Neurourology and Urodynamics

How to Dene a Refractory Idiopathic Overactive Bladder?

ronique Phe ,1* Stefan de Wachter,2 Morgan Roupre ^t,1 and Emmanuel Chartier-Kastler1 Ve
1

-Salpe ^trie re Academic Hospital, Assistance Publique-Ho ^pitaux de Paris, Department of Urology, Pitie Pierre et Marie Curie Medical School, Paris 6 University, Paris, France 2 Department of Urology, University Hospital Antwerpen, Antwerpen, Belgium

Aims: To present the different denitions of refractory IOAB. Materials and Methods: A review of the literature based on PubMed and Cochrane library databases has been conducted. The criteria for dening the success or failure of antimuscarinic treatment and the different denitions of refractory IOAB used in studies evaluating the effects of posterior tibial nerve stimulation, sacral neuromodulation and intradetrusor botulinum toxin-A injections, have been presented. The primary endpoints of these studies were compared. Additionally, different denitions of refractory IOAB were retrieved. Results: There are discrepancies in the denition of refractory IOAB in the literature. The denitions of antimuscarinic success in clinical trials are not always transposable into daily practice. Moreover, these clinical trial endpoints do not explore the entirety of a meaningful patient-centered outcome. The failure of antimuscarinic treatments may be dened by different factors, including lack and loss of efcacy, intolerance to side effects, contraindications, willingness of patients to go further with treatment and inadequacy of patients expectations. Ideally, the best functional outcomes would assess patients expectations and the physicians objectives and objective measurements. Finally, assessing quality of life might be the most reliable outcome to measure, by considering of all the discussed data. Conclusions: An appropriate denition is complex and needs to consider subjective tools. The refractory IOAB needs to be more specically dened so that alternative treatments can be used at the appropriate time. Neurourol. Urodynam. # 2013 Wiley Periodicals, Inc. Key words: antimuscarinics; botulinum toxin; failure; neuromodulation; overactive bladder; refractory; success
INTRODUCTION

Idiopathic overactive bladder (IOAB) was dened by the International Continence Society as urinary urgency that is frequently accompanied by urinary frequency and nocturia, with or without urgency urinary incontinence. IOAB is a common condition affecting more than 10% of the global population with negatively impacts on quality of life.1 According to the fth International Consultation on Incontinence (ICI), initial IOAB management should involve lifestyle intervention, pelvic oor muscle training, and bladder retraining. IOAB management should be combined with pharmacological therapy using antimuscarinics. In cases of IOAB that are refractory to this rst-line therapy, alternative therapies, such as sacral neuromodulation, posterior tibial nerve stimulation (TENS) or intradetrusor botulinum toxin-A (BTX-A) injections can be considered. The ICI guidelines state that after attempting to treat IOAB for 3 months with an antimuscarinic, taking the step towards second-line therapy is worthwhile and justied. However, there is no current consensus on an appropriate denition of the concept of refractory IOAB.2 As the terms failure and refractory and lack or loss of efcacy are not well dened in the eld of IOAB, the appropriate timing of second-line therapies for IOAB remains unclear. Moreover, the concept of refractory is dened as a physician perspective in most cases; however, the patient and the type of symptoms may also have a role. The aim of the study was to present the different denitions of refractory IOAB.
METHODS

intradetrusor botulinum toxin-A injection; refractory; failure; and success. The research was restricted to the English language between 2000 and 2013. Studies evaluating the effects of antimuscarinics as rst-line therapies and studies evaluating the effects of second- and third-line therapies were included. The criteria for dening the success or failure of antimuscarinics have been presented. The effects of TENS, sacral neuromodulation, and intradetrusor BTX-A injections as treatments of IOAB and the primary endpoints of the studies published between 1999 and 2013 have been compared. For BTX-A injections, only randomized controlled studies were considered. Additionally, different denitions of refractory IOAB were retrieved.
RESULTS First-Line Therapy by Antimuscarinics Relevant clinical endpoints dening the success of antimuscarinics. Several anticholinergic drugs are currently available

on the market. The effect of anticholinergic drugs in IOAB has been assessed in several studies (i.e., observational and randomized controlled trials).3 Currently, there is still uncertainty regarding which anticholinergic drugs are the most effective and at what dose of these drugs will provide the greatest patient outcome. IOAB is diagnosed solely from patient
Eric Rovner led the peer-review process as the Associate Editor responsible for the paper. Conflict of interest: None. Correspondence to: V eronique Ph e, M.D., Department of Urology, Piti e-Salp^ etri ere ^pital, 75651 Paris Cedex 13, France. Academic Hospital, 47-83 boulevard de lho E-mail: veronique.phe@gmail.com Received 6 September 2013; Accepted 23 September 2013 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22512

