end point percent changes in patients with mixed urinary incontinence. Reproduced with permission from Kelleher et al. [12]. with 33% in the placebo group. About 25% of the MUI group taking solifenacin no longer experienced urgency (27% and 24% on 5 mg and 10 mg solifenacin, respectively) compared with 14% in the placebo group, and about a third had normalisation of frequency (31% and 39% on 5 mg and 10 mg solifenacin, respectively) compared with 24% in the placebo group. Normalisation of frequency was defined as achieving fewer than eight micturitions per 24 h. Treatment was well tolerated in both MUI and UUI patients. In patients with MUI, 4% and 8% of patients receiving solifenacin 5 mg and 10 mg, respectively, discontinued treatment due to adverse events compared with 6% of patients receiving placebo. In the open-label study 52% of patients with mixed symptoms regained continence and 34% reported resolution of symptomatic urgency [13]. 5. Conclusions Antimuscarinic agents are the most commonly used treatments for OAB and there is growing awareness of their value as first-line treatment for patients with MUI. Evidence suggests that they are as effective in patients with urge-predominant MUI as they are in OAB [14 18]. In a recent review of international guidelines on the treatment of female urinary incontinence, Viktrup et al. reported a general consensus in the use of conservative pharmacologic treatment in MUI in the first instance [19]. In fact, in patients with MUI, antimuscarinic agents have consistently been associated with significant reductions in urgency episodes, urinary frequency, and incontinence. In conclusion, antimuscarinic agents can be considered the first-line treatment in patients complaining of MUI, when the predominant symptom is urge incontinence. References [1] Andersson KE. The overactive bladder: pharmacologic basis of drug treatment. Urology 1997;50:74 84, discussion 85 9 (review). [2] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society. Neurourol Urodyn 2002;21: [3] Karram MM, Bhatia NN. Management of coexistent stress and urge urinary incontinence. Obstet Gynecol 1989; 73:4 7. [4] Dmochowski RR, Davila GW, Zinner NR, for the Transdermal Oxybutynin Study Group. Efficacy and safety of

5 european urology supplements 5 (2006) transdermal oxybutynin in patients with urge and mixed urinary incontinence. J Urol 2002;168: [5] Dmochowski RR, Sand PK, Zinner NR, et al., Transdermal Oxybutynin Study Group. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 2003;62: [6] Goepel M. Therapy of mixed urinary incontinence. Urologe A 2003;42: [7] Kreder Jr KJ, Brubaker L, Mainprize T. Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BJU Int 2003; 92: [8] Khullar V, Hill S, Laval K-U, et al. Treatment of urgepredominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology 2004;64: [9] Scotti RJ, Angell G, Flora R, Greston WM. Antecedent history as a predictor of surgical cure of urgency symptoms in mixed incontinence. Obstet Gynecol 1998;91:51 4. [10] Van Kerrebroeck P, Kreder K, Jonas U, et al., for the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001;57: [11] Michel MC, de la Rosette JJ, Piro M, Goepel M. Does concomitant stress incontinence alter the efficacy of tolterodine in patients with overactive bladder? J Urol 2004; 172: [12] Kelleher C, Cardozo L, Kobashi K, Lucente V. Solifenacin: as effective in mixed urinary incontinence as in urge urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2006;17: [13] Staskin DR, Te AE. Short- and long-term efficacy of solifenacin treatment in patients with symptoms of mixed urinary incontinence. BJU Int 2006;97: [14] Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005; 48:5 26. [15] Dmochowski R, Staskin D. Mixed incontinence: definitions, outcomes, and interventions. Curr Opin Urol 2005;15: [16] Anger JT, Rodriguez LV. Mixed incontinence: stressing about urge. Curr Urol Rep 2004;5: [17] Wein AJ. Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. J Urol 2005;173: [18] Chapple CR, Martinez-Garcia R, Selvaggi L, et al., for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48: [19] Viktrup L, Summers KH, Dennett SL. Clinical urology guidelines for the initial assessment and treatment of women with urinary incontinence: a review. Eur Urol Suppl 2005;4(1):38 45.