Evaluating the Effectiveness of Therapies for Urinary Incontinence

Abstract

Subjective criteria, behavioral/emotional factors, and quality-of-life assessments are necessary components in evaluating incontinence therapies. Behavioral regimens often yield a response that lasts beyond the end of therapy and, when combined with pharmacologic therapy, are likely to extend duration of response. In addition to objective efficacy criteria, a number of instruments evaluate quality-of-life issues. Shortened forms of these will likely overcome limitations on patient compliance and completion. New instruments continue to be developed, but until one or more are universally accepted, variations in reported outcomes can be expected.

To effectively evaluate interventions for urinary incontinence, it is crucial to consider both subjective and objective criteria that may provide insight into its impact on quality of life. Given the multiplicity of interventions (pharmacologic, behavioral, surgical) now available, these measures should be sufficiently malleable to assess the patient’s symptomatic distress independently of the type of intervention (ie, to be disease-specific, not intervention-specific). Clinical experience has shown the importance of including subjective measures in the assessment of incontinence. One of the most important lessons this affords is that symptomatic distress has a high degree of interindividual variability and is not necessarily predictable on the basis of any specific patient factor, even degree of incontinence. Voiding diary data provide significant insight into a patient’s behavioral response to the voiding dysfunction and demonstrate that a behavioral/emotional component exists. Critical quantification of these responses to the urgency/frequency syndrome and other types of voiding dysfunction is an absolute necessity in the analysis of baseline symptomatic distress and also in assessing the change in distress and in quality of life in response to intervention.

BFLUTS

Bristol Female Lower Urinary Tract Symptom

IIQ

Incontinence Impact Questionnaire

LUTS

Lower urinary tract symptoms

OAB

Overactive bladder

SF-36

Short Form-36 Item Health Survey

SUI

Stress urinary incontinence

UDI

Urogenital Distress Inventory

UUI

Urge urinary incontinece

Evaluating the Outcomes of Incontinence Therapy

Owing to the subjective, symptomatic nature of the quality-of-life impact associated with voiding dysfunction and incontinence, there is no gold standard for outcomes assessment. Patients’ perceptions of their condition, physicians’ analyses of therapy (with or without investigator bias), and the real probability of incomplete symptomatic response to intervention contribute to the difficulty of evaluating the success of any therapy. This adds to the complexity of the reporting and evaluation of incontinence outcomes data. It is no longer possible to rely only on nonspecific diary or pad test data, without a quality-of-life assessment, for clinical outcomes reporting. Even regulatory agencies have become much more focused on requiring use of quality-of-life instruments as an adjunct to objective results reporting.

One of the major pitfalls in outcomes reporting is that, other than a cure, there is no one accepted standard definition for the results of incontinence therapy that is easily replicated. This lack of an absolute measure has required the creation of multiple instruments and methods for grading symptomatic response in an effort to assess therapeutic impact and symptomatic change. In addition, a recognized significant placebo effect occurs in as many as 30% to 40% of patients in randomized studies of the treatment of voiding dysfunction and overactive bladder (OAB).^1–3 This has been attributed to the strong behavioral component in voiding dysfunction. It has also been attributed to the putative benefit of increasing patients’ awareness of this dysfunction by using outcomes measures such as voiding diaries, as well as to intense interaction with the monitoring personnel carrying out a study.

Thus, it is necessary to demonstrate that a drug and/or other treatment effect exceeds the placebo effect. If one third of patients can be expected to show improvement with placebo, then much larger numbers of patients must be included in studies of voiding dysfunction to demonstrate effectiveness and improve the power of statistical analysis, especially if the effect is only marginal. For instance, in recent community-use studies of tolterodine, substantial numbers of patients were included to demonstrate a statistically significant treatment effect over placebo.³

Study Design

Because of the variety of instruments for evaluating outcomes of incontinence therapy, there is some question about the validity or reproducibility of individual measures. That is certainly the case for some of the quality-of-life instruments now available, as well as for some of the disease-specific instruments used to monitor treatment results.

Additionally, U.S. Food and Drug Administration (FDA) requirements drive the design of studies, so the pharmaceutical industry has had to conduct well-designed studies that include placebo control, blinding, randomization with patient stratification, crossover design when applicable, and a washout period to eliminate prior drug effect. The washout period has proven particularly challenging, because patients who are satisfied with anticholinergics are unlikely to stop their current therapy to return to their baseline states. This can be emotionally distressing and complicates induction studies involving patients who have responded to prior medication.