A review of the literature based on the PubMed et Cochrane library databases was performed using the following keywords alone and/or in combination: overactive bladder; antimuscarinics; posterior tibial nerve stimulation; neuromodulation;
#

2013 Wiley Periodicals, Inc.

Ph e et al.
analyzed 69 trials which enrolled 26,229 IOAB patients to compare the adverse effects of antimuscarinics with a network meta-analytic approach. Adverse events are important to consider because the intolerance of a drug can lead to poor compliance or even the interruption of treatment, which also denes a treatments failure. A classication that would evaluate the impact of the severity of side effects is urgently needed. Furthermore, it would be interesting to determine the severity of side effects at the baseline condition and during the follow-up. Factors that predict the failure of antimuscarinics. Few studies have assessed the predictive factors of anticholinergic success in patients with IOAB. Zinner et al.10 showed that younger patients exhibited a greater reduction in micturition frequency compared to those older than 65 years of age. However, no difference was noted when urge incontinence episodes, voided volume or drug side effects were examined in the two groups. Synthesis. To conclude, assessing the failure of a treatment by antimuscarinics has to be considered using different parameters, as follows: lack of efcacy, loss of efcacy, occurrence and severity of side effects, contraindications to its initiation, and inability to meet with patients expectations. Treatment success can be different depending on whether it is considered from the physicians or the patients perspective. For instance, a decrease in the number of episodes of urgency can be considered a clinical success; however, one patient may only consider a successful treatment to be the elimination of all symptoms. IOAB leads to different bothersome symptoms for different patients, and the parameters measured in clinical trials are not always applicable to all patients decisions to continue treatment. Available diagnostic tools also underestimate the heterogeneity of the IOAB patient population. Indeed, among patients reporting urgency, it is difcult to conrm that continent (IOAB-dry) patients are describing the same symptoms as patients with IOAB who have urge urinary incontinence (IOAB-UUI) and that these patients will have the same responses to treatment. These observations should also be evaluated and considered. Additionally, IOAB may best be considered as a condition that can be successfully managed but not necessarily cured through treatment. In a relevant study, Abrams et al.11 emphasized this point by reporting all the objective and subjective outcomes and measures of randomized controlled studies. These studies demonstrated that objective outcomes obtained through bladder diaries or urodynamic studies do not always agree with subjective outcomes. Although objective measures are important in the assessment and management of patients, they are not reliable indicators of the inconvenience experienced by all patients with IOAB. Despite the clear importance and appropriateness of including subjective measures in the management of IOAB symptoms, only a few studies have included such subjective measures as primary endpoints. Figure 1 summarizes all the factors that can contribute to the success of antimuscarinic treatment. A patients satisfaction with treatment provides information on its effectiveness and is believed to affect the clinical outcome. A high patient satisfaction level regarding medication may correlate with compliance. Although the role of expectations in satisfaction assessments cannot be ignored, they can be accounted for or controlled by ensuring that patient expectations are measured at the beginning of treatment.
Second-Line Therapies

