Executive Summary

Pharmacologic treatment

Content of the literature. We identified 13 randomized controlled trials (RCTs) of oxybutynin for treatment of OAB. A total of 22 study arms compared oxybutynin at varied doses, formulations, and intervals. These studies included five placebo arms. Most participants were recruited from specialty populations with seven studies performed in the United States,^82–88 three in Europe,^89–91 and one each in Japan,⁹² Taiwan,⁹³ and South Korea.⁹⁴ These studies included a total of 2,575 women in treatment arms, and 383 women in the placebo arms.

For tolterodine there were 19 RCTs, including 29 drug arms and 13 placebo arms. Most were multinational studies conducted at centers in Europe, the United States, Australia, and Asia. A total of 6,564 women were in the treatment arms, with 3,109 women in the placebo arms.

Two RCTs compared fesoterodine at 4 and 8 mg to placebo for reducing symptoms of OAB and met criteria for inclusion in the systematic review.^{95, 96} These studies included a total of 1,017 women in the treatment arms, and a total of 518 women in the placebo arms.

Three RCTs investigated solifenacin compared to placebo for reducing symptoms of OAB.^97–99 These studies included a total of 1,541 women in the solifenacin treatment arms, and a total of 638 women in the placebo arms.

Four RCTs provided data on the effectiveness of darifenacin.^{82, 100–102} These four studies included at total of 690 women in the darifenacin treatment arms and a total of 304 women in the placebo arms.

Five RCTs evaluated trospium for reduction of symptoms of OAB. Four trials compared trospium to placebo, and one compared trospium to oxybutynin. Four were conducted in the United States,^103–106 and the fifth at multiple centers in Europe and Asia.⁹⁰ These studies included a total of 1,309 women in the trospium treatment arms, and a total of 1,130 women in the placebo arms.^103–106

Three studies assessed the role of oral estrogen therapy in different doses and formulations in the alleviation of OAB symptoms.^107–109 All studies were performed in Europe and Scandinavia with a total of 514 women. Two were RCTs and one was a prospective cohort. After review and analysis of all 110 studies, of which four were good quality, 75 fair and 31 poor, including 68 RCTs, the strength of the evidence for managing OAB with pharmacologic treatment is weak to moderate for short term outcomes and weak for long term outcomes and harms.

Outcomes of treatment. All pharmacologic treatments were effective at improving one or more OAB symptoms when compared to placebo. Reductions ranged from 0.9 to 4.6 in incontinence episodes per day across all drug treatments and from 0.7 to 4.2 in voids per day. Study by study, extended release formulations achieved modestly better effects than immediate release, statistical significance varied. No one drug was definitively superior to others by preponderance of evidence, including more recently approved drugs. As estimated by meta-analysis, extended release forms (taken once a day) reduce UUI by 1.78 (95 percent CI: 1.61, 1.94) episodes per day, and voids by 2.24 (95 percent CI: 2.03, 2.46) per day. Immediate release forms (taken twice or more a day) reduce UUI episodes by 1.46 (95 percent CI: 1.28, 1.64) per day, and voids by 2.17 (95 percent CI: 1.81, 2.54) per day. Of note, placebo reduces UUI episodes by 1.08 (95 percent CI: 0.86, 1.30), and voids by 1.48 (95 percent CI: 1.19, 1.71) per day. Even in the context of small to moderate affect on symptoms, pharmacologic treatments were generally associated with increased quality of life and reductions in measures of impact or distress, compared to baseline and to placebo.

Table 1 below provides estimates of treatment effects for pharmacologic treatments represented by more than one trial arm. Some drugs and doses of drugs are not reported because the publications with trial arms for that treatment did not provide sufficient information to estimate variance in meta-analysis models.

Since baseline episodes of UUI per day ranged from 1.6 to 5.3, and voids per day from 7.2 to 13.7, these reductions (Table 1) reflect modest margins of benefit from baseline above placebo. Data was not consistently provided across studies to estimate the proportion of women who became symptom free.

