Comparison of the efficacy and complications of tolterodine and α-adrenergic receptor blockers in improving ureteral stent-related symptoms: A systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic evaluation of the therapeutic efficacy and complications of tolterodine and α-adrenergic receptor blockers in alleviating ureteral stent-related symptoms. METHODS: Until August 2023, we conducted a comprehensive literature search on PubMed, Embase, Web of Science, and Cochrane Library to identify randomized controlled trials evaluating the efficacy and complications of tolterodine and α-adrenergic receptor blockers in treating ureteral stent-related symptoms. Two reviewers independently screened studies and extracted data. The scores from various domains of the Ureteral Stent Symptom Questionnaire (USSQ) were summarized and compared, and statistical analysis was performed using RevMan 5.4.0 software. RESULTS: A total of 8 studies met the inclusion criteria for our analysis. These studies were conducted at different centers. All studies were randomized controlled trials, involving a total of 487 patients, with 244 patients receiving α-adrenergic receptor blockers and 243 patients receiving tolterodine. The results showed that tolterodine demonstrated significantly better improvement in body pain (MD, 1.56; 95% CI [0.46, 2.66]; p = 0.005) (MD, 0.46; 95% CI [0.12, 0.80]; p = 0.008) (MD, 3.21; 95% CI [1.89, 4.52]; p = 0.00001) among patients after ureteral stent placement compared to α-adrenergic receptor blockers at different time points. Additionally, at 4 weeks, tolterodine showed superior improvement in general health (MD, 0.15; 95% CI [0.03, 0.27]; p = 0.01) and urinary symptoms (MD, 1.62; 95% CI [0.59, 2.66]; p = 0.002) compared to α-adrenergic receptor blockers, while at 6 weeks, tolterodine showed better improvement in work performance (MD, -1.60; 95% CI [-2.73, -0.48]; p = 0.005) compared to α-adrenergic receptor blockers. Additionally, the incidence of dry mouth (RR, 4.21; 95% CI [1.38, 12.87]; p = 0.01) is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, there were no significant statistical differences between the two drugs in other outcomes. CONCLUSION: This meta-analysis suggests that tolterodine is superior to α-adrenergic receptor blockers in improving physical pain symptoms after ureteral stent placement, while α-adrenergic receptor blockers are more effective than tolterodine in enhancing work performance. Additionally, the incidence of dry mouth is higher with the use of tolterodine compared to α-adrenergic receptor blockers. However, higher-quality randomized controlled trials are needed to further investigate this issue.

[Assessment of prescribing practices in overactive bladder pharmacotherapy across different specialties of India: a prescription trend analysis].

PURPOSE: To assess the prescribing practices for overactive bladder (OAB) pharmacotherapy based on the prescription trend analysis across different specialties of India. METHOD: s: IQVIA (Quintiles and IMS Health) secondary sales audit (SSA), as well as a prescription audit for antimuscarinics and beta-3 adrenoceptor agonists (mirabegron) from 2014 to 2021, were analyzed. The data includes SSA data of various antimuscarinics like solifenacin, oxybutynin, tolterodine, darifenacin, trospium and mirabegron change in the prescription trend of antimuscarinics and mirabegron across different specialties; prescribers overlap analysis for solifenacin and mirabegron among Indian urologists were also analyzed. RESULTS: Urologists prescription rates of OAB drugs were 65% in 2016 and 54% in 2021. The rate of OAB medication prescription by non-urologist was highest from the surgeon (11%), followed by gynecologists (9%) and consultant physicians (8%) in 2021. In addition, among OAB medication prescription rates for antimuscarinics were 100% in 2016 and 58% in 2021 whereas for mirabegron, it was 0% in 2016 and 42% in 2021. Solifenacin was most frequently prescribed anticholinergics, followed by oxybutynin, tolterodine, darifenacin, and trospium. The proportion of prescribers of OAB medication among urologists was 38% in 2016 and 33% in 2021. Exclusive prescribers of solifenacin were 748 in 2018 and 739 in 2021 at the urologist, whereas for mirabegron, it was 961 in 2018 and 934 in 2021. The compound annual growth rate for prescription of the last 6 years (from 2016-2021) for solifenacin and mirabegron was -3% and 8% respectively. CONCLUSIONS: Urology remained a top prescribing specialty for OAB drugs, although prescription share increased at surgeon and consultant physician. OAB medicines prescriptions by urologists are shifting from leading antimuscarinic solifenacin to beta-agonist mirabegron. Data from this study will ultimately lead to the OAB medication preference by the specialist that could lead to more advanced OAB management.