symptoms and does not rely on urodynamic evaluations. Urgency is recognized as the main symptom of IOAB. Functional outcomes after treatment have been reported differently in the literature, with no consensual denition of response. In clinical studies, the endpoints used to assess the success of antimuscarinics were baseline changes in of the following items:3 the number of urgency episodes/24 h, the number of incontinence episodes/24 h, the number of pads used per day, the number of daytime incontinence episodes/ 24 h, the number of nocturnal incontinence episodes/24 h, the number of nocturnal awakening related to overactive bladder/ 24 h, the volume of urine voided per micturition, the number of micturitions/24 h, the maximum cystometric capacity based on voiding diary, the number of patients achieving normal micturition frequency (78 micturitions/24 h) at the trial endpoint, and the number of patients returned to continence at the trial end point (recording no incontinence episodes on their last voiding diary entry). However, these denitions of success that have been proposed in clinical trials are not always transferable into daily practice. Additionally, the chosen endpoints do not measure the entirety of a meaningful patient-centered outcome. As urgency remains the main symptom of IOAB syndrome, lowering urgency should be a primary target for assessing the effectiveness of the treatment for any IOAB condition. However, there is no consensual evaluation of the key symptom of urgency.4 Clinical trials have focused only on single-outcome variables and have not consider a composite endpoint, including several key symptoms that might more accurately reect the patients response to treatment. Moreover, most of the current trials were proposed by pharmaceutical companies, suggesting that the denition of success might be biased by the known mechanism of action of the drug and/or the most clinically signicant improved item. In conclusion, making comparisons between studies is challenging because different parameters have been used for each study. Furthermore, it remains unclear whether the most clinically important parameters have been adequately evaluated. Quality of life. IOAB contributes to a lower QoL5 and thus its evaluation in association with the impact on QoL is essential. In clinical studies, this evaluation was not often performed. Different methods of evaluation have been proposed, which included: general questionnaires (Short Form-36 and Short Form-12), disease-specic questionnaires (Incontinence Impact Questionnaire, KHQ, UDI, and IOAB-q), and number of patients reporting improvements in disease or the visual analogical scale of improvement.3 Some randomized controlled studies evaluated the effect of different antimuscarinics on QoL,6 and a no improvement result in QoL can be considered as a treatments failure. Currently, there is no study that evaluates IOAB patients satisfaction and expectations. Ultimately, relevant clinical endpoints should correlate with improvements in the patients QoL. Interestingly, Vecchioli et al.7 reported that the cost of an anticholinergic might be responsible for both the early discontinuation of treatment and the incomplete adherence to therapy that leads to unsatisfactory results on the presentation of the symptoms and an incorrect assessment of the effectiveness of the drug by the urologist. We believe that QoL is a promising parameter that should be used in daily practice. Based on the Likert scale and similar to pain management, a Visual Analogical Scale may be used.8 Endpoints that dene the tolerance of antimuscarinics. To date, a standardized scoring method to assess the severity of side effects of antimuscarinics is lacking. For instance, the intensity of dry mouth should be classied as mild/moderate/ severe, mild/moderate or, even, moderate/severe. Kessler et al.9
Neurourology and Urodynamics DOI 10.1002/nau

Another approach for the evaluation of failure of the initial therapy should be the detection of indicators for second-line

Refractory Idiopathic Overactive Bladder

Fig. 1. Elements dening the success of a treatment by antimuscarinics.

therapies and criteria, which have been used within published papers to validate efcacy. A number of trials testing secondline therapies involved patients with refractory IOAB. For sacral neuromodulation, the primary endpoints that were frequently used in studies were the following 1214: >50% improvement or healing, global improvement, number of voidings/24 h, number of episodes of urinary leakage/day, number of pads/day, maximum cystometric capacity, and continence. However, the denition of refractory IOAB has never been clearly dened, and this point seems to be essential to dene the ideal candidates for sacral neuromodulation. Tables Ia and Ib,1214 IIa and IIb,1519 and IIIa and IIIb2028 summarize the denition of refractory IOAB that were used in the main studies assessing the effects sacral neuromodulation, TENS and intradetrusor BTX-A injections. Interestingly, before determining that the treatment failed, there is no consensus in the duration of treatment with antimuscarinic drugs, the type of antimuscarinics used, the number of antimuscarinics used, the utility of combining antimuscarinics, the description and prescription of behavioral therapies, the consideration of the tolerance of antimuscarinics in the denition, the primary objective and subjective endpoints of each study, and the consideration of the maintenance of antimuscarinic therapy during a trial or wash-out and stoppage. Furthermore, the primary endpoints of second-line therapies are different from those of antimuscarinics. Thus, the criteria for the success of second-line therapies are different from the criteria for the success/failure for antimuscarinics. BTX-A injections have been shown to effectively improve IOAB symptoms in patients who either do not respond to or do not tolerate anticholinergic drugs. Interestingly, Makovey et al.29 determined that intradetrusor BTX-A injections for the management of refractory IOAB symptoms (dened as the persistence of IOAB symptoms despite the maximum approved therapeutic dosing of two or more anticholinergic drugs) were

more successful in patients with anticholinergic intolerability compared to patients with poor medication efcacy (86% vs. 60%, P < 0.02). Recently, Visco et al.30 published that there is an equivalent effect of antimuscarinic drug therapy and BTX-A therapy for patients as a rst-line therapy trial.
Synthesis

