Antimuscarinic Therapy for the Treatment of Mixed Incontinence

TREATMENT OF OVERACTIVE BLADDER Antimuscarinic Therapy for the Treatment of Mixed Incontinence Scott MacDiarmid, MD Wake Forest University School of Medicine, Winston-Salem, NC Mixed urinary incontinence, the combination of stress incontinence and urge incontinence, affects millions of Americans, significantly impacting their quality of life. Treatment of mixed incontinence is a therapeutic challenge, and the debate over whether patients are best managed initially with medication or surgery is ongoing. The literature supports the efficacy of both antimuscarinic therapy and surgery for the treatment of mixed incontinence, but patient selection likely influences treatment outcome. Following is a literature review that critically evaluates the efficacy of antimuscarinic agents for the treatment of mixed incontinence and addresses some of the controversial issues regarding surgical and pharmacologic therapy. Clinical parameters that might influence therapeutic outcomes and recommendations regarding treatment are also presented. [Rev Urol. 2003;5(suppl 8):S18-S25] © 2003 MedReviews, LLC Key words: Antimuscarinic agents • Mixed incontinence • Surgical therapy • Tolterodine • Oxybutynin rinary incontinence affects more than 17 million persons in the United States, and 10% to 35% of Americans older than 65 years have this condition.1 It is well recognized that urinary incontinence has detrimental effects on quality of life and is costly, not only to the American health care system2 but also to the individual patient. During the past few decades, there have been numerous advances in the understanding of urinary incontinence pathophysiology, with subsequent improvements in both pharmacologic and surgical therapies for the disorder. U S18 VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY Antimuscarinic Therapy for Mixed Incontinence The treatment of mixed incontinence, the combination of stress incontinence and urge incontinence, has always been considered a therapeutic challenge. Controversy remains as to whether patients with mixed incontinence symptoms are best managed initially with nonsur- bladder neck hypermobility, intrinsic sphincter deficiency, or both. Urge incontinence with detrusor overactivity has been defined as a condition resulting from bladder instability demonstrated during urodynamics. Many patients with overactive bladder and urge incontinence do not An estimated 35% to 65% of patients with stress urinary incontinence have either urge incontinence or bladder instability during conventional or ambulatory urodynamics. gical or surgical therapy. It is estimated that 29% to 44% of the incontinent female population suffer from mixed incontinence. It is well recognized that the newer antimuscarinic, anticholinergic medications approved for the treatment of overactive bladder are highly effective in reducing urinary frequency and urge incontinence. These medications include tolterodine immediate release (tolterodine IR), tolterodine extended release (tolterodine ER), oxybutynin extended release (oxybutynin ER), and oxybutynin transdermal delivery system (oxybutynin TDS).3-8 Less is known regarding the efficacy of these drugs in patients with mixed symptoms. This article reviews the literature and critically evaluates the efficacy of antimuscarinic agents for the treatment of mixed incontinence and addresses some of the controversial issues regarding medical and surgical therapies. Clinical parameters that might influence therapeutic outcomes and recommendations regarding treatment are also presented. Pathophysiology It is important to have a basic understanding of the pathophysiology of mixed urinary incontinence. Stress incontinence results from urethral sphincter weakness, arising either from demonstrate motor urgency during cystometrogram. These patients often have a normal cystometric pattern with reduced bladder capacity, a finding referred to as sensory urgency. Less commonly, urodynamics demonstrates poor bladder compliance, and the filling phase can be normal in up to 30% of cases. Although the mechanism of motor and sensory urgency is poorly understood, many experts believe that sensory and motor urge incontinence are gradations of the same condition. Urethral relaxation during bladder filling may also play a role in some patients with overactive bladder. The condition resulting from this unstable urethra is referred to as urethral relaxation incontinence.9 The relationship between stress urinary incontinence and overactive bladder is complex. The vesicourethral mechanism and the pelvic floor are intimately related and should be considered as a single functioning unit. For instance, weakness of the pelvic floor or urethral sphincter mechanism may result in motor urgency, whereas, in other cases, an effective urethra and pelvic