Procedural and surgical treatment

Content of the literature. We identified 18 studies about surgical treatments and procedures for OAB. Eleven were of sacral neuromodulation, one of peripheral neuromodulation, and one of electromagnetic therapy. Three studied bladder instillation or injection of drugs; one was on bladder distention; and one about bladder transection. This literature included 13 case series studies: nine prospective^110–118 and three retrospective.^119–121

One study had both retrospective and prospective components.¹²² Given consideration of 18 studies, of which 11 were fair quality and seven poor, including five RCTs, the strength of the evidence for managing OAB with procedural and surgical treatment is weak for all aspects of understanding outcomes of care. One study was a prospective cohort that compared outcomes among participants receiving sacral neuromodulation to participants who had lead placement without activation of electrical stimulation.¹²³ Four studies were RCTs: one looked at sacral neuromodulation versus medical therapy,¹²⁴ one evaluated transcutaneous electromagnetic stimulation versus sham,¹²⁵ and two evaluated instillation of a drug into the bladder versus placebo – one using oxybutynin¹²⁶ and one using resiniferatoxin.¹²⁷

Outcomes of treatment. Among the trials of procedures and surgery, one study demonstrated a statistically significant benefit of sacral neuromodulation over usual care for the reduction of episodes of incontinence per day (average reduction of 7.1 compared to 2.1 increase among subjects who had failed medical management).¹²⁴ One trial demonstrated benefit of instillation of oxybutynin compared to sterile water in the reduction of voids per day (average reduction of 6.8 compared to 2.4)¹²⁶ and another reported benefits from botulinum toxin treatment which is compatible with the findings of a recent Cochrane Collaboration literature review and meta-analysis.¹²⁸

Behavioral interventions

Content of the literature. We identified nine studies that included only behavioral approaches; no two studies compared the same set of approaches. They included assessment of bladder training, multicomponent behavioral training, with or without biofeedback, pelvic muscle exercises or training, vaginal electrical stimulation, and caffeine reduction. The literature base included three retrospective case series.^129–131 All three were conducted in community-based clinical settings.

One prospective cohort study compared three approaches to providing bladder training: self-administered, coaching, and cognitive strategies.¹³² Five studies were RCTs. One compared bladder training to a “control” condition.¹³³ One compared bladder training to pelvic muscle exercises.¹³⁴ One included three arms: pelvic floor muscle training, pelvic floor muscle training assisted with biofeedback, and vaginal electrical stimulation.⁹³ Another compared three different approaches to multicomponent behavioral training: biofeedback, verbal feedback and self-administered.¹³⁵ A last study compared bladder training to bladder training with caffeine reduction.¹³⁶ After review and analysis of 29 studies, of which 14 were fair quality and 15 poor, including 17 RCTs, the strength of the evidence for managing OAB with behavioral approaches treatment is moderate to weak for short term outcomes and weak for long term outcomes and harms.

Outcomes of treatment. No two studies could be combined to produce summary data. Overall, behavioral approaches can be effective in reducing episodes of incontinence and daily voids. Multicomponent approaches are most effective, and they perform relatively equivalently to pharmacologic treatment. Generally speaking, improvements were modest, with decreases in incontinence episodes of up to 1.9 per day, and reductions in voids per day of up to about four. The addition of caffeine reduction reduced frequency, but made no difference in reduction of incontinence episodes. There is no evidence that behavioral approaches enhance the effectiveness of pharmacologic therapy for reducing episodes of incontinence or voiding, although they may improve patient satisfaction and quality of life measures.

Complementary and alternative therapies

Content of the literature. We identified three studies that used complementary and alternative medicine therapies to treat OAB: a fair quality trial of acupuncture,¹³⁷ a fair quality trial of foot reflexology,¹³⁸ and a poor quality prospective case series of hypnotherapy.¹³⁹ There is weak to no evidence for complementary and alternative approaches to managing OAB.

Outcomes of treatment. The small trial of acupuncture has intriguing results related to decreased frequency of voiding and reduced symptoms of urgency which are associated with changes in cystometrics related to improved bladder capacity that are logical intermediates of the improvement in symptoms. Women felt they were improved as measured by scales that capture bother and quality of life. Evidence is insufficient to support definitive choice of acupuncture but offers preliminary information that promises modest improvements similar to those reported in many pharmacologic trials.

Reflexology is represented by a small trial with unmasking of participants that could have biased the results. No evidence supports choice of this modality. Likewise, hypnotherapy is not supported by the scant information provided by one case series with little detail, patient reported outcomes, or statistical assessment. Given the scope of placebo effects demonstrated in other well-conducted studies of OAB treatment, it is difficult to know whether to attribute any effect to hypnotherapy.