The perspectives that need to be considered to assess the outcome of treatments are threefold: (1) The perspectives of the patient, the perspectives of the physician, and the perspectives driven by objective measurements. The ideal outcome should consider all of these perspectives. Using changes in QoL to validate clinical efcacy measurements reects the current rationale in the eld of urology, with an emphasis on analyzing both the objective measures and patient perspective, as in the treatment of stress urinary incontinence.31 Currently, it is impossible to determine the optimum outcome measure for use in IOAB clinical trials. Endpoints should focus on changes in urgency, with or without other symptoms, and QoL If these two measures were combined, they might adequately cover all of the aspects that are important to patients. If a single composite endpoint can be agreed on and adopted for use by all clinical trials, it would signicantly help to standardize the reporting of trial data and remove the current confusion created by individual symptom reporting. (2) The development of a simple, reproducible, and reliable method to measure urgency is essential. The new denition of urgency only applies to fear of leakage, and this is implicit in the denition sudden compelling desire to pass urine which is difcult to defer.32 However, when patients say they have urgency, it is difcult to be sure that those

TABLE IA. Criteria for Dening Refractory IOAB That Were Used in Studies Evaluating the Effects of Sacral Neuromodulation in the Second-Line Treatment of IOAB Are side effects or contraindications considered in the definition of the failure of treatment? NR NR NR Is quality of life considered in the definition of the failure of treatment? NR NR NR

Refs. Schmidt et al.12 Hassouna et al.13 Weil et al.14 NR, not reported.

Type of study Prospective Prospective Prospective

Type of first-line treatment of IOAB NR NR NR

Definition of failure of first-line treatment NR NR NR

Neurourology and Urodynamics DOI 10.1002/nau

TABLE IB. Objective and Subjective Outcomes of Studies Evaluating the Effects of Sacral Neuromodulation in the Second-Line Treatment of IOAB

Ph e et al.

Refs. Objective measures SF 36 Improved SF 36 Subjective measures Objective outcomes Subjective outcomes UUI

Are antimuscarinics stopped before sacral neuromodulation?

Inclusion criteria (urological symptoms)

Evaluation of adverse events Yes

Schmidt et al.12

155

NR

Hassouna et al.13

51

NR

Voiding diary; number of pads; daily incontinence; episodes; number of severe; episodes UUI bladder Number of voids daily; volume capacity voided per void; cystometry; >100 ml measurements

Improvements in the degree of urgency; improvements of SF 36 Improvement of quality of life

Yes

Neurourology and Urodynamics DOI 10.1002/nau

UUI Voiding diaries; quality of life; questionnaires; urodynamic testing Number of pads; daily incontinence episodes; number of severe episodes SF 36; degree of urgency beSignificant improvements with fore void; degree of pelvic/ respect to the number voids bladder discomfort daily the volume per void; significant improvements in cystometric parameters Physical functioning Physical Mean leakage episodes; leakage role; Social functioning severity; pad usage; " Bodily pain; Mental health urodynamically assessed Emotional role; Vitality bladder volume at the first General health; Standarcontraction and maximum fill dized physical health; Standardized mental health Yes Type of first-line treatment of IOAB Antimuscarinics and reeducation Antimuscarinics Antimuscarinics Not defined Not defined Definition of failure of first-line treatment Are side effects or contraindications considered in the definition of the failure of treatment? No No No No No Is quality of life considered in the definition of the failure of treatment? No No No No No 2 Antimuscarinics  6 months reeducation Not defined Self-reported failed conservative care Not defined Not defined

Weil et al.14

44

NR

UUI, urge urinary incontinence; NR, not reported.

TABLE IIA. Criteria for Dening Refractory IOAB That Were Used in Studies Evaluating the Effects of TENS in the Second-Line Treatment of IOAB

Refs.

Type of study

Yoong et al.15

Prospective

Prospective

Congregado Ruiz et al.16 Peters et al.17 Surwit et al.18 Govier et al.19

Prospective Prospective Prospective

TABLE IIB. Objective and Subjective Outcomes of Studies Evaluating the Effects of TENS in the Second-Line Treatment of IOAB

Refs. Objective outcomes Daytime frequency by 50%; nocturnal frequency by 50%; daily urge leak episodes; number of pads changed in 24 h IIQ-7 improved median acceptability of the technique when scored by Visual Analogue Score: 9.6/10 Subjective outcomes

Are antimuscarinics stopped before TENS? Inclusion criteria (urologic symptoms) Objective measures No Subjective measures Evaluation of adverse events

Treatment modalities

Yoong et al.15

43

Yes (6 weeks)

Weekly 30 min over 6 weeks

Congregado Ruiz et al.16

51 Daytime frequency; daytime voiding volume; daytime leakage episodes; nighttime frequency; nighttime voiding volume; nighttime leakage episodes

