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Keywords:

  • antimuscarinics;
  • botulinum toxin;
  • failure;
  • neuromodulation;
  • overactive bladder;
  • refractory;
  • success

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES

Aims

To present the different definitions of “refractory” IOAB.

Materials and Methods

A review of the literature based on PubMed and Cochrane library databases has been conducted. The criteria for defining the success or failure of antimuscarinic treatment and the different definitions 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 definitions of refractory IOAB were retrieved.

Results

There are discrepancies in the definition of “refractory” IOAB in the literature. The definitions 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 defined by different factors, including lack and loss of efficacy, intolerance to side effects, contraindications, willingness of patients to go further with treatment and inadequacy of patient's expectations. Ideally, the best functional outcomes would assess patient's expectations and the physician's 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 definition is complex and needs to consider subjective tools. The “refractory” IOAB needs to be more specifically defined so that alternative treatments can be used at the appropriate time. Neurourol. Urodynam. 34:2–11, 2015. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES

Idiopathic overactive bladder (IOAB) was defined 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 fifth International Consultation on Incontinence (ICI), initial IOAB management should involve lifestyle intervention, pelvic floor muscle training, and bladder retraining. IOAB management should be combined with pharmacological therapy using antimuscarinics. In cases of IOAB that are refractory to this first-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 justified. However, there is no current consensus on an appropriate definition of the concept of “refractory” IOAB.[2] As the terms “failure” and “refractory” and “lack” or “loss” of efficacy are not well defined in the field of IOAB, the appropriate timing of second-line therapies for IOAB remains unclear. Moreover, the concept of “refractory” is defined 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 definitions of “refractory” IOAB.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES

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; 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 first-line therapies and studies evaluating the effects of second- and third-line therapies were included. The criteria for defining 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 definitions of refractory IOAB were retrieved.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES

First-Line Therapy by Antimuscarinics

Relevant clinical endpoints defining 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 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 definition 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 (≤7–8 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 definitions 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 reflect the patient's response to treatment. Moreover, most of the current trials were proposed by pharmaceutical companies, suggesting that the definition of success might be biased by the known mechanism of action of the drug and/or the most clinically significant 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 QoL[5] 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-specific 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 treatment's 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 define 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 classified as mild/moderate/severe, mild/moderate or, even, moderate/severe. Kessler et al.[9] 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 defines a treatment's failure. A classification 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 efficacy, loss of efficacy, 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 physician's or the patient's 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 difficult to confirm 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 patient's 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.

image

Figure 1. Elements defining the success of a treatment by antimuscarinics.

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Second-Line Therapies

Another approach for the evaluation of failure of the initial therapy should be the detection of indicators for second-line therapies and criteria, which have been used within published papers to validate efficacy. A number of trials testing second-line therapies involved patients with “refractory IOAB.” For sacral neuromodulation, the primary endpoints that were frequently used in studies were the following [12-14]: >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 definition of “refractory” IOAB has never been clearly defined, and this point seems to be essential to define the ideal candidates for sacral neuromodulation. Tables Iaa and Ibb,[12-14] IIaa and IIbb,[15-19] and IIIaa and IIIbb[20-28] summarize the definition 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 definition, 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.

Table Ia. Criteria for Defining Refractory IOAB That Were Used in Studies Evaluating the Effects of Sacral Neuromodulation in the Second-Line Treatment of IOAB
Refs.Type of studyType of first-line treatment of IOABDefinition of failure of first-line treatmentAre 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?
  1. NR, not reported.

Schmidt et al.[12]ProspectiveNRNRNRNR
Hassouna et al.[13]ProspectiveNRNRNRNR
Weil et al.[14]ProspectiveNRNRNRNR
Table Ib. Objective and Subjective Outcomes of Studies Evaluating the Effects of Sacral Neuromodulation in the Second-Line Treatment of IOAB
Refs.NAre antimuscarinics stopped before sacral neuromodulation?Inclusion criteria (urological symptoms)Objective measuresSubjective measuresObjective outcomesSubjective outcomesEvaluation of adverse events
  1. UUI, urge urinary incontinence; NR, not reported.