Comparative assessment of efficacy and safety of approved oral therapies for overactive bladder: a systematic review and network meta-analysis.

bladder based on a systematic review and network meta-analysis approach. METHODS: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. RESULT: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. CONCLUSION: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.

Desmopressin Plus Tolterodine vs Desmopressin Plus Indomethacin for Refractory Pediatric Enuresis: An Open-label Randomized Controlled Trial.

OBJECTIVE: To compare the efficacy of desmopressin plus tolterodine (D+T) with desmopressin plus indomethacin (D+I) for treating enuresis in children. DESIGN: Open-label randomized controlled trial. SETTING: Bandar Abbas Children's Hospital, a tertiary care children's hospital in Iran, from March 21, 2018, to March 21, 2019. PARTICIPANTS: 40 children older than five years with monosymp-tomatic and non-monosymptomatic primary enuresis resistant to desmopressin monotherapy. INTERVENTION: Patients were randomized to receive either D+T (60 µg sublingual desmopressin and 2 mg tolterodine) or D+I (60 µg sublingual desmopressin and 50 mg indomethacin) every night before bedtime for five months. OUTCOME: Reduction in the frequency of enuresis was evaluated at one, three, and five months, and response to treatment at five months. Drug reactions and complications were also noted. RESULTS: After adjustment for age, consistent incontinence from toilet training, and non-monosymptomatic enuresis, D+T was significantly more efficacious than D+I; mean (SD) percent in nocturnal enuresis reduction at 1 [58.86 (7.27)% vs 31.18 (3.85) %; P<0.001], 3 [69.78 (5.99) % vs 38.56 (3.31) %; P<0.000], and 5 [84.84(6.21) % vs 39.14 (3.63) %; P<0.001] months showing a large effect. At 5 months, complete response to treatment was only observed with D+T, while treatment failure was significantly higher with D+I (50% vs 20%; P=0.047). None of the patients in either group developed cutaneous drug reactions or central nervous system symptoms. CONCLUSION: Desmopressin plus tolterodine appears to be superior to desmopressin plus indomethacin for treating pediatric enuresis resistant to desmopressin.

Patient Perception of Bladder Condition after Treatment with Solifenacin and Tolterodine in Overactive Bladder Patients.

BACKGROUND: Solefinacin and Tolterodine are new generation antimuscarinics claimed to have bladder specific action and less adverse effect like dry mouth. The objective of the study was to compare the improvement in urinary symptoms among patients using solefinacin and tolterodine with overactive bladder symptoms. METHODS: A hospital based cross-sectional comparative study was done for one year duration. All patients with overactive bladder symptoms were included and in every alternate patient's solefinacin and tolterodine were given after taking note of baseline OAB symptoms, PPBC score and UPS score. Participants were followed up after one month and noted improvement in endpoint OAB symptoms. Comparison of baseline to end-point symptoms changes among each group of participants were analyzed for statistical significance. RESULTS: Among 101 participants included in the study, 49 participants were in solefinacin group and 52 participants were in tolterodine group. The end-point comparison of urgency symptoms were improved by 20.1±6.76 (mean ± SD) units in solefinacin group and by 17.0 ± 9.18 units in tolterodine group. Urgency perception score improved to 2.1±0.66 for patients under solefinacin and 2±0.73 for tolterodine. Patient perception of bladder condition (PPBC) showed improvement in solefinacin group by 3.2±1.26 units and in tolteradine by 2.8±1.54 units (p = 0.165). Comparing the patient's perception of treatment outcome, massive improvement was reported by 81.6% of those receiving Solefinacinand 65.4% receiving tolterodine, though not statistically significant ( p = 0.131). CONCLUSIONS: Solefinacin and Tolterodine showed improvement in urinary symptoms, UPS and PPBC. Both showed comparable efficacy without significant superiority over one another.