NR

Weekly 30 min over 10 weeks

Urinary frequency Bladder symptom HRQL: IIQ-7 of >8 voids/ diaries 24 h; UUI episodes of >3/week; nocturia; phasic detrusor contractions in the filling phase of saline cystometry NR Daytime voiding QoL questionfrequency; naire; nighttime hypogastric voiding frequency; pain daytime incontinence; nighttime incontinence; daytime voiding volume; nighttime voiding volume

Hypogastric pain; none of the patients felt unhappy; 9 felt bad (17.6%); 13 felt indifferent (25.4%); 23 felt happy (45.09%); 6 felt pleased (11.76%); 8 patients evaluated the results as excellent (15.68%); 27 as favorable (52.94%); 9 as fair (17.64%); 7 found no difference (13.72%)

Yes

Peters et al.17

220

Yes (2 weeks)

Weekly 30 min over 12 weeks

GRA, OAB-q scores, SF-36

Urinary urgency frequency; UUI; " voiding volume

A subgroup of 26 women presented with frequency or urgency, but not with incontinence. 3 Women (11.53%) felt bad; 5 (9.80%) felt indifferent; 16 (61.53%) felt happy; 2 (3.92%) felt pleased; 3 patients evaluated the results obtained as excellent (11.53%); 17 as favorable (33.3%); 4 as fair (7.84%); 2 found no difference (7.69%). Another subgroup of 22 patients presented with urge incontinence. 5 Patients felt bad (22.72%); 5 felt indifferent (22.72%); 9 felt happy (17.64%); 3 felt pleased (13.63%); 4 patients considered them excellent (18.18%); 8 as favorable (36.36%); 5 as fair (22.7%); 5 found no difference (22.72%) SF 36 improved; GRA improved; OAB- q improved

Yes

Surwit et al.18

256

NR

Weekly over 8 weeks

OAB-V8 score

93% Totally dry status; incontinence episodes; UUI episodes

93% OAB-V8 score <8

Yes

Govier et al.19

53

NR

Weekly during 12 weeks

A score of 4 on Urgency; frequency the OAB-q short UUI; 3-day form for urgency; voiding diaries average urinary frequency of 10 voids per day; self-reported bladder symptoms 3 months Urge incontinence Success absence and mixed of incontinent incontinence episodes (dry) and an OAB-V8 score less than 8 NR Urodynamic evaluation 3-day voiding diaries

QoL impact continence questionnaire

In mean daytime; in mean nighttime voiding frequencies; reduction of UUI

Improvements in selective pain and quality of life indexes.

Yes

6 Ph e et al.

TABLE IIIA. Criteria for Dening Refractory IOAB That Were Used in Randomized Studies Evaluating the Effects of Botulinum Toxin-A in the Second-Line Treatment of IOAB

Neurourology and Urodynamics DOI 10.1002/nau

Type of first-line treatment of IOAB Antimuscarinics Antimuscarinics Yes Yes Definition of failure of the first-line treatment Are side effects or contraindications considered in the definition of the failure of treatment? Is quality of life considered in the definition of the failure of treatment? No No Antimuscarinics Antimuscarinics 2 Antimuscarinics retraining 1 Antimuscarinics retraining Antimuscarinics Not defined Yes Yes No No No Yes No No No No No No Insufficient efficacy or intolerable side effects 8 Weeks of treatment with any anticholinergic drug and one or more of the following: improvement, rated a little better or worse on the Patient Global Impression of Improvement (PGI-I) scale; verbal report of unacceptable improvement; treatment stopped because of side effects; and patients previously treatment with no benefit Antimuscarinic drugs during 312 months Inadequate response or intolerable side effects to antimuscarinic drugs Inadequate symptom control after at least 2 first-line therapies At least 1 anticholinergic medication and behavioral modifications Not defined After a trial of antimuscarinics for 6 weeks due to either poor efficacy or tolerability

Refs.