floor may counteract detrusor instability and prevent urge incontinence. Abnormality in any of the elements of the bladder-urethra-pelvic floor mechanism can result in dysfunction of the other compartments. Therapy is directed not only toward the primary problem but also toward the associated dysfunction. Many experts believe that there is great variability among patients with mixed symptoms of incontinence and caution against considering and treating these patients as a homogeneous cohort. Clearly, many patients with mixed incontinence have a dominating urge or stress component to their symptom complex, and there is a continuum of patients in between these 2 possibilities. Symptoms are secondary to variable dysfunctions of the bladder, urethra, and pelvic floor, and patients should not be expected to respond equally to therapy. Surgical Management of Mixed Incontinence An estimated 35% to 65% of patients with stress urinary incontinence have either urge incontinence or bladder instability during conventional or ambulatory urodynamics.10,11 Satisfactory results have been reported with surgical management of mixed incontinence by addressing the bladder neck hypermobility and/or urethral sphincter deficiency.12,13 Morgan and colleagues12 assessed the surgical outcome of the pubovaginal sling in 247 patients with stress urinary incontinence, 109 (44%) of whom had concomitant urge incontinence preoperatively. At a mean follow-up of 51 months, the overall continence rate was 88%, and more than 90% of patients reported a high degree of satisfaction as measured by a quality-of-life questionnaire. Of the 109 patients with preoperative urge incontinence, 29 patients (26%) had persistent urge incontinence following surgery. The incidence of de novo urge incontinence was 7%. In a second series, Cross and colleagues13 reported a 93% stress incontinence cure rate in 150 patients treated with a pubo- VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S19 Antimuscarinic Therapy for Mixed Incontinence continued vaginal sling. Of 45 patients (34%) who reported urge incontinence preoperatively, 75% had resolution of the condition following surgery. De novo urge incontinence occurred in 3% of cases. Carr and colleagues14 compared the surgical outcome of the pubovaginal sling for the treatment of stress incontinence and mixed incontinence in 19 women older than 70 years versus that in 77 younger control subjects. Eight geriatric (42%) and 18 control (23%) patients reported urge incontinence prior to surgery. Stress incontinence resolved in 100% and 97% of the elderly and control women, respectively. Postoperative urge incontinence persisted in 50% of the geriatric patients and 39% of control patients. De novo urge incontinence occurred in 10% of the cases but was generally controlled with anticholinergic agents. Chou and colleagues15 assessed the efficacy of the autologous fascia pubovaginal sling in women with stress incontinence and in those with mixed incontinence. Patients were evaluated with a urologic questionnaire, 24-hour voiding diary, and pad test. The cure/improved rate was 97% in the 44 patients who had pure stress incontinence, compared with 93% in the 47 cases of mixed incontinence (P = .33). Univariate analysis of the patients with mixed incontinence demonstrated that an increasing number of urgency and urge incontinence episodes preoperatively correlated directly with surgical failure (r = .33 [P = .038] and r = .35 [P = .048], respectively). Many experts believe that the presence of detrusor instability or urge incontinence does not appear to adversely influence the outcome of surgical management of stress incontinence.16 The data generally support that urge incontinence and bladder instability resolve in 50% to 75% of S20 VOL. 5 SUPPL. 8 2003 patients following surgery and persist in approximately 15% to 30% of cases. The incidence of de novo urge incontinence ranges from 3% to 15%. It is important to realize that these data are based on a number of retrospective analyses of patients with stress incontinence, of whom a subset also complained of overactive bladder and urge incontinence. There is usually no mention of the severity of the overactive bladder symptomatology or the findings on cystometrogram. It is likely that the majority that patients with persistent urgerelated symptoms following surgery had the lowest degree of satisfaction as measured by a quality-of-life questionnaire. In a series by Carr and colleagues,14 50% of the patients with persistent urge incontinence did not respond to anticholinergic therapy, although their overall degree of incontinence was much improved. The clinical relevance of significant or worsening urge incontinence following surgery is dramatic, and its occurrence is somewhat unpredictable. For the majority of patients with mixed incontinence, a combination of medical and