Cost-effectiveness evaluation of mirabegron versus anti-muscarinics and third-line therapies: a systematic review.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency, usually with urinary frequency and nocturia. . The current treatment for OAB includes conservative management, surgery, and pharmacotherapy. Mirabegron is a new drug acting by the ß3-adrenoceptor agonism. This study aimed to review the cost-effectiveness of mirabegron in the treatment of OAB. AREAS COVERED: We searched published articles in electronic search databases. Ten studies were included in the qualitative analysis. Various antimuscarinics, including oxybutynin, fesoterodine, tolterodine, darifenacin, and trospium were compared with mirabegron. The results were evaluated and compared according to the quality-adjusted life-years (QALY), cost/year, and incremental cost-effectiveness ratio (ICER). Of the ten studies in only three, mirabegron was not a cost-effective strategy. In seven cases, mirabegron was cost-effective. EXPERT OPINION: The cost-effectiveness of mirabegron was variable in different regions; however, most of the studies show the cost-effectiveness of mirabegron. Our study illustrates that mirabegron's ICER in comparison with its comparators is below the willingness to pay threshold even in the countries with low GDP/Capita. Our proposal for future economic studies for OAB pharmacotherapy is to compare different doses, formulations, and administration forms in a real-world context.

Vibegron for the Treatment of Patients with Dry and Wet Overactive Bladder: A Subgroup Analysis from the EMPOWUR Trial.

Background: Overactive bladder (OAB) is characterized by urgency and frequency with (OAB wet) or without (OAB dry) urge urinary incontinence (UUI). In the phase 3 EMPOWUR trial, vibegron-a selective ß 3-adrenergic receptor agonist for the treatment of OAB-significantly improved daily number of urgency episodes and micturitions vs. placebo (P < 0.01). These post hoc analyses aimed to compare the efficacy of vibegron vs. placebo in OAB dry and wet populations. Methods: Patients were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, for 12 weeks. Baseline criteria for OAB dry included an average of ≥8 micturitions, ≥3 urgency episodes, and <1 UUI episode per diary day and for OAB wet included an average of ≥8 micturitions and ≥1 UUI episode per diary day. Change from baseline in mean daily number of urgency episodes and micturitions was assessed in both populations. Results: Of the 1463 patients included in the full analysis set, 336 (23%) had OAB dry (vibegron, N = 123; placebo, N = 115; and tolterodine, N = 98), and 1127 (77%) had OAB wet (vibegron, N = 403; placebo, N = 405; and tolterodine, N = 319). Vibegron was associated with significant reductions (95% CIs of the least squares mean differences [LSMD] does not include 0) from baseline at week 12 vs. placebo in mean daily urgency episodes for the dry (LSMD [95% CI], ‒1.0 [‒2.0, ‒0.1]) and wet (‒0.6 [‒1.0, ‒0.1]) populations. Vibegron was associated with significant reductions from baseline at week 12 vs. placebo in mean daily micturitions for the dry (LSMD [95% CI], ‒0.8 [‒1.5, ‒ 0.1]) and wet (‒0.5 [‒0.8, ‒0.1]) populations. There were no significant differences in either outcome between tolterodine and placebo for either the dry or wet populations in this study. Conclusions: In this subgroup analysis from the EMPOWUR trial, vibegron was associated with significant reductions compared with placebo in urgency episodes and micturitions in both the OAB dry and wet populations, suggesting that vibegron is similarly efficacious for these endpoints in patients with and without UUI. This trial is registered with NCT03492281.

Effect of combined use of tolterodine and continuous positive airway pressure vs continuous positive airway pressure only treatment on overactive bladder symptoms in women with moderate-to-severe obstructive sleep apnea syndrome: a randomized clinical trial.

