Key Findings

A number of important findings emerged from this review.

Diagnosis

Clinical evaluation with validated tools for diagnosis of UI, its type, frequency, severity, and impact on quality of life informs nonsurgical treatment decisions.

Compared with diagnosis by patients’ symptom reports, multichannel urodynamics did not better predict which patients would benefit from nonsurgical treatments.

Measuring Treatment Success

Women with daily stress UI perceived important clinical benefit from reductions of approximately 50 percent in UI frequency, and important incremental clinical value from reductions of 75 percent and 90 to 100 percent.

Women reported improved quality of life and clinical success only when they experienced a greater than 70 percent reduction in UI episode frequency assessed by a voiding diary.

More than 60 percent of women with persistent urgency, stress, or mixed UI reported complete treatment satisfaction when they experienced more than 70 percent reduction of UI episodes. Validated tools have been used to assess minimum important differences in UI in women.

Validated tools have been used to assess threshold values of clinical importance for evaluating treatment success.

Pharmacological Treatments

All anticholinergic medications were more effective than placebo in achieving continence and improving UI, but the degree of benefit was low for all drugs, with fewer than 200 cases of continence attributable to treatment per 1,000 patients treated (absolute risk difference with placebo <20 percent).

Treatment benefits, including continence, were achieved with antimuscarinic drugs, including trospium, solifenacin, fesoterodine, tolterodine, and oxybutynin.

Drugs for urgency UI demonstrated similar effectiveness. Treatment discontinuation due to adverse effects was most common with oxybutynin and least common with solifenacin.

Pharmacological treatments for stress UI, including off-label use of low-dose topical estrogen formulations, may improve stress UI in postmenopausal women.

Duloxetine has an unfavorable balance between improvement in stress UI and treatment discontinuation due to adverse effects.

Compliance rates for prescription drugs are low; discontinuation due to side effects is common. Dry mouth, constipation, and blurred vision were among the most frequent adverse effects.

There is insufficient evidence of the long-term safety of pharmacological treatments.

Women with urgency UI whose prior treatments failed may benefit from solifenacin; however, poor responders would not benefit from increasing the dose of the drug.

Oxybutynin, trospium, and darifenacin improved UI in older women.

Nonpharmacological Treatments

Nonpharmacological treatments result in significant clinical benefit with a low risk of adverse effects. The magnitude of benefit is large, with more than 100 percent relative difference in continence rates. Women with stress UI can achieve continence performing PFMT. Continence rates are similar between those who undergo PFMT with and without biofeedback.

UI Diagnosis

Diagnosis of different types of UI in ambulatory care settings includes clinical history and evaluation, voiding diary, and validated scales. Urodynamic diagnosis is more invasive and not applicable to ambulatory settings. Although it more sensitively distinguishes detrusor overactivity, it did not better predict treatment benefits for patients undergoing nonsurgical UI treatments. Baseline urodynamic diagnosis did, however, better predict harms from surgery for women with refractory stress UI by identifying women with detrusor overactivity, which is associated with greater risk of postsurgical urgency UI. Diagnosis of pure urodynamic stress UI or detrusor overactivity can influence treatment decisions for women undergoing surgical treatments for urogenital prolapse or pelvic floor trauma.345,714 An ongoing trial conducted by the Urinary Incontinence Treatment Network will shed light on the association between utility of urodynamic testing and better prediction of outcomes of stress UI surgery.715

Previously published systematic reviews also demonstrated a weak association between self-reported UI symptoms and instrumental urodynamic findings.73,716 However, investigators still use urodynamic evaluation as a reference method. In contrast, guidelines recommend urodynamic evaluation as one component of the complex algorithm for women with pelvic floor dysfunction.10 Evaluations of women who report UI symptoms begin with physical examination and exclusion of several potential underlying conditions, including urinary tract infection, pelvic organ prolapse, poor bladder emptying, and post-void residual volume determination.69 Examination methods for urinary tract infection and pelvic organ prolapse have been addressed by previous reviews, and are beyond our scope.69,717 Measurement of PVR urine volume can be used to diagnose UI associated with poor bladder emptying. Some experts consider urinary catheterization the gold standard for measuring PVR.718 However, invasive urinary catheterization can be performed only in specialized care settings. Portable ultrasound is an accurate and feasible method for estimating PVR urine volume in ambulatory care settings.719,720 Ultrasound is preferable to catheterization when decreased bladder emptying is suspected.69 Vaginal and transrectal ultrasound accurately diagnosed urodynamic stress UI.291,292 Other instrumental radiological and magnetic resonance imaging is useful for diagnosis of anatomical pelvic pathology including fibroids, ovarian and uterine tumors, foreign bodies, or diverticulum.10 Associations are unclear between the criteria for excessive bladder neck mobility identified via ultrasound or MRI and UI treatment outcomes.

Considering the multifactorial syndromatic nature of UI, any one instrument, symptom, or test cannot accurately diagnosis UI type. Clinicians utilize several aspects of patient history, pelvic exam, and other assorted factors to determine UI type and severity.