Although many studies look at placebo control as the gold standard, use of active comparators—comparing an established drug therapy to the study drug—has gained popularity. For example, several studies are now using active comparator drugs to study medications undergoing FDA trials. The goals of the study or the outcomes sought are often determined by the agent chosen for comparison.

End points of interest include efficacy and tolerability. The parameters for efficacy are magnitude of effect and longevity of response. The latter—especially in pharmacologic studies—is arbitrarily limited by the duration of the study. A decrease in response is expected over time if efficacious drug ingestion is terminated.

This is not true for behavioral management strategies. When these are used, patients receive active education in physiotherapy and then graduate from that one-on-one encounter with a nurse to a more open, self-motivated regimen of activity. This type of intervention has the potential to increase the longevity of the response beyond the end of treatment. When drug therapy and behavioral modification are combined (either formally or due to the requirements of study design, eg, diary recording), longevity of response needs to be expressed with regard to the time of the last behavioral treatment.

Several authors have evaluated the response of OAB symptoms either to behavioral therapy alone (biofeedback, behavioral modification) or to anticholinergic medications and placebo. Fantl found that only 15% of patients had complete symptomatic resolution with biofeedback alone but that 50% experienced a 50% to 75% reduction in overall symptom severity.⁴ Burgio found that behavioral modification was superior to drug therapy, with an 81% reduction in urge incontinence episodes in patients with OAB, as opposed to approximately 50% with anticholinergic medications.⁵ A further benefit to combination therapy with drugs and behavioral modification has been demonstrated in older patients in a controlled crossover study.⁶

Efficacy Criteria and Outcomes Evaluation Instruments

There are a number of criteria for assessing the efficacy of interventions for incontinence. Physical examination, the primary modality for demonstrating the presence of incontinence, is an objective gold standard. Pad tests and urodynamic evaluation are other objective criteria for assessing the presence, and possibly the magnitude, of incontinence. Urodynamics is somewhat problematic as an independent criterion, for two reasons. First, some patients who are symptomatically cured still experience incontinence on urodynamic testing. Second, urodynamics is a demanding procedure, and many researchers do not include this modality in their clinical studies. However, it remains the only functional evaluation of bladder and urethral activity that can segregate detrusor and urethral contributions to incontinence and voiding dysfunction.

In addition to these objective criteria, there are quality-of-life instruments, including generic instruments such as the SF-36, which assesses global quality-of-life issues. There are also disease-specific measurements, which include symptoms, and symptom-specific measurements, which evaluate factors such as sexual dysfunction and nocturia. Finally, voiding diaries can present data useful for definition of disease, symptom presence, perceived severity, and associated behaviors. The voiding diary also represents a simple but profound counseling tool for patient education.

There are multiple derivative instruments for assessing female lower urinary tract symptoms (LUTS) (Table 1).⁷ At issue is whether any of these is ideal. The ones most commonly encountered are the various derivatives of the Urogenital Distress Inventory (UDI) and Incontinence Impact Questionnaire (IIQ), which are used together.^8,9 There is also the Gaudenz score, a German construct that is commonly used in Europe and has only recently been validated in English.^10,11 European investigators currently believe this to be potentially the most useful tool. In England, Abrams’ group advocates the Bristol Female Lower Urinary Tract Symptom (BFLUTS) as the gold standard for the evaluation of symptomatic response.^12,13 Currently, the Bristol group and others are looking at a shorter form of this instrument, which, like all of these derivative instruments, is quite long. The ideal instrument would, like the AUA-7 score for incontinence, allow the best assessment of therapy with the shortest form possible. Length and ease of use clearly influence patient compliance and completion of methodologic instruments.

Table 1.