Chapple et al.27 Tincello et al.28

Denys et al.20 Dmochowski et al.21

Brubaker et al.22

Flynn et al.23

Kuo Sahai et al.25

24

TABLE IIIB. Objective and Subjective Outcomes of Studies Evaluating the Effects of Botulinum Toxin-A Injections in the Second-Line Treatment of IOAB

Refs. Objective measures Number of UI; post-voiding residual Significant improvement of condition; significant improvement of I-QoL and KHQ Urgency severity score; improved ICIQ and IQOL scores Treatment benefit scale: greatly improved, improved, not changed, worsened; I-QoL, KHQ UI episodes; all other symptoms of OAB (UUI, micturition, urgency, nocturia); " post-voiding residual volume Voiding frequency/24 h; incontinence episodes /21 h; urgency 24 h; improved continence Subjective measures Objective outcomes 100 U 3 Episodes of urgency with or without UUI/ 3d; 8 voidings/24 h; PVR<100 ml OAB symptoms and DO on urodynamics; 8 voidings/24 h; 2 moderate or severe urgency episodes/24 h Urinary voiding frequency; incontinence episode frequency 3 Episodes of urgency with or without UUI/ 3d; 8 voidings/24 h 24-h frequency of micturition; mean UUI urgency episodes/day; pads/day recorded on a 3-day micturition diary; volume at the first and at a strong contraction; maximum detrusor pressure; maximum cystometric capacity; post-voiding residual Urgency episode frequency (moderate or severe on the Indevus Urgency Severity Scale [IUSS]) from a 3-day voiding diary; ICIQ-SF; IQOL I-Qol; EQ-5D

Are antimuscarinics stopped before BoNTA? Doses of BoNTA Inclusion criteria (urologic symptoms) Subjective outcomes Evaluation of adverse events Yes

Chapple et al.27

277

Yes

Tincello et al.28 200 U

122

Yes

Yes

Denys et al.20 50/100/ 150 U

99

NR

Improved QoL

Yes

Dmochowski et al.21

313

NR

50/100/ 150/ 200/ 300 U

8 or more UUI episodes a week; 1 incontinence-free day; 8 micturitions/day

HRQL

- >50% improvement versus baseline in urgency and UUI in 65% and 56% of patients who, respectively, received 100 U and 150 U BoNTA i njections; >75% improvement in 40% of patients of both groups (100 U and 150 U); complete continence in 55% and 50% patients after 100 U and 150 U BoNTA; frequency symptoms Weekly UUI episodes, weekly episodes of micturition, urgency, and nocturia; " volume voided/micturition

Improved HRQL

Yes

Brubaker et al.22

43

NR

200 U

6 Urge incontinence episodes in a 3-day bladder diary; proven DO

Electronic bladder diary for 7 consecutive days; urine volume voided during a 24-h period; number of weekly UUI episodes; weekly frequency of micturition, urgency and nocturia; volume voided per micturition; incontinence episodes Frequency of incontinence episodes; PVR PGI-I

Number of urinary incontinence; "PVR

PGI-I 4 score

Yes

continued

TABLE IIIB. (Continued)

Refs. Objective measures UDI-6; IIQ-7 UI episodes/day; number of pads/day Improved IIQ-7 et UDI-6 Subjective measures Objective outcomes 200/300 U 2 Daily incontinence episodes occurring with urge on a 3-day bladder diary; a 24hour pad weight 100 g

Are antimuscarinics stopped before BoNTA? Doses of BoNTA Inclusion criteria (urologic symptoms) Subjective outcomes

Evaluation of adverse events Yes

Flynn et al.23

22

Yes

Kuo24 100 U in bladder trigone, suburothelium or detrusor IDO General satisfaction rating (categorized as excellent, moderately improved, mildly improved and stationary, as measured by the symptomatic improvement of 75%, 5075%, 2550%, or 25%. Successful outcome was defined as an excellent or moderately improved result IIQ-7; UDI-6; KHQ IIQ-7; UDI-6

45

NR

Number of incontinence episodes/day; 24-hour pad weights; number of pads used/24 hours; 24-hour voiding frequency; diurnal urinary frequency and nocturia; maximum cystometric contractions; volume of first uninhibited detrusor contraction; presence of stress leakage; value of detrusor pressure at peak flow; peak urine flow; PVR on micturition study. Urgency severity score during a 3-day period; number of urgency and incontinence episodes during a 3-day period, maximum flow rate; voiding detrusor pressure; cystometric bladder capacity; PVR Improved QoL

Yes

Sahai et al.25 200 U 200 U No

34

No

A successful result at 3 months was achieved in 14 (93%) patients with detrusor, 12 (80%) with suburothelial and 10 (67%) with bladder base injection; urgency severity scores improved significantly in all groups; " cystometric capacity and PVR compared to baseline in the detrusor and suburothelial but not in the bladder base group NR Frequency, urgency, UUI