Conflict of interest. Changing trends in editorial standards have resulted in more complete reporting of funding source and author conflict of interest over the period in which the OAB literature was developing. Sources of funding were not reported for the majority of publications that appeared in the 1980s; and no publications in that decade reported on author conflict of interest. In the 1990s through the end of 2008, nine (56 percent) studies of procedural treatments (including sacral neuromodulation and bladder instillation or injection) reported source of funding, and six of the nine studies (67 percent) were industry sponsored. The other three were institutionally funded. Among studies of medications, 89 (77 percent) reported source of funding and among those, 82 (92 percent) were industry sponsored. Among studies that had a behavioral component, 13 (68 percent) reported on funding source and four had industry support. Author conflict of interest was poorly reported until the current decade, with fewer than half of all publications providing information. Within papers that did report conflict of interest, more than half of the authors (272 of 407) indicated that they had a financial relationship with one or more companies relevant to the research.

Comparisons between pharmacologic treatments

Content of the literature. Twelve RCTs included direct comparisons of pharmacologic approaches. Specific comparisons have been made in the literature for the following pairs of drugs to identify differences in reduction in urge urinary incontinence or voids per day:

• Oxybutynin ER to Tolterodine ER⁸⁴
• Oxybutynin ER to Tolterodine IR⁸³
• Oxybutynin IR to Tolterodine IR^{89, 91, 94}
• Oxybutynin IR to Darifenacin⁸²
• Oxybutynin IR to Trospium IR⁹⁰
• Oxybutynin TDS to Tolterodine ER⁸⁸
• Tolterodine ER to Tolterodine IR^{140, 141}
• Tolterodine ER to Solifenacin⁹⁹
• Tolterodine ER to Fesoterodine⁹⁶
• Tolterodine IR to Solifenacin⁹⁷

Outcomes of treatment. In the majority of comparisons, neither drug was reported more effective at reducing either incontinence episodes or voids per day with a few exceptions. Both oxybutynin and tolterodine in their extended release forms demonstrated superiority in reducing urge incontinence episodes over tolterodine immediate release.^{83, 140, 142} Oxybutynin extended release was more effective at reducing voids per day than tolterodine in immediate⁸³ or extended release formulations.⁸⁴

Comparisons between procedural and pharmaceutical treatments

Content of the literature. One RCT compared sacral neuromodulation to medical therapy. In this study, 98 participants were randomized to immediate sacral nerve stimulation or delayed sacral nerve stimulation. The delay group continued unspecified medical management for a six month period before having the procedure.

Outcomes of treatment. This study, which randomized after successful test stimulation, found a reduction in daily urge incontinence episodes from 9.7 to 2.6 in the sacral neuromodulation group, compared to an increase of 9.3 to 11.3 in the medical management group at 6 months (p<0.01) for patients with refractory OAB.124 At 18 months, 76 percent of participants receiving sacral neuromodulation reported that they were completely dry or had experienced a reduction in symptoms of 50 percent or greater. Note that the comparison is not ideal, as subjects continuing to receive medical therapy had already failed medical management.

Comparisons between behavioral and pharmacologic treatments

Content of the literature. Seven studies (nine papers) included behavioral and pharmacologic arms in direct comparisons.^{93, 143–150} This literature included one prospective cohort study,¹⁴⁷ and six RCTs.^{93, 143–146, 148–150}

The behavioral approaches examined included bladder training,^{151, 146–150} multicomponent behavioral approaches,^143–145 and electrical stimulation.⁹³

One study reported significantly greater reductions in incontinence episodes with multicomponent behavioral modification compared to oxybutynin,¹⁴³ but no studies found a difference in reductions in voids per day. In the same study that found greater reductions in incontinence with behavioral treatment, participants reported higher satisfaction with behavioral compared to pharmacologic interventions.

Comparison of combined behavioral and pharmacologic treatment to pharmacologic alone

Content of the literature. Six studies examined the effect of adding a behavioral intervention to drug compared to drug alone.^150–155 In all but one study, the drug was tolterodine.The literature included five RCTs^{150–152, 154, 155} and one randomized open-label trial.¹⁵³

Outcomes of treatment. No added benefit for reducing incontinence episodes or voids per day was found by adding behavioral treatments to pharmacologic approaches for reduction in incontinence. Two studies associated the addition of behavioral modification with reductions in voids per day, but two reported no difference.