Female Lower Urinary Tract Symptom Questionnaires

Name	Purpose	Description
Detrusor Instability Score (DIS)14	Discriminate between stress and	10 items
	urge incontinence
Gaudenz Incontinence Questionnaire10,11	Discriminate between stress and	Original German version has 26 items,
	urge incontinence	stress and urge subscales; English
		version used in Japan has 15 items.
Stress Incontinence Questionnaire15 (SIQ)	Specific for SUI	18 items
		4 subscales for types of activity
		causing leak
Severity Index (Sandvik)16	Severity of stress and urge incontinence	2 items (amount, frequency)
Symptom Severity Index	Measures severity and effect of SUI	Severity Index: 5 items
and Symptom Impact Index17		Impact Index: 3 items
Bristol Female Lower Urinary Tract Symptom	Severity, impact, QOL	33 items, 4 domains
Questionnaire (BFLUTS)12,13		Many items have a bother component,
		scored separately
Incontinence Impact Questionnaire (IIQ)	Impact of and patient response	IIQ: 30 items, 6 subscales
and Urogenital Distress Inventory (UDI)8,9	to incontinence	UDI: 19 items, 3 subscales
Short versions		IIQ-7: 7 items, 4 subscales
		UDI-6: 6 items, 3 subscales
Urge-specific forms		U-IIQ: 30 items , six domains
		U-UDI: 9 items , single domain
Interstitial Cystitis Severity Index (ICSI)	Severity and impact of interstitial	Paired indices, 4 items each
and Interstitial Cystitis Problem Index (ICPI)18	cystitis symptoms in both sexes
Incontinence Quality-of-Life Measure (I-QOL)19	QOL specific for incontinence	22 items
Urge Impact Score	Older men and women with	24 items
(URIS-24)20	urge incontinence
York Incontinence Perception Scale (YIPS)21	Impact of incontinence	8 items
Kings Health Questionnaire22	QOL specific for incontinence	21 items
		8 domains

QOL,quality of life; SUI, stress urinary incontinence.

The rest of this section reviews the specifics of the scores developed for voiding dysfunction in women. All can be self-administered. The primary aspects assessed include differentiation of stress urinary incontinence (SUI) from urge urinary incontinence (UUI), symptom severity, impact of symptoms on activity, and quality-of-life issues.

Detrusor Instability Score. The Detrusor Instability Score (DIS), first described in 1982, is designed as a diagnostic tool to discriminate between SUI and UUI. Ten closed questions, scored from 0 to 2, determine the extent of instability symptoms. Low scores are consistent with pure SUI.

Gaudenz Incontinence Questionnaire. Initial studies demonstrated high validity. A template is required to score the 26 items into separate stress and urge subscores. An English-language variation of the Gaudenz Incontinence Questionnaire comprising 15 items has been used in Japan and is undergoing further validation. Good correlation has been noted between questionnaire score and objective testing criteria.

Visual Analog Scales. Several studies have assessed the accuracy of the Visual Analog Scales (VAS) in the documentation of incontinence. Different authors have achieved varying levels of success with this instrument.

The Stress Incontinence Questionnaire. The Stress Incontinence Questionnaire (SIQ) has been used to determine whether specific activities women routinely perform that result in SUI have diagnostic value. Subjects use a four-point scale to note urinary leakage when performing 18 specific maneuvers. Complex statistical analysis identified four subscales, or factors, designated active, passive, planned, and unplanned maneuvers.

The Severity Index (Sandvik). This questionnaire, a tool for prevalence data collection, determines the extent to which women are bothered by incontinence. It consists of two questions: one asks about frequency of UI, and the second assesses the amount of leakage per urinary incontinence event. The numerical values, 1 to 4 for frequency and 1 to 3 for amount, are multiplied to give a score from 1 to 12. The updated version includes a “very severe” category, which identifies a subgroup of older women in an epidemiologic study.

The Symptom Severity Index and the Symptom Impact Index for Stress Incontinence. These paired indices are specific for SUI, dividing “severity” and “impact” into two separate scores. Eight items make up the two indices; there is also a question on sexual activity that does not contribute to the scores. The number of responses differs for the questions in each index, but each item is scaled from 0 to 4. Scoring requires familiarity with the instrument.

The Bristol Female Lower Urinary Tract Symptoms Questionnaire. The BFLUTS questionnaire covers 4 domains—incontinence severity, associated symptoms, quality of life, and sexual function—in 33 questions. Many of the questions have an additional component assessing level of bother associated with incontinence. All voiding diary parameters except daytime frequency correlate well with BFLUTS scores. This subjective assessment of the degree of incontinence correlates less well with pad test results.