INTRODUCTION AND HYPOTHESIS: Obstructive sleep apnea syndrome is associated with urological symptoms, including overactive bladder (OAB). This study aims to determine whether combined tolterodine and CPAP therapies are more effective for patients with OSAS than CPAP treatment only. METHODS: Women who underwent polysomnography test and were diagnosed with moderate-to-severe OSAS with apnea-hypopnea index (AHI) were included in the study. Data were collected on AHI, OAB awareness-8-item tool (OAB-V8), incontinence questionnaire-urinary incontinence short form (ICIQ-UI-SF), total daily urine volume (DUV), and the Benefit, satisfaction with treatment and willingness (BSW) tool. Eligible patients were randomized to receive either CPAP treatment only or combined CPAP and tolterodine treatment for 3 months. RESULTS: Among 103 participants, a total of 60 were included. Patients in both treatment arms showed significant improvements in OAB-V8, ICIQ-UI-SF, and total DUV compared to their baseline. The mean OAB-V8 was 15.7 at baseline and 5.6 at 3 months for the combined treatment arm and 16.6 and 7.6 at 3 months for the CPAP group only (mean baseline-adjusted between-group difference -1.1 [95% CI, -12.3 to -7.4]; p < 0.001). The improvement in the mean ICIQ-UI-SF was also statistically more significant in the combined therapy group than in the CPAP only arm (mean baseline-adjusted between-group difference -3.27 [95% CI, -4.6 to -1.59]; p < 0.001). No statistical significance was found in the improvement of total DUV between the groups. CONCLUSIONS: In this study, combined use of tolterodine with CPAP provides beneficial effects to CPAP treatment only regarding OAB symptoms. Further research is required to confirm these findings in a large cohort.

Different interventions for preventing postoperative catheter-related bladder discomfort: a systematic review and meta-analysis.

OBJECTIVE: Catheter-related bladder discomfort (CRBD) is a common complication of intraoperative urinary catheterization. Various studies have evaluated the efficacy of different interventions in postoperative CRBD. The present review was performed to assess the efficacy of these interventions. METHODS: PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were systematically searched to identify randomized controlled trials (RCTs) investigating the efficacy of different drugs for the prevention of postoperative CRBD. This review evaluated the incidence and severity of CRBD after different interventions at 0, 1, 2, and 6 h postoperatively. RESULTS: Forty-five studies including 31 different drugs were analyzed. Eleven drugs were investigated in more than two RCTs, of which dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and pudendal nerve block (PNB) generally showed significantly higher efficacy than controls postoperatively. Solifenacin only showed significant efficacy compared with the control at 0 h, and intravenous lidocaine only showed significant efficacy compared with the control at 6 h. There were insufficient trials to draw conclusions regarding atropine, butylscopolamine, chlorpheniramine, clonidine, darifenacin, diphenhydramine, glycopyrrolate, intravesical bupivacaine, ketamine-haloperidol, pethidine-haloperidol, ketorolac, lidocaine-prilocaine cream, magnesium, hyoscine n-butyl bromide, oxycodone, paracetamol, parecoxib, trospium, resiniferatoxin, or amikacin. However, all but pethidine-haloperidol and chlorpheniramine showed some efficacy at various time points compared with controls. CONCLUSION: This review suggests that dexmedetomidine, gabapentin, tolterodine, tramadol, ketamine, nefopam, oxybutynin, pregabalin, and PNB are effective in preventing postoperative CRBD. Considering the efficacy and adverse effects of all drugs, dexmedetomidine and gabapentin were ranked best.

Mirabegron for treatment of erectile dysfunction concomitant with lower urinary tract symptoms in patients with benign prostatic obstruction: A randomized controlled trial.

OBJECTIVE: To assess the efficacy of mirabegron in the treatment of erectile dysfunction concomitant with lower urinary tract symptoms in benign prostatic obstruction patients. METHODS: In this randomized controlled trial, 55 sexually active lower urinary tract symptoms/benign prostatic obstruction patients with concomitant erectile dysfunction were randomly allocated in two groups: the first received mirabegron 50 mg plus doxazosin 2 mg once daily (mirabegron group) and the second received tolterodine 4 mg plus doxazosin 2 mg (tolterodine group) for 12 weeks. The evaluation was based on the International Index of Erectile Function questionnaire, Erection Hardness Score questionnaire, International Prostate Symptom Score, quality of life, uroflowmetry and post-voiding residual. The therapeutic outcomes were assessed at 4 and 12 weeks compared with the baseline. RESULTS: Only the mirabegron group achieved significant improvement in sexual functions after 4 and 12 weeks. By using ≥5 points difference from the baseline as a cut-off point of change, there was a significant difference in change of direction of the International Index of Erectile Function-15 total score in favor of the mirabegron group; after 12 weeks, the International Index of Erectile Function-15 total score decreased in 0%, was unchanged in 8.3% and improved in 91.7% in the mirabegron group compared with 8.7%, 65.2% and 26.1%, respectively, in the tolterodine group (P < 0.001). Regarding the urinary characteristics, both groups showed significant improvement in the International Prostate Symptom Score, quality of life, and post-voiding residual after 4 and 12 weeks, with no significant difference among them. CONCLUSION: Mirabegron improves urinary characteristics and the associated sexual dysfunction in patients with lower urinary tract symptoms/benign prostatic obstruction.