behavioral therapy as first-line treatment should be endorsed. of study participants represent a select group of patients with mixed symptoms, excluding those with severe overactive bladder and those in whom the primary complaint is urge incontinence. Chou and colleagues15 reported that increasing episodes of urgency and urge incontinence on preoperative voiding diaries correlated directly with poor surgical outcomes, suggesting that patients with mixed incontinence with a significant overactive component fare less favorably with surgery. Therefore, one must be cautious when interpreting the surgical data, because it is unlikely that these results can be anticipated in all patients with mixed stress and urge incontinence. Persistent (or worsening) urge incontinence following surgery, especially when severe and refractory to medication, can dramatically adversely affect a patient and his or her quality of life. The majority of the surgical literature does not adequately report on the population of patients in whom overactive symptoms persist postoperatively. Morgan and colleagues12 reported REVIEWS IN UROLOGY For this reason, for the majority of patients with mixed incontinence, a combination of medical and behavioral therapy as first-line treatment should be endorsed. Pharmacologic Management of Mixed Incontinence Clinical experience and the literature support the efficacy of antimuscarinic agents for the treatment of urinary frequency and urge incontinence. The reported reduction in urge incontinence episodes with the newer anticholinergic agents—tolterodine IR, tolterodine ER, oxybutynin ER, and oxybutynin TDS—ranges from 46% to 92%.3-8 Although less is known about the efficacy of these drugs in the treatment of mixed incontinence, it appears that a similar reduction in the number of leaking episodes is achieved. The efficacy and tolerability of tolterodine IR, the first drug developed specifically for the treatment of overactive bladder, have been demonstrated in a number of placebo-controlled, randomized, clinical trials. A total of 1120 patients were treated in 4 multicenter studies and subse- Antimuscarinic Therapy for Mixed Incontinence quently evaluated in a pooled analysis.3 The patients were randomized to tolterodine IR, 1 mg twice daily; tolterodine IR, 2 mg twice daily; oxybutynin IR, 5 mg 3 times daily; or placebo. In 3 of the studies, tolterodine therapy achieved mean reductions in daily urge incontinence episodes of 50%, 56%, and 55%, which were not statistically superior to placebo. When the data were line was 67% in the mixed incontinence group and 75% in the pure urge incontinence group (P = .39). Dryness was achieved in 39% and 44% of the mixed incontinence and urge incontinence patients, respectively, and 24% of patients in each group achieved a voiding pattern of fewer than 8 voids per day. It was hypothesized that the slightly lower dry rate in the subjects with mixed Dry mouth was the most commonly reported adverse event, occurring in 30% of the subjects who received tolterodine and 8% of the subjects who received placebo. pooled, tolterodine was statistically more efficacious than placebo and was better tolerated than oxybutynin. In another study, Chancellor and colleagues4 evaluated 1022 patients with urge incontinence who were randomized to treatment with tolterodine IR, 2 mg twice daily, or placebo. The reductions in urge incontinence episodes experienced with tolterodine and placebo were 46% and 30%, respectively (P = .0005). Dry mouth was the most commonly reported adverse event, occurring in 30% of the subjects who received tolterodine and 8% of the subjects who received placebo. Although patients with mixed incontinence (with predominantly urge incontinence) were included in the majority of these studies, subanalysis of the mixed incontinence population was not reported. In a single-blind, flexible-dose, multicenter trial, Kreder and colleagues17 evaluated tolterodine therapy in 239 patients with mixed incontinence (urge incontinence predominating) and 755 patients with urge incontinence. Subjects received tolterodine IR, 1 mg to 2 mg twice daily for 16 weeks, titrated according to efficacy and side effects. The median reduction in urge incontinence from base- incontinence symptoms was due to the persistence of stress incontinence, but this was not analyzed. Tolterodine ER, a newer once-aday formulation of tolterodine, was designed to provide greater patient convenience and improved compliance compared with the twice-daily formulation. The efficacy and tolerability of tolterodine ER, 4 mg daily, and tolterodine IR, 2 mg twice daily, were compared in a large, doubleblind, multicenter, placebo-controlled study.5 A total of 1529 patients with urge incontinence or mixed incontinence (with predominantly urge incontinence) were randomized to receive tolterodine ER (n = 507), tolterodine