The Incontinence Impact Questionnaire and the Urogenital Distress Inventory. This paired symptom questionnaire measures the quality-of-life impact and level of distress of voiding dysfunction in women. Several variations of these two products include short forms and more specific forms. The 7-item IIQ-7 retains the four subscales. The UDI-6 was constructed by taking 2 items from each of the 3 original subscales. The original IIQ and UDI have been adapted to be more specific for the urge component of incontinence. The Urge-IIQ (U-IIQ) contains 30 items, with subscales for travel, activities, feelings, physical activities, relationships, and sexual function. The Urge-UDI (U-UDI) has nine items, some of which have an associated bother question.

The Interstitial Cystitis Symptom Index and the Interstitial Cystitis Problem Index. The Interstitial Cystitis Symptom Index (ICSI) and the Interstitial Cystitis Problem Index (ICPI), each composed of four items, resulted from extensive analysis of a 23-item index administered to interstitial cystitis (IC) patients. Data are presented in graphic form. The four items in each index compare favorably with the original 23 items in their ability to discriminate between IC patients and controls.

Incontinence Quality-of-Life Measure. This tool is specific for urinary incontinence of all types in both sexes. Twenty-eight items are included in the Incontinence Quality-of-Life Measure (I-QOL). The index uses a four-point scale, with lower values given for negative impact on quality of life.

Urge Impact Score. This 24-item quality-of-life measure is useful for older persons with urge incontinence. The original 32-item Urge Impact Score (URIS) questionnaire was developed from comprehensive interviews with 21 older men and women with urge incontinence. The shorter URIS-24 is a well-constructed tool with a defined target population of older adults.

York Incontinence Perception Scale. A short index of 8 items, the York Incontinence Perception Scale (YIPS) measures the impact of incontinence in women. A 7-point numeric scale is used for responses to all questions. Psychometric techniques were used to select the items.

King’s Health Questionnaire. The King’s Health Questionnaire (KHQ) is a 21-item quality of life index specific both for women and for urinary incontinence. The final version of 21 items uses a 4-point scale and contains six domains. Increasing scores reflect worsening quality of life. Symptom severity is scored separately.

General health questionnaires. Several generic quality of life measures have been used to evaluate LUTS in women. The disease-specific questionnaires will likely prove more sensitive tools for incontinence and replace the general questionnaires.

Short Form-36 Item Health Survey. A 36-item health survey questionnaire developed from its 108-item parent, the Short Form-36 Item Health Survey (SF-36) measures 8 domains: limitations in physical activity, limitations in social activity, limitations in usual role activities secondary to health and emotional problems (two domains), pain, mental health, energy, and perception of health.²³

Nottingham Health Profile Questionnaire. Used extensively in Great Britain and Sweden, the Nottingham Health Profile Questionnaire measures six domains that are similar to those used in the SF-36.²⁴

Sickness Impact Profile. A general health status measure, the Sickness Impact Profile comprises 136 items in 12 categories.

Other Methods of Assessment of Safety and Tolerability

Visual analog scales used to assess voiding dysfunction have been adopted from the pain management literature and are a validated testing methodology. These scales are straightforward and easy for patients to understand, and provide statistically sound data. Particular symptoms can be queried for and assessed using visual analog scales before and after intervention to determine efficacy or lack thereof. Recent studies have used this technique to assess specific patient symptom types. The Ditropan XL Long Term Community Use Study specifically assessed general health and distress, sleep impact (enuresis and nocturia), and incontinence impact on quality of life using this type of scale/response system.²⁵ The clearly discernible results data provided very easy analysis of post-therapy results. The IIQ was also used in this study to analyze the impact of incontinence and therapy on overall quality of life and provided similarly convenient data.

A notable facet of this study, as demonstrated by the VAS methodology, was detection of a phenomenon of habituation to certain side effects on evaluation of scale results. Anticholinergic side effects were stratified, including those that resulted in discontinuance of therapy, from both an immediate and a long-term perspective. These data showed that discontinuation of therapy due to an anticholinergic side effect tended to occur early (within the first 3 months of therapy initiation); very few patients dropped out late in therapy. This suggests that patients become inured to the adverse effects, which become less symptomatically significant for the individual.

The Likert scale is much more of a formalized grading scale, utilizing analog data reporting in quintile distributions. With this technique, a patient and/or investigator ranks the symptom of interest in terms of the response to treatment and/or the significance of the tolerability issue with regard to a specific adverse event. The World Health Organization (WHO) has a similar recommended ranking system (using quartiles), and recent FDA criteria suggest adding this type of analysis in pharmacologic protocol development. The Likert scale is considered a more patient-oriented approach, whereas the WHO classification is usually administered and completed by the investigator or designee. Both scales are straightforward and provide a way to stratify adverse event data by degree and severity for ease of reporting.