Schmidt et al.[12]155NRUUIVoiding diary; number of pads; daily incontinence; episodes; number of severe; episodesSF 36[DOWNWARDS ARROW] Number of pads; [DOWNWARDS ARROW] daily incontinence episodes; [DOWNWARDS ARROW] number of severe episodesImproved SF 36Yes
Hassouna et al.[13]51NRUUI bladder capacity >100 mlNumber of voids daily; volume voided per void; cystometry; measurementsSF 36; degree of urgency before void; degree of pelvic/bladder discomfortSignificant improvements with respect to the number voids daily the volume per void; significant improvements in cystometric parametersImprovements in the degree of urgency; improvements of SF 36Yes
Weil et al.[14]44NRUUIVoiding diaries; quality of life; questionnaires; urodynamic testingPhysical functioning Physical role; Social functioning Bodily pain; Mental health Emotional role; Vitality General health; Standardized physical health; Standardized mental health[DOWNWARDS ARROW] Mean leakage episodes; [DOWNWARDS ARROW] leakage severity; [DOWNWARDS ARROW] pad usage; [UPWARDS ARROW] urodynamically assessed bladder volume at the first contraction and maximum fillImprovement of quality of lifeYes
Table IIa. Criteria for Defining Refractory IOAB That Were Used in Studies Evaluating the Effects of TENS in the Second-Line Treatment of IOAB
Refs.Type of studyType of first-line treatment of IOABDefinition of failure of first-line treatmentAre 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?
Yoong et al.[15]ProspectiveAntimuscarinics and reeducation2 Antimuscarinics ≥ 6 months + reeducationNoNo
Congregado Ruiz et al.[16]ProspectiveAntimuscarinicsNot definedNoNo
Peters et al.[17]ProspectiveAntimuscarinicsSelf-reported failed conservative careNoNo
Surwit et al.[18]ProspectiveNot definedNot definedNoNo
Govier et al.[19]ProspectiveNot definedNot definedNoNo
Table IIb. Objective and Subjective Outcomes of Studies Evaluating the Effects of TENS in the Second-Line Treatment of IOAB
Refs.NAre antimuscarinics stopped before TENS?Treatment modalitiesInclusion criteria (urologic symptoms)Objective measuresSubjective measuresObjective outcomesSubjective outcomesEvaluation of adverse events
Yoong et al.[15]43Yes (6 weeks)Weekly 30 min over 6 weeksUrinary frequency of >8 voids/24 h; UUI episodes of >3/week; nocturia; phasic detrusor contractions in the filling phase of saline cystometryBladder symptom diariesHRQL: IIQ-7[DOWNWARDS ARROW] Daytime frequency by 50%; [DOWNWARDS ARROW] nocturnal frequency by 50%; [DOWNWARDS ARROW] daily urge leak episodes; [DOWNWARDS ARROW] number of pads changed in 24 hIIQ-7 improved median acceptability of the technique when scored by Visual Analogue Score: 9.6/10No
Congregado Ruiz et al.[16]51NRWeekly 30 min over 10 weeksNRDaytime voiding frequency; nighttime voiding frequency; daytime incontinence; nighttime incontinence; daytime voiding volume; nighttime voiding volumeQoL questionnaire; hypogastric pain[DOWNWARDS ARROW] Daytime frequency; [DOWNWARDS ARROW] daytime voiding volume; [DOWNWARDS ARROW] daytime leakage episodes; [DOWNWARDS ARROW] nighttime frequency; [DOWNWARDS ARROW] nighttime voiding volume; [DOWNWARDS ARROW] nighttime leakage episodes[DOWNWARDS ARROW] 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
        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%) 
Peters et al.[17]220Yes (2 weeks)Weekly 30 min over 12 weeksA score of ≥4 on the OAB-q short form for urgency; average urinary frequency of ≥10 voids per day; self-reported bladder symptoms ≥3 monthsUrgency; frequency UUI; 3-day voiding diariesGRA, OAB-q scores, SF-36[DOWNWARDS ARROW] Urinary urgency frequency; [DOWNWARDS ARROW] UUI; [UPWARDS ARROW] voiding volumeSF 36 improved; GRA improved; OAB- q improvedYes
Surwit et al.[18]256NRWeekly over 8 weeksUrge incontinence and mixed incontinenceSuccess = absence of incontinent episodes (dry) and an OAB-V8 score less than 8OAB-V8 score93% Totally dry status; [DOWNWARDS ARROW] incontinence episodes; [DOWNWARDS ARROW] UUI episodes93% OAB-V8 score <8Yes
Govier et al.[19]53NRWeekly during 12 weeksNRUrodynamic evaluation 3-day voiding diariesQoL impact continence questionnaire[DOWNWARDS ARROW] In mean daytime; [DOWNWARDS ARROW] in mean nighttime voiding frequencies; [DOWNWARDS ARROW] reduction of UUIImprovements in selective pain and quality of life indexes.Yes
Table IIIa. Criteria for Defining Refractory IOAB That Were Used in Randomized Studies Evaluating the Effects of Botulinum Toxin-A in the Second-Line Treatment of IOAB
Refs.Type of first-line treatment of IOABDefinition of failure of the first-line treatmentAre 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?
Chapple et al.[27]AntimuscarinicsInsufficient efficacy or intolerable side effectsYesNo
Tincello et al.[28]Antimuscarinics8 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 benefitYesNo
Denys et al.[20]AntimuscarinicsAntimuscarinic drugs during 3–12 monthsYesNo
Dmochowski et al.[21]AntimuscarinicsInadequate response or intolerable side effects to antimuscarinic drugsYesNo
Brubaker et al.[22]2 Antimuscarinics + retrainingInadequate symptom control after at least 2 first-line therapiesNoNo
Flynn et al.[23]≥1 Antimuscarinics + retrainingAt least 1 anticholinergic medication and behavioral modificationsNoNo
Kuo[24]AntimuscarinicsNot definedNoNo
Sahai et al.[25]Not definedAfter a trial of antimuscarinics for ≥6 weeks due to either poor efficacy or tolerabilityYesNo