IR (n = 514), or placebo (n = 508). The mean reductions in weekly urge incontinence episodes with tolterodine ER and tolterodine IR were 53% and 46%, respectively (P > .05). The median reductions in urge incontinence episodes from baseline were 71% for tolterodine ER, 60% for tolterodine IR, and 33% for placebo; tolterodine ER was 18% more effective than the immediate-release formulation (P < .05). The rates of dry mouth in the tolterodine ER, tolterodine IR, and placebo groups were 23%, 30%, and 8%, respectively. Subanalysis of patients with mixed symptoms was not reported.5 Additional data regarding the efficacy of antimuscarinic agents for the treatment of mixed incontinence are presented in 2 head-to-head trials comparing oxybutynin ER and tolterodine.6,7 Oxybutynin ER gained approval of the Food and Drug Administration (FDA) and was introduced in 1999. This therapy uses a patented, push-pull, osmotic delivery system (OROS) to deliver oxybutynin at a fixed rate over 24 hours. In a prospective, randomized, double-blind, parallel-group study, referred to as the Overactive Bladder: Judging Effective Control and Treatment (OBJECT) study, the efficacy and tolerability of oxybutynin ER, 10 mg, and tolterodine IR, 2 mg twice daily, were compared.6 Of 378 patients randomized, 276 women and 56 men completed the study. Patients with mixed incontinence were eligible if the majority of their leakage accidents were related to urge incontinence. The reductions in weekly total (urge plus stress) incontinence episodes in patients who received oxybutynin ER and tolterodine IR were 75% and 66%, respectively (P = .02). Similarly, oxybutynin ER was statistically more effective than tolterodine IR in reducing urge incontinence: 76% versus 68%, respectively (P = .03) (see Table 1). Both medications were equally and well tolerated.6 A recent randomized, double-blind study entitled the Overactive Bladder: Performance of Extended-Release Agents (OPERA) trial compared the efficacy and tolerability of oxybutynin ER and tolterodine ER. Oxybutynin ER, 10 mg/d, or tolterodine ER, 4 mg/d, was administered to 790 women with 21 to 60 weekly urge incontinence or mixed inconti- VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S21 Antimuscarinic Therapy for Mixed Incontinence continued Table 1 Reductions in Urge and Total Incontinence Episodes With Oxybutynin ER and Tolterodine Mean No. Weekly Leaking Episodes, Baseline – End of Study (% Reduction) Study Agent Urge Incontinence Total Incontinence OBJECT6 Oxybutynin ER Tolterodine IR Oxybutynin ER Tolterodine ER Oxybutynin ER Oxybutynin ER Oxybutynin ER 25.6 24.1 37.1 36.7 27.4 18.6 18.8 28.6 27.0 43.4 42.4 29.3 20.2 22.2 OPERA7 Anderson et al8 Versi et al18 Gleason et al19 – – – – – – – 6.1 (76) 7.8 (68) 10.8 (71) 11.2 (69) 4.8 (83) 2.9 (84) 2.8 (85) – – – – – – – 7.1 (75) 9.3 (66) 12.3 (72) 13.8 (67) 6.0 (80) 3.5 (83) 4.0 (82) ER, extended release; IR, immediate release. nence episodes. Women were eligible if their number of urge incontinence episodes was greater than their nonurge events. The mean weekly episodes of total (urge plus stress) incontinence decreased from 43.4 recorded at baseline to 12.3 (last observation carried forward) for the oxybutynin ER group and from 42.4 to 13.8 (last observation carried forward) for the tolterodine ER group. This represented statistically similar reductions in total incontinence episodes of 72% and 67% for oxybutynin ER and tolterodine ER, respectively. Similarly, the mean reductions in weekly urge incontinence episodes were 71% with oxybutynin ER and 69% with tolterodine ER (P > .05) (see Table 1). The proportion of patients who reported total dryness was 23% for those who received oxybutynin ER versus 16.8% for those who received tolterodine ER; this difference was statistically significant (P = .03).7 The reported rate of dry mouth was statistically lower in patients who received tolterodine versus oxybutynin (22.3% vs 29.7%), primarily due to a lower incidence of mild dry mouth. The incidence of moderate and severe dry mouth and the rate of S22 VOL. 5 SUPPL. 8 2003 patient drop-out due to anticholinergic side effects were similar with both medications.7 The reductions in total incontinence episodes reported in the OBJECT and OPERA studies represent decreases in the total number of leaks (urge plus stress episodes) for the entire patient population and were not subanalyses of subjects with only mixed incontinence symptoms. Thus, these data provide us with only an indirect measure regarding the efficacy of oxybutynin ER and tolterodine for the treatment of mixed incontinence. A number of additional studies demonstrate the efficacy of oxybutynin ER for the treatment of total (urge plus stress) incontinence. In a study by Anderson and colleagues,8 105 patients with urge incontinence or mixed incontinence (with predominantly an urge component) were