Summation scores provide a simple, inexpensive method for both the subjective and objective assessment of incontinence. Groutz and colleagues used three measures of incontinence—the 16-item questionnaire, a partially validated questionnaire; a 24-hour voiding diary; and a 24-hour pad test—which the patient completes prior to he postoperative visit.²⁶ Each of these 3 items received a score from 0 to 2. Patients were then categorized into one of four outcome groups based on cumulative score. Evaluation of these three items showed excellent correlation among them and with physician assessment for categorizing patients into outcome groups.

Conclusion

The methodology of symptomatic appraisal continues to develop. Until one or a few instruments are universally accepted, the variation in results reporting will continue. Reasonable instruments now exist for assessing disease-specific quality-of-life disruption and efficacy of intervention. These most assuredly should be presented in combination with objective testing results reporting (pad testing, physical examination, urodynamic evaluation) to provide the most complete assessment outcomes for voiding dysfunction interventions.

The recent development of summation scores using voiding diaries, the pad test, and questionnaires have provided perhaps the best tool for measuring the success of incontinence surgery. Further developments may lead to similar cumulative data assessment and reporting for other aspects of voiding dysfunction, including pharmacologic management of the overactive bladder.

Main Points.

• Both subjective and objective criteria may provide insight into the impact of incontinence on an individual’s quality of life; the former have a high degree of interindividual variability.

• Owing to the subjective and symptomatic nature of incontinence, there is no gold standard for outcomes assessment.

• The significant placebo effect in incontinence interventions studies, due largely to a behavioral component, requires inclusion of large numbers of patients to show effect beyond placebo.

• Unlike the effects of drug therapy, behavioral changes in response to behavior therapy persist past the interval of treatment.

• The wide variety of evaluation instruments leads to uncertainty regarding the validity or reproducibility of any individual measure and to a disparity in reported results.

Figure 1.

Obstructive symptoms in women.

Figure 2.

Irritative symptoms.

Figure 3.

Iatrogenic obstruction.

Appendix: Outcomes and Urodynamics

Other methods of outcomes assessment and quantification of disease severity exist for incontinence and voiding dysfunction, including: pad tests, diaries, physical examination, and urodynamics. Urodynamics represents the most advanced, yet invasive, method for objectifying bladder function and dysfunction. However, urodynamics should be utilized as a component of the global assessment of the voiding dysfunction patient (inclusive of the other included methods). Shown below are several examples of the utility of urodynamics for patient diagnosis and prognosis.

A 58-year-old woman presented with a many-year history of straining to void and sensation of incomplete bladder emptying. Multiple dilations and urethrotomies had been previously performed in an effort to ameliorate symptoms. Urodynamics were performed to elucidate complaints.

Urodynamics (Obstructive voiding)

Filling parameters are essentially unremarkable, specifically, there is no instability or change in bladder pressures with filling.

However, on voiding, detrusor contraction is sustained but of low amplitude initially. Contraction continues, increasing in amplitude, but with persistent prolongation of diminished amplitude until full facilitation occurs near the end of the contraction event.

Options for therapy include pharmacologic decrease in outlet resistance with alpha blockade.

A 60-year-old female presented with a 4-year history of worsening urgency incontinence refractory to oral anticholinergics. Prior history was remarkable for pelvic radiation for endometrial carcinoma 30 years ago.

Urodynamics (Poor compliance)

The filling curve is remarkable for rapid changes in bladder pressure with filling until at capacity the patient experienced spontaneous loss of urine across the sphincteric mechanism associated with persistent urgency symptoms.

Bladder augmentation or continent diversion were presented to the patient as options.

A 32-year-old woman underwent uncomplicated bladder suspension for typical symptomatic stress incontinence. Post surgery, she remained catheter dependent for 3 weeks, and then was persistently symptomatic with incomplete bladder emptying, positional voiding dysfunction, and frequency. On examination, urethral hypersuspension was not prominent.

Urodynamics (Iatrogenic obstruction)

Filling characteristics are unremarkable, with not significant change in bladder pressures or volume being noted. However, the pressure/flow study reveals substantially increased voiding pressures and poor flow characteristics.

Urethrolysis was recommended.