Table IIIb. Objective and Subjective Outcomes of Studies Evaluating the Effects of Botulinum Toxin-A Injections in the Second-Line Treatment of IOAB
Refs.NAre antimuscarinics stopped before BoNTA?Doses of BoNTAInclusion criteria (urologic symptoms)Objective measuresSubjective measuresObjective outcomesSubjective outcomesEvaluation of adverse events
Chapple et al.[27]277Yes100 U≥3 Episodes of urgency with or without UUI/3d; ≥8 voidings/24 h; PVR<100 mlNumber of UI; post-voiding residualTreatment benefit scale: greatly improved, improved, not changed, worsened; I-QoL, KHQ[DOWNWARDS ARROW] UI episodes; [DOWNWARDS ARROW] all other symptoms of OAB (UUI, micturition, urgency, nocturia); [UPWARDS ARROW] post-voiding residual volumeSignificant improvement of condition; significant improvement of I-QoL and KHQYes
Tincello et al.[28]122Yes200 UOAB symptoms and DO on urodynamics; ≥8 voidings/24 h; 2 “moderate” or “severe” urgency episodes/24 hUrinary voiding frequency; incontinence episode frequencyUrgency episode frequency (moderate or severe on the Indevus Urgency Severity Scale [IUSS]) from a 3-day voiding diary; ICIQ-SF; IQOL[DOWNWARDS ARROW] Voiding frequency/24 h; [DOWNWARDS ARROW] incontinence episodes /21 h; [DOWNWARDS ARROW] urgency 24 h; improved continence[DOWNWARDS ARROW] Urgency severity score; improved ICIQ and IQOL scoresYes
Denys et al.[20]99NR50/100/150 U≥3 Episodes of urgency with or without UUI/3d; ≥8 voidings/24 h24-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 residualI-Qol; EQ-5D- >50% improvement versus baseline in urgency and UUI in 65% and 56% of patients who, respectively, received 100 U and 150 U BoNTA injections; >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; [DOWNWARDS ARROW] frequency symptomsImproved QoLYes
Dmochowski et al.[21]313NR50/100/150/200/300 U≥8 or more UUI episodes a week; ≤1 incontinence-free day; ≥8 micturitions/dayElectronic 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 episodesHRQL[DOWNWARDS ARROW] Weekly UUI episodes, weekly episodes of micturition, urgency, and nocturia; [UPWARDS ARROW] volume voided/micturitionImproved HRQLYes
Brubaker et al.[22]43NR200 U≥6 Urge incontinence episodes in a 3-day bladder diary; proven DOFrequency of incontinence episodes; PVRPGI-I[DOWNWARDS ARROW] Number of urinary incontinence; [UPWARDS ARROW]PVR[DOWNWARDS ARROW] PGI-I 4 scoreYes
Flynn et al.[23]22Yes200/300 U≥2 Daily incontinence episodes occurring with urge on a 3-day bladder diary; a 24-hour pad weight ≥100 gNumber 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.UDI-6; IIQ-7[DOWNWARDS ARROW] UI episodes/day; [DOWNWARDS ARROW] number of pads/dayImproved IIQ-7 et UDI-6Yes
Kuo[24]45NR100 U in bladder trigone, suburothelium or detrusorIDOUrgency 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; PVRGeneral satisfaction rating (categorized as excellent, moderately improved, mildly improved and stationary, as measured by the symptomatic improvement of ≥75%, 50–75%, 25–50%, or ≤25%. Successful outcome was defined as an excellent or moderately improved resultA 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; [UPWARDS ARROW] cystometric capacity and PVR compared to baseline in the detrusor and suburothelial but not in the bladder base groupImproved QoLYes
Sahai et al.[25]34No200 UOAB symptoms ≥6 months; Proven DONoIIQ-7; UDI-6; KHQNR4 KHQ[RIGHTWARDS ARROW]better quality of lifeNo
Dowson et al. 2012[26]100NR200 UOAB symptoms; proven DO3-day voiding diary; PVRIIQ-7; UDI-6[DOWNWARDS ARROW] Frequency, urgency, UUIImproved IIQ-7 and UDI-6Yes

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 (defined 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 efficacy (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 first-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 efficacy measurements reflects the current rationale in the field 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 significantly 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 definition of urgency only applies to fear of leakage, and this is implicit in the definition “sudden compelling desire to pass urine which is difficult to defer.”[32] However, when patients say they have urgency, it is difficult to be sure that those 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 efficacy of a treatment.

The regulatory authorities have not defined 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/Scientific_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 efficacy should be stated after 12 weeks of treatment.” Once more, the failure has not been defined accurately.

In future studies, a greater emphasis on subjective assessments using instruments that have undergone rigorous 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 flow chart for the evaluation of the treatments in IOAB.

image

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

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CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES

A review of the literature showed large inconsistencies in the definition of “refractory” IOAB. The success or failure of IOAB first-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 efficacy 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 efficacy 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 specifically defined 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 specific and defined parameters that go from one management step to another.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. CONCLUSIONS
  7. REFERENCES