randomized to receive oxybutynin ER, 5 mg to 30 mg once daily, or oxybutynin IR, 5 mg 1 to 4 times daily. Dose titration started at 5 mg, and dose was increased every 4 to 7 days until 1 of 3 end points was achieved: the patient reported no urge incontinence during the final 2 days of the dosing period, the maximum tolerable dose (defined as 5 mg lower than REVIEWS IN UROLOGY that which resulted in significant side effects) was reached, or the maximum allowable dose (30 mg for oxybutynin ER and 20 mg for oxybutynin IR) was given. Total incontinence episodes decreased from a weekly baseline of 29.3 to 6.0 with oxybutynin ER and from 26.3 to 3.8 with oxybutynin IR. The mean percentage reductions in weekly total incontinence and urge incontinence episodes with oxybutynin ER were 80% and 83%, respectively, which were statistically similar to the immediate-release formulation (see Table 1). Complete urinary continence was achieved in 41% of patients who received oxybutynin ER and 40% of those who received oxybutynin IR. Dry mouth was reported more often with oxybutynin IR than with oxybutynin ER (87% vs 68%; P = .04).8 In another dose-titration study,18 226 patients were randomized to receive oxybutynin ER or oxybutynin IR. All patients were started on 5 mg daily and the dose was increased weekly by 5 mg per day to a maximum of 20 mg per day or until patients reached the most favorable balance between efficacy and side effects. The mean reductions in weekly total incontinence with oxybutynin ER and oxybutynin IR were 83% (20.2 to 3.5 episodes) and 75% (22.4 to 5.4 episodes), respectively. The mean reduction in urge incontinence episodes with oxybutynin ER was 84% versus 76% with oxybutynin IR (see Table 1). Gleason and colleagues19 evaluated 256 patients with urge or mixed incontinence (with a significant urge component) in a third dose-escalation study. Patients receiving oxybutynin ER titrated their dosage upward until continence was achieved for 2 days or until a satisfactory balance between continence and adverse effects was attained. The reductions in mean weekly total incontinence and Antimuscarinic Therapy for Mixed Incontinence 35 Oxybutynin TDS, 3.9 mg/d 30 Median Number of Weekly Incontinence Episodes urge incontinence episodes were 82% and 85%, respectively (see Table 1). Recently, oxybutynin TDS was approved by the FDA for the treatment of overactive bladder. The transdermal delivery system offers several advantages over oral administration, including twice weekly dosing and the potential for improved patient compliance and tolerability. The transdermal delivery system avoids the extensive presystemic metabolism that occurs with oral administration, greatly reducing the formation of the metabolite Ndesethyloxybutynin. It is generally believed that N-desethyloxybutynin is responsible for the dry mouth associated with anticholinergic agents. In a multicenter, randomized, placebo-controlled, dose-titration study,20 520 patients with pure urge incontinence or a predominance of urge episodes were randomized to receive oxybutynin TDS, 1.3 mg/d, 2.6 mg/d, or 3.9 mg/d, or placebo. Oxybutynin TDS, 3.9 mg, significantly reduced the median number of 31 Placebo 30 25 61% Reduction 20 15 15 10 12 5 0 Baseline Week 12 Figure 1. Oxybutynin transdermal delivery system (TDS), 3.9 mg/d, significantly reduced the number of urinary incontinence episodes per week compared with placebo (61% vs 50%; P = .0165). Data from Dmochowski RR et al. J Urol. 2002;168:580-586.20 ER, 4 mg/d; or placebo. Oxybutynin TDS and tolterodine ER significantly reduced the number of daily incontinence episodes (median change: oxybutynin TDS, 3; tolterodine ER, 3; placebo, 2; P < .05), with a 75% improvement reported with both compounds. The incidences of dry mouth with oxybutynin TDS, tolterodine ER, and placebo were The transdermal delivery system offers several advantages over oral administration, including twice weekly dosing and the potential for improved patient compliance and tolerability. weekly incontinence episodes by 19 (61%), compared with a 14.5 reduction (50%) with placebo (P = .0165) (Figure 1). Sixteen (13%) of the 123 patients who received oxybutynin TDS, 3.9 mg/d, achieved complete urinary continence. The incidences of dry mouth and constipation with oxybutynin TDS, 3.9 mg/d, were 9.6% and 0.8%, respectively, which were equivalent to those with placebo. In a second study,21 361 patients with urge incontinence or mixed incontinence (with a predominance of urge) were randomized to receive oxybutynin TDS, 3.9 mg/d; tolterodine 4.1%, 7.3%, and 1.7%, respectively. Although both studies included patients with mixed incontinence, subanalysis of the mixed population was not reported. Duloxetine, a selective serotonin (5-HT) and norepinephrine reuptake inhibitor, is currently being reviewed by the FDA for the treatment of stress