Diagnosis of Baseline Frequency, Severity, and Bothersomeness of UI

Urodynamic evaluations diagnose the presence of UI but not baseline severity, frequency, or bothersomeness of the condition, all of which help inform the best treatment options. Ambulatory care physicians may choose between several validated tools for diagnosing predominant stress or urgency UI and for judging treatment effectiveness. Treatment effectiveness for female UI should be assessed according to issues women value: 50 to 70 percent or greater reduction in UI episode frequency, meaningful changes in quality of life measures, and overall treatment satisfaction.721 Women do not consider small reductions in UI frequency or in urinary loss as treatment success, even though such reductions are statistically significant.295 Clinically important differences have been determined for several questionnaires and scales.259,264,296299 Many validated tools are available to monitor quality of life in women with different UI types. Several tools that define clinically important differences in scores can be used to assess treatment success in clinical settings.300302 All tools for assessing symptom bother have been validated. The Incontinence Severity Index,334,335 Patient Global Impression of Improvement and of Severity,331 Urogenital Distress Inventory,222,336,337 and Patient Perception of Bladder Condition333,338,339 have identified minimum thresholds levels for improvements of clinical importance in UI. Treatment success in clinical settings can be determined according to improvements that meet or exceed these threshold levels.

UI Treatment

Defining and Measuring Outcomes of Treatments for UI

Meaningful assessment of treatment outcomes depends on how those outcomes are defined. Market approval and coverage decisions have been made based on intermediate outcomes rather than on continence or on women’s treatment satisfaction. Despite intensive discussions about the importance of patient centered outcomes, the majority of drug studies aimed to detect statistical differences in the frequency of UI episodes. The most common outcome examined by RCTs was a reduction in UI episode frequency.115,305326 Previous reviews of drugs for overactive bladder also focused on a reduction in the frequency of UI episodes and the frequency of micturitions.112,722,723 The FDA reviews focused primarily on the same continuous reduction in UI episode frequency, and not on continence or self-reported treatment success and satisfaction.115,306,307,327330 In contrast, our review emphasized the role of clinical outcomes, including continence, quality of life, and adverse effects of treatment.

Treatments for UI

PFMT, bladder training, and electrical stimulation more often result in continence than does no active treatment. Weight loss and exercise improve UI in obese women. Long-term adherence to and benefits of these treatments are not clear, nor are specific characteristics of women associated with better benefits and compliance. The best time to start pelvic muscle floor exercise and bladder training in relation to either menopause or the onset of UI is not clear. Adverse effects with nonpharmacological treatments were uncommon and the magnitude of effect was large.

All drugs for overactive bladder, when compared to placebo, demonstrated better rates of continence and improved UI. All drugs offered similar benefits, but treatment discontinuation due to adverse effects was most common with oxybutynin. Informed decisions, therefore, should consider the drugs’ adverse effects. RCTs rarely reported long-term comparative drug safety. In contrast with RCTs, continuous prescription-event monitoring as a part of postmarketing surveillance has provided valuable information about unfavorable long-term safety of tolterodine, which posed significantly higher risk of hallucinations than 10 drugs of other therapeutic classes.724 Postmarketing surveillance may provide data on long-term safety of UI drugs when combined with other medications for comorbidities. RCTs did not examine the role of concurrent treatments. For instance, limited information exists on the cognitive effects of drugs in older adults. Older adults had lower risk of depression with tolterodine ER than with oxybutynin IR group (HR, 0.865; 95 percent CI, 0.78 to 0.95).725 The relative risks of ventricular arrhythmias (adjusted RR 5.5, 95 percent CI, 1.3 to 22.3) or sudden death (adjusted RR 21.5, 95 percent CI, 5.2 to 88.3) were very high in elderly patients using UI medications in combination with antihistamine/cytochrome inhibitors.726

Only a few RCTs examined the comparative effectiveness of drugs and nonpharmacological treatments. Direct evidence was insufficient to draw valid conclusions about the benefits of combined modalities compared to monotherapy. Existing guidelines recommend PFMT combined with stress and bladder training as the first treatment choice for women with urgency UI but do not provide evidence-based recommendations about combined therapy.118 Other guidelines list many treatment options, including electrical intravaginal stimulation and percutaneous tibial nerve stimulation, but do not provide evidence-based recommendations about first therapy options or combined modalities. Existing guidelines may provide individualized treatment recommendations based on age or predominant type of UI, but they do not address baseline severity of UI or comorbidities.

Meanwhile, very few studies provided evidence for individualized treatment decisions. Evidence of aggregate treatment effects may not be applicable to individuals with specific characteristics.727 An average treatment effect in a clinically diverse population may not reflect the actual effect for a specific group.728 Yet, few existing studies examined the role of clinical predictors of treatment failure and success in patient subpopulations.729 Patient comorbidity and baseline severity of UI were associated with differences in treatment benefits. The direction and magnitude of the association varied. Benefits from solifenacin and fesoterodine were greater in those with more than two or three daily episodes of UI; trospium was not better than placebo in those with frequent baseline UI (>5 episodes/day). We are not certain which factors are associated with differences in harms.