No Yes

Dowson et al. 201226

100

NR

OAB symptoms 6 months; Proven DO OAB symptoms; proven DO

3-day voiding diary; PVR

4 KHQ!better quality of life Improved IIQ-7 and UDI-6

Refractory Idiopathic Overactive Bladder

Fig. 2. Flow chart for the evaluation of treatments in IOAB.

continent (IOAB-dry) patients are describing the same symptoms as patients with IOAB who have urge urinary incontinence (IOAB-UUI). (3) Assessing QoL might be the sole outcome measured, as improvement from the patient perspective is the ultimate aim of treating benign conditions. However, there will always be a need to understand how therapy affects individual symptoms, and there is evidence that objectives measures beyond QoL are also needed to assess the efcacy of a treatment. The regulatory authorities have not dened accurately the concept of refractory IOAB or even the failure of treatment by anticholinergics. Indeed, the Food and Drug Administration approved BTX-A injections in the treatment of adults with IOAB who cannot use or do not adequately respond to a class of medications known as anticholinergics (http://www.fda.gov/ newsevents/newsroom/pressannouncements/ucm336101.htm). In the guideline regarding clinical investigation of medicinal products for the treatment of urinary incontinence (http:// www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2013/07/WC500146177.pdf), the European Medicine Agency stated drugs intended for the use in urge incontinence should be tested in placebo controlled and that patient perception of treatment effect should be included in the primary endpoint in phase III trials [ ] Assessing efcacy should be stated after 12 weeks of treatment. Once more, the failure has not been dened accurately. In future studies, a greater emphasis on subjective assessments using instruments that have undergone rigorous
Neurourology and Urodynamics DOI 10.1002/nau

validation studies in IOAB patients is recommended. Relationships between objective and subjective end points should be evaluated in quantitative terms using the appropriate statistical methods. Figure 2 demonstrates a ow chart for the evaluation of the treatments in IOAB.

CONCLUSIONS

A review of the literature showed large inconsistencies in the denition of refractory IOAB. The success or failure of IOAB rst-line treatment is dependent upon the interaction of many factors, and it appears that although a treatment based on objective endpoints can be considered as successful by clinicians, the patients perception regarding the efcacy of the treatment is essential. The objectives of IOAB therapy should be to improve symptoms, with a subsequent improvement in QoL. Further research will be required to determine the most effective measure of treatment efcacy in terms of patient outcomes. A study comparing a treatment that was considered to be a success by the clinicians and by the patients is of a great interest. Indeed, refractory IOAB needs to be more specically dened so that the second- and third-line treatments can be properly evaluated. Finally, published general guidelines reporting on the diagnosis and management of urinary incontinence related to IOAB or neurogenic OAB should be fully reviewed with the perspective of specic and dened parameters that go from one management step to another.

10

Ph e et al.
REFERENCES
of overactive bladder syndrome: Results from the SUmiT trial. J Urol 2010;183:143843. Surwit EA, Campbell J, Karaszewski K. Neuromodulation of the pudendal, hypogastric, and tibial nerves with pelvic oor muscle rehabilitation in the treatment of urinary urge incontinence. Neuromodulation 2009;12:1759. Govier FE, Litwiller S, Nitti V, et al. Percutaneous afferent neuromodulation for the refractory overactive bladder: Results of a multicenter study. J Urol 2001;165:11938. Denys P, Le Normand L, Ghout I, et al. Efcacy and safety of low doses of Onabotulinumtoxin A for the treatment of refractory idiopathic overactive bladder: A multicentre, double-blind, randomised, placebo-controlled doseranging study. Eur Urol 2012;61:5209. Dmochowski R, Chapple C, Nitti VW, et al. Efcacy and safety of Onabotulinumtoxin A for idiopathic overactive bladder: A double-blind, placebo controlled, randomized, dose ranging trial. J Urol 2010;184:241622. Brubaker L, Richter HE, Visco A, et al. Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008;180:21722. Flynn MK, Amundsen CL, Perevich M, et al. Outcome of a randomized, doubleblind, placebo controlled trial of Botulinum A toxin for refractory overactive bladder. J Urol 2009;181:260815. Kuo H-C. Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007;178:135963. Sahai A, Dowson C, Khan MS, et al. Improvement in quality of life after botulinum toxin-A injections for idiopathic detrusor overactivity: Results from a randomized double-blind placebo-controlled trial. BJU Int 2009;103:150915. Dowson C, Watkins J, Khan MS, Dasgupta P, Sahai A. Repeated Botulinum Toxin Type A Injections for Refractory Overactive Bladder: Medium-Term Outcomes, Safety Prole, and Discontinuation Rates. Eur Urol 2012;61:834 839. Chapple C, Sievert K-D, MacDiarmid S, et al. Onabotulinumtoxin A 100 U signicantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: A randomised, double-blind, placebo-controlled trial. Eur Urol 2013;S03022838:003552. doi: 10.1016/j.eururo.2013.04.001 Tincello DG, Kenyon S, Abrams KR, et al. Botulinum Toxin A versus placebo for refractory detrusor overactivity in women: A randomised blinded placebo-controlled trial of 240 women (the RELAX study). Eur Urol 2012;62:50714. Makovey I, Davis T, Guralnick ML, et al. Botulinum toxin outcomes for idiopathic overactive bladder stratied by indication: Lack of anticholinergic efcacy versus intolerability. Neurourol Urodyn 2011;30:153840. Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. Onabotulinumtoxin A for urgency urinary incontinence. NEJM 2012;367:180313. Rodr guez LV, Blander DS, Dorey F, et al. Discrepancy in patient and physician perception of patients quality of life related to urinary symptoms. Urology 2003;62:4953. Abrams P. Urgency: The key to dening the overactive bladder. BJU Int 2005;96:13.

1. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20:32736. 2. Nitti VW, Kopp Z, Lin ATL, et al. Can we predict which patient will fail drug treatment for overactive bladder? A think tank discussion. Neurourol Urodyn 2010;29:6527. 3. Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in overactive bladder: An update of a systematic review and meta-analysis. Eur Urol 2008;54:54362. 4. Chapple CR, Artibani W, Cardozo LD, et al. The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: Current concepts and future prospects. BJU Int 2005;95:33540. 5. Coyne KS, Sexton CC, Kopp ZS, et al. The impact of overactive bladder on mental health, work productivity and health-related quality of life in the UK and Sweden: Results from EpiLUTS. BJU Int 2011;108:145971. 6. Choo M-S, Lee JZ, Lee JB, et al. Efcacy and safety of solifenacin succinate in Korean patients with overactive bladder: A randomised, prospective, doubleblind, multicentre study. Int J Clin Pract 2008;62:167583. 7. Vecchioli Scaldazza C, Morosetti C, Pace G, Azizi B, Giannubilo W, Ferrara V. Has the cost of anti-muscarinic a key role in the success rate of patients diagnosed with overactive bladder syndrome? Arch Ital Urol Androl 2012;84:6873. 8. Lukacz ES, Lawrence JM, Burchette RJ, et al. The use of Visual Analog Scale in urogynecologic research: A psychometric evaluation. Am J Obstet Gynecol 2004;191:16570. 9. Kessler TM, Bachmann LM, Minder C, et al. Adverse event assessment of antimuscarinics for treating overactive bladder: A network meta-analytic approach. PLoS ONE 2011;6:e16718. doi: 10.1371/journal.pone.0016718 10. Zinner NR, Mattiasson A, Stanton SL. Efcacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients. J Am Geriatr Soc 2002;50:799807. 11. Abrams P, Artibani W, Gajewski JB, et al. Assessment of treatment outcomes in patients with overactive bladder: Importance of objective and subjective measures. Urology 2006;68:1728. 12. Schmidt RA, Jonas U, Oleson KA, et al. Sacral nerve stimulation for treatment of refractory urinary urge incontinence. J Urol 1999;162:3527. 13. Hassouna MM, Siegel SW, Lyclama Anyeholt AAB, et al. Sacral neuromodulation in the treatment of urgency-frequency symptoms: A multicenter study on efcacy and safety. J Urol 2000;163:184954.  JL, Eerdmans PH, et al. Sacral root neuromodulation in the 14. Weil EH, Ruiz-Cerda treatment of refractory urinary urge incontinence: A prospective randomized clinical trial. Eur Urol 2000;37:16171. 15. Yoong W, Ridout AE, Damodaram M, et al. Neuromodulative treatment with percutaneous tibial nerve stimulation for intractable detrusor instability: Outcomes following a shortened 6-week protocol. BJU Int 2010;106:16736. ~ o XM, Campoy Martinez P, et al. Peripheral 16. Congregado Ruiz B, Pena Outeirin afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol 2004;45:659. 17. Peters KM, Carrico DJ, Perez-Marrero RA, et al. Randomized trial of percutaneous tibial nerve stimulation versus sham efcacy in the treatment

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22. 23.

24.

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Neurourology and Urodynamics DOI 10.1002/nau