urinary incontinence. Duloxetine increases the contractility of the rhabdosphincter via stimulation of the pudendal motor neuron 1-adrenergic and 5HT-2 receptors. It may also decrease sensory impulses from the bladder through modulation of the 5-HT and adrenergic receptors in the spinal cord, resulting in relaxation of the bladder. For this reason, duloxetine may prove efficacious for the treatment of mixed urinary incontinence. In a large double-blind, placebocontrolled study,22 683 patients were randomized to receive duloxetine, 40 mg twice daily (n = 344), or placebo (n = 339) for 12 weeks. Patients with pure stress incontinence and those with mixed incontinence symptoms (with predominantly stress incontinence) were included in the analysis. There was a significant reduction in the incontinence episode frequency with duloxetine compared with placebo (50% vs 27%; P < .001). In addition, 51% of patients who received duloxetine reported a 50% to 100% reduction in incontinence episodes compared with 34% of those who received placebo (P < .001). Efficacy of duloxetine in patients with mixed incontinence was not reported. The data support the efficacy of antimuscarinic agents for the treatment of mixed incontinence. Unlike in the surgical literature, efficacy has been demonstrated in a number of prospective, randomized, doubleblind, placebo-controlled trials in VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S23 Antimuscarinic Therapy for Mixed Incontinence continued which the patient population has been well defined. Although a subanalysis of patients with pure mixed incontinence has not been performed with oxybutynin ER, the reported reduction in total leaking episodes is a reasonable (though not perfect) indicator of its efficacy in patients with mixed symptoms. The reported reduction in total leaking episodes with antimuscarinic agents ranges from 66% to 82% and is consistently similar to what is achieved with urge incontinence (see Table 1). It is important to realize that these successful outcomes were achieved in a select population of mixed incontinence patients who primarily had urge incontinence. Patients with significant stress incontinence as part of their symptom complex were not included in the analyses. For this reason, one must be cautious in generalizing these outcomes to all patients with mixed incontinence symptoms, especially those who have moderate-to-severe stress urinary incontinence. Clinical Decision Making Most physicians recognize the complexity and challenges associated with the treatment of mixed urinary incon- tinence. It is accepted by many that any one treatment is not appropriate for all patients with mixed incontinence symptoms and that therapy should be tailored to the individual patient. A number of factors should be considered when selecting therapy, because their presence may influence outcomes with both pharmacologic and surgical therapy. The influence of these factors is largely based on clinical experience and opinion and not on scientific analysis. The most important factors that influence the decision to recommend pharmacologic and behavioral therapy versus surgery when treating mixed urinary incontinence are the patient's dominating symptom and the severity of his or her overactive bladder. We initially manage all patients whose primary complaints are frequency and urge incontinence and patients with moderate-tosevere overactive bladder symptoms with nonsurgical therapy, regardless of the severity of their stress incontinence. In many cases, controlling the overactive bladder successfully reaches the patient’s treatment goals and, therefore, surgery is not necessary. Surgical intervention is reserved for those who fail nonsurgical treat- ments or who continue to suffer from significant stress incontinence after their bladder hyperactivity has been controlled. In this way, when surgery is needed, patients are often more educated regarding surgical outcomes, realizing that their overactive bladder may persist postoperatively. Persistent or worsening urinary frequency and urge incontinence following successful surgical management of stress incontinence can be debilitating to patients and, in some cases, difficult to troubleshoot and manage. Even patients who report mild overactive bladder symptoms in combination with significant stress incontinence can greatly benefit from a combination of behavioral therapy, pelvic floor muscle re-education, and antimuscarinic therapy before proceeding with surgery. Some experts believe that the chronology in terms of which symptom came first (stress vs urge) may affect therapeutic outcomes when treating mixed urinary incontinence. In a series of 50 patients, Scotti and colleagues23 reported better surgical outcomes following Burch colposuspension in women in whom stress incontinence predated urge leakage. More recently, Khullar