Very limited evidence exists for long-term benefits and harms from drugs and nonpharmacological treatments for UI. The bulk of RCTs reported clinical outcomes at 12 to 24 weeks of treatment. A few nonrandomized studies and long-term followup RCTs reported rates of benefits and harms with active treatments, but did not include control comparisons. Such uncontrolled crude rates cannot provide valid information about long-term effects.

Very few studies addressed adherence to prescribed nonpharmacological and drug regimens. Observational economic evaluations730732 demonstrated greater absolute rates of treatment discontinuation due to adverse effects or treatment failure than have been demonstrated in RCTs. Long-term adherence to drug treatment for overactive bladder was as low as 13 percent.725 Among possible explanatory factors for poor adherence is that polypharmacy or previous use of the drugs for urinary tract infections was associated with adherence to drugs for overactive bladder in California Medicaid program beneficiaries.731

Cost-effectiveness analyses730,733736 were beyond the scope of our review. Our review provides valid information about treatment benefits according to patient-centered outcomes including continence, and about adverse effects that can be used for cost-effectiveness analyses.

The quality of most drug RCTs was good. The majority of drug studies were double blind with adequate randomization, clear reporting of planned intention to treat analysis, and adequate allocation concealment. Benefits and harms with drugs did not differ by individual quality criteria. We concluded low risk of bias in drug studies.

The quality of most nonpharmacological RCTs was good. Baseline data demonstrated adequacy of randomization in the majority of RCTs. Double or single blinding was reported in approximately half of RCTs. Quality of the studies, including intention to treat principle and adequacy of allocation concealment, did not demonstrate significant modification of the association between treatments and patient outcomes. We concluded moderate risk of bias in nonpharmacological studies.

Our review has limitations. We restricted our review to English language studies published in journals, presented at scientific meetings, reviewed by the FDA,737 or reported on the ClinicalTrials.gov Web site. Even after such an exhaustive review of evidence, we do not know how many studies we missed in our review. We did not review regulatory documents or grant databases from other countries. Evidence was insufficient for individualized treatment recommendations by age, race, comorbidity, and baseline UI. Evidence specific to women whose prior treatments had failed was also insufficient. However, previous research has demonstrated that women with stress UI whose conservative treatments failed may benefit from tension-free vaginal tape procedure.738 For women with urgency UI whose conservative treatments failed, percutaneous tibial nerve stimulation,739 sacral neuromodulation,740 and botulinum toxin injections741 may be of benefit. We were unable to explain the substantial variability in outcome rates with placebo treatments. Future large, well-designed head-to-head randomized trials may conclude superior efficacy of combined treatment modalities with nonsurgical treatments.

Our findings can inform clinicians’ evidence-based recommendations for UI diagnosis and management (Tables 17 and 18). Ambulatory care physicians may arrive at treatment decisions and monitor treatment effectiveness by diagnosing predominant stress or urgency UI and evaluating the frequency, severity, and quality of life at baseline and with treatment. Nonpharmacological treatments offer a better balance between benefits and adverse effects than do drugs. First treatment choice, therefore, might be based on known benefits and harms with nonpharmacological and drug treatments, along with patient preference. Evidence was insufficient to conclude better benefits from nonpharmacological treatments combined with drugs. Women’s opinions about treatment success should be considered before combining nonpharmacological treatments with available drugs or increasing the doses of the drugs.

Table 17. Conclusions about diagnosis of UI in women.

Table 17

Conclusions about diagnosis of UI in women.

Table 18. Conclusions about management of UI in women.

Table 18

Conclusions about management of UI in women.

Future Research

Our report points to areas for future research (Table 19). First, future research should clarify which female characteristics are associated with greater benefits and lower harms of treatments and better treatment adherence. Second, treatment success should be assessed with outcomes centered on women, including long-term continence, clinically important reduction in UI episodes, and improvement in scales of severity and quality of life. More work is needed on how physiological measures correspond with symptoms. Third, all harms should be analyzed, regardless of investigator judgment about possible association with tested treatments. Fourth, better drugs are needed. Few of the currently used medications are sustained for even a year, and fewer still are very effective. Fifth, nonsurgical treatments for predominant stress UI are limited to PFMT, with very few ongoing studies of bulking agents and devices. One issue with PFMT is sustaining it. Programs should explore how to extend the period of adherence. Future research should explore new treatment options for women with stress UI and should also address the preventive potential of various nonpharmacological treatments, including PFMT, bladder training, and electrical stimulation, for premenopausal women. The results from all studies, including 25 closed and 124 ongoing registered studies, should be made available for future reviews of the evidence.

Table 19. Future research recommendations.

Table 19

Future research recommendations.