Main Points • Treatment of mixed incontinence is a therapeutic challenge, and debate continues as to whether patients are best managed initially with medication or surgery. The literature supports the efficacy of both antimuscarinic agents and surgery for the treatment of mixed incontinence, but patient selection likely influences therapeutic outcomes. • Stress incontinence results from urethral sphincter weakness, arising either from bladder neck hypermobility, intrinsic sphincter deficiency, or both. Urge incontinence with detrusor overactivity has been defined as a condition resulting from bladder instability demonstrated during urodynamics. • Satisfactory results have been reported with surgical management of mixed incontinence by addressing the bladder neck hypermobility and/or urethral sphincter deficiency. • Clinical experience and the literature support the efficacy of antimuscarinic agents for the treatment of urinary frequency and urge incontinence. The reported reduction in urge incontinence episodes with the newer anticholinergic agents ranges from 46% to 92%. Although less is known about the efficacy of these drugs in the treatment of mixed incontinence, it appears that a similar reduction in the number of leaking episodes is achieved. • The most important factors that influence the decision to recommend pharmacologic and behavioral therapy versus surgery when treating mixed urinary incontinence are the patient's dominating symptom and the severity of his or her overactive bladder. S24 VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY Antimuscarinic Therapy for Mixed Incontinence and colleagues24 found no difference in clinical outcomes in patients with mixed incontinence managed with tolterodine ER, 4 mg, regardless of which symptom (stress or urge) began first, implying that the etiology of urge incontinence in the mixed incontinence population does not influence response to anticholinergic therapy. A number of other factors may adversely affect response to pharmacologic and surgical therapy and should be considered. In these cases, we prefer to treat with nonsurgical therapy first to minimize the chance of persistent irritative symptoms postoperatively. Older patients with symptoms of long duration and those with significant functional impairment may not respond as well to treatment. Overactive bladder symptoms related to neurologic disease typically persist postoperatively and should be aggressively managed before recommending surgery. In contrast, patients with advanced pelvic floor weakness and those who cannot isolate their pelvic floor musculature may be less capable of resisting sudden episodes of urgency and may fare better with surgical intervention. The degree of bladder neck hypermobility does not necessarily predict a negative response to pharmacologic management of overactive bladder symptoms and does not influence the treatment algorithm. Likewise, the presence of a cystocele does not influence the effectiveness of pharmacologic therapy, so long as the patient can empty efficiently. Although unproven, a number of findings demonstrated during urodynamics may predict response to therapy. Large-volume incontinence associated with high pressure instability, lack of a pelvic floor guarding reflex, or contractions poorly perceived by the patient may be factors associated with poorer outcomes. Urge incontinence due to loss of bladder compliance or neurogenic bladder dysfunction should be expected to persist following surgery and is best managed initially with medication. Patients with mixed symptoms and significantly low Valsalva leak point pressures may be more likely to require successful management of their intrinsic sphincter deficiency in order to reach their treatment goals. 8. 9. 10. 11. Summary Evidence supports the efficacy of both antimuscarinic therapy and surgery for the treatment of mixed urinary incontinence. Patient selection bias influences outcomes and should be considered when interpreting the pharmacologic and surgical literature. Treatment should be tailored to the individual patient, taking into consideration a number of clinical and urodynamic factors. In select patients, the reduction in total (or mixed) incontinence episodes with antimuscarinic agents is similar to that achieved for urge incontinence. Prospective studies evaluating the efficacy of antimuscarinic agents in the entire spectrum of patients with mixed incontinence would be beneficial. 12. 13. 14. 15. 16. 17. 18. 19. References 1. 2. 3. 4. 5. 6. 7. Thom DH. Overactive bladder: epidemiology and impact on quality of life. Patient Care. 2000;6-14. Wagner TH, Hu TW. Economic costs of urinary incontinence in 1995. Urology. 1998;51:355-361. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997;50:90-96. Chancellor M, Freedman S, Mitcheson HD, et al. 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