Receipt of Overactive Bladder Drugs and Incident Dementia: A Population-based Case-control Study.

BACKGROUND: The differential risk of incident dementia associated with receiving various overactive bladder (OAB) drugs is unknown. OBJECTIVE: To estimate the association of antimuscarinic OAB drug (exposure), compared with a ß-3 agonist (mirabegron), and incident dementia. DESIGN, SETTING, AND PARTICIPANTS: A population-based nested case-control study was conducted in patients treated with OAB medications in Ontario, Canada. A total of 11 392 patients aged ≥66 yr with a new diagnosis of dementia between 2010 and 2017, and 29 881 age- and sex-matched controls without dementia were included in the study. INTERVENTION: Receipt of an antimuscarinic OAB drug or receipt of mirabegron, within the previous 6-12 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cases developed dementia and Alzheimer's disease. Controls were derived from the general population and matched to cases based on important baseline characteristics. Odds ratios (ORs) for incident dementia, adjusted for demographic and health-related characteristics, were determined. RESULTS AND LIMITATIONS: Patients receiving solifenacin (OR 1.24; 95% confidence interval 1.08-1.43) and darifenacin (OR 1.30; 95% CI 1.08-1.56) in the prior 6 mo had increased odds of incident dementia compared with those receiving mirabegron. In the 6 mo to 1 yr prior to diagnosis, receipt of solifenacin (OR 1.34; 95% CI 1.11-1.60), darifenacin (OR 1.49; 95% CI 1.19-1.86), tolterodine (OR 1.21; 95% CI 1.02-1.45), and fesoterodine (OR 1.39; 95% CI 1.14-1.71) was associated with increased odds of incident dementia compared with receipt of mirabegron. No effect was seen with oxybutynin or trospium. Limitations included misclassification of the outcome and residual confounding associated with the use of health administrative databases. CONCLUSIONS: Older adults receiving solifenacin and darifenacin in the 6 mo prior to diagnosis, and those receiving solifenacin, darifenacin, tolterodine, or fesoterodine in the year prior to diagnosis, have increased odds of incident dementia, compared with those receiving mirabegron. Oxybutynin and trospium were not associated with dementia, likely due to a protopathic bias. Careful drug selection is warranted when treating patients with OAB. PATIENT SUMMARY: In a large Canadian cohort of patients who developed dementia after starting an overactive bladder (OAB) medication, those taking some anticholinergic medications for OAB have an increased risk of dementia compared with those taking mirabegron.

The cognitive effect of anticholinergics for patients with overactive bladder.

Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.

Vibegron improves quality-of-life measures in patients with overactive bladder: Patient-reported outcomes from the EMPOWUR study.

BACKGROUND: Quality of life (QOL) can be significantly impacted by symptoms of overactive bladder (OAB). Vibegron is a highly selective ß3 -adrenergic receptor agonist that showed efficacy in treatment of symptoms of OAB in the randomised, double-blind, placebo- and active-controlled phase 3 EMPOWUR trial. Here we report patient-reported QOL outcomes from the EMPOWUR trial. METHODS: Patients were randomly assigned 5:5:4 to receive vibegron 75 mg, placebo or tolterodine 4 mg extended release, respectively, for 12 weeks. Patients completed the OAB questionnaire (OAB-q) at baseline and at week 12 and the patient global impression (PGI) scales for severity, control, frequency and leakage at baseline and at weeks 4, 8 and 12. Change from baseline at week 12 and responder rates (OAB-q: patients achieving a ≥10-point improvement; PGI: patients reporting best possible response) were assessed. Vibegron was compared with placebo, and no comparisons were made between vibegron and tolterodine. RESULTS: Of the 1518 patients randomised, 1463 (placebo, n = 520; vibegron, n = 526; tolterodine, n = 417) had evaluable data for efficacy measures and were included in the analysis. Mean baseline OAB-q and PGI scores were comparable among treatment groups. At week 12, patients receiving vibegron had greater improvements from baseline in OAB-q subscores of coping, concern, sleep, health-related QOL total and symptom bother (P < .01 each) compared with patients receiving placebo; a greater proportion of patients receiving vibegron vs placebo were responders in the OAB-q coping (P < .05) and symptom bother scores (P < .0001). Compared with placebo, a greater proportion of patients who received vibegron achieved the best response on all PGI end-points at week 12 (P < .05 each) and were classified as responders (P < .05 each). CONCLUSIONS: In the 12-week EMPOWUR trial, treatment with vibegron was associated with significantly greater and clinically meaningful improvement in OAB-q and PGI scores compared with placebo, consistent with improvements in OAB symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03492281.

Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR).

PURPOSE: The long-term safety, tolerability and efficacy of vibegron in adults with overactive bladder were evaluated in the 40-week phase 3 EMPOWUR extension study. MATERIALS AND METHODS: Patients who completed 12 weeks of once-daily vibegron 75 mg or tolterodine 4 mg extended release in EMPOWUR continued double-blind treatment; patients who completed 12 weeks of placebo were randomly assigned 1:1 to receive double-blind vibegron or tolterodine. The primary outcome was safety, measured by incidence of adverse events. Secondary outcomes included change from baseline at week 52 in average daily number of micturitions and urgency episodes (all patients), and urge and total urinary incontinence episodes (patients with overactive bladder wet) based on 7-day diary data. RESULTS: Of 506 patients randomized 505 received ≥1 dose of medication, and 430 (85%) completed the study. A total of 12 patients (2.4%) discontinued owing to adverse events. The most common adverse events with vibegron/tolterodine (>5% in either group) were hypertension (8.8%/8.6%), urinary tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) and dry mouth (1.8%/5.2%). Improvements in efficacy end points were maintained for patients receiving vibegron for 52 weeks; least squares mean change from baseline to week 52 in micturitions was ‒2.4 for vibegron vs ‒2.0 for tolterodine; in urge urinary incontinence episodes ‒2.2 vs ‒1.7 (p <0.05); in urgency episodes ‒3.4 vs ‒3.2; and in total incontinence episodes ‒2.5 vs ‒1.9 (p <0.05). Among patients with overactive bladder wet 61.0% receiving vibegron experienced ≥75% reduction in urge urinary incontinence episodes after 52 weeks of treatment vs 54.4% with tolterodine, while 40.8% vs 34.2% experienced a 100% reduction. CONCLUSIONS: Vibegron demonstrated favorable long-term safety, tolerability and efficacy in patients with overactive bladder, consistent with results of the 12-week study.

International Phase III, Randomized, Double-Blind, Placebo and Active Controlled Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder: EMPOWUR.

PURPOSE: We assessed efficacy, safety and tolerability of vibegron, a novel, potent, highly selective ß3-adrenoceptor agonist, administered 12 weeks at 75 mg once daily to patients with overactive bladder in an international phase III trial with placebo and active control. MATERIALS AND METHODS: Adult patients with overactive bladder with 8.0 or more micturitions per day were randomized 5:5:4 to 75 mg vibegron, placebo or extended-release 4 mg extended-release tolterodine. Up to 25% of patients could have dry overactive bladder (less than 1.0 urge incontinence episode per day). Patients completed 7-day voiding diaries at baseline and weeks 2, 4, 8 and 12. RESULTS: Of 1,518 randomized patients 90.4% completed the trial. At 12 weeks micturitions decreased by an adjusted mean of 1.8 episodes per day for vibegron vs 1.3 for placebo (p <0.001, co-primary end point) and 1.6 for tolterodine. Among incontinent patients urge incontinence episodes decreased by an adjusted mean 2.0 episodes per day for vibegron vs 1.4 for placebo (p <0.0001, co-primary end point) and 1.8 for tolterodine. Moreover, vibegron was statistically significantly superior to placebo for key secondary measures of number of urgency episodes, volume per micturition and proportion of incontinent patients with a 75% or greater reduction in urge incontinence episodes (all p <0.01). Among vibegron treated patients 1.7% discontinued treatment because of adverse events vs 1.1% for placebo and 3.3% for tolterodine. Incidence of hypertension was 1.7% for vibegron and for placebo. CONCLUSIONS: Once daily 75 mg vibegron provided statistically significant reductions in micturitions, urgency episodes and urge incontinence, and increased the volume per micturition. Treatment was well tolerated with a favorable safety profile.

Antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica / Antimuscarinics (oxybutynin, tolterodine, solifenacin and darifenacin) for the treatment of storage dysfunction in patients with neurogenic bladder

INTRODUÇÃO: A bexiga neurogênica é um termo aplicado ao mau funcionamento da bexiga urinária e do esfíncter urinário, devido à disfunção neurológica que resulta de trauma, doença ou lesão interna ou externa. Alguns pacientes com disfunção neurogênica do trato urinário inferior apresentam sintomas que se relacionam com o armazenamento prejudicado de urina, como o aumento da frequência de micção, urgência urinária e incontinência urinária. PERGUNTA: Qual a eficácia e a segurança da oxibutinina, tolterodina, solifenacina e darifenacina para disfunção de armazenamento em pacientes adultos com bexiga neurogênica? TECNOLOGIAS: Antimuscarínicos (oxibutinina, tolderodina, solifenacina e darifenacina). EVIDÊNCIAS CIENTÍFICAS: Para a pergunta sobre a eficácia e segurança dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) foram recuperadas 868 referências por meio das estratégias de busca, das quais cinco foram incluídos, sendo todos ECR. Os principais desfechos de eficácia avaliados pelos estudos incluídos foram: capacidade máxima da bexiga, número de episódios de incontinência diária, número de cateterizações diárias, Incontinence Quality of Life (I-QoL) e escore Patient Perception of Bladder Condition (PPBC). Além dos desfechos de eficácia, foram avaliados os eventos adversos. Um estudo evidenciou que a oxibutina intravesical promoveu maior ganho em volume cistométrico que a oxibutinina oral (aumento médio (DP) de 116,6 (27,5) e 18,1 (27,5) mL, respectivamente para oxibutinina vesical e oral ­ p = 0,009). Ademais, um outro estudo evidenciou que a solifenacina, nas dosagens de 5 e 10 mg, e a oxibutinina, na dose de 15 mg, proporcionaram aumento significativo no volume cistométrico em relação ao placebo (aumento médio (DP) de 77,8 (115,4) mL, 134,2 (124,7) mL, e 134,2 (124,7) mL, respectivamente para solifenacina 5 mg, solifenacina 10 mg e oxibutinina de 15 mg ­ p<0,01 para todas as comparações versus placebo). Dois estudos compararam a tolterodina versus placebo, para o desfecho volume cistométrico. Um dos estudos não exibiu diferença entre os grupos. O outro mostrou efeito dose resposta para a tolterodina, sendo a dose de 4 mg a mais eficaz em relação ao placebo (p=0,009). Para o desfecho número de episódios de incontinência/dia, após quatro semanas, a oxibutinina 15 mg apresentou uma redução média (DP) de ­2,71 (2,84) episódios de incontinência/dia, enquanto o grupo que recebeu solifenacina 10 mg apresentou redução de ­0,57 (2,29) episódios de IU/dia (p<0,01), após quatro semanas. Outro estudo, que comparou a oxibutinina à tolterodina, ambas em dose personalizada (média de 8,4 mg/dia para tolterodina e 12,5 mg/dia para a oxibutinina), não mostrou diferença significante entre as terapias, para qualquer um dos desfechos de eficácia avaliados. O desfecho primário de qualidade de vida (I-QoL), apenas apresentou resultados de comparação para a oxibutinina, quando em formulação vesical versus oral. Nesse caso, não houve diferença estatisticamente significativa (p = 0,730). Para além dessa comparação, os desfechos de qualidade de vida (I-QoL) e funcionalidade (PPBC), não apresentaram resultados de comparação para qualquer outro estudo avaliado. Ademais, mesmo para o desfecho de redução de episódios de IU, existe dúvida em relação à significância clínica do resultado, haja vista que a redução média de episódios foi < 2 para a maioria dos estudos, diante de um cenário basal de 2-5 episódios/dia. A qualidade metodológica dos estudos foi baixa e não existem comparações diretas que englobem os quatro antimuscarínicos considerados (darifenacina, oxibutinina, tolterodina e solifenacina). AVALIAÇÃO ECONÔMICA: Os estudos avaliados neste relatório não incluíram a análise da darifenacina. Além disso, não existe um estudo que avalie os antimuscarínicos versus um comparador em comum e, mesmo que fosse estabelecida a comparação indireta entre eles, o desfecho primordial, que avalia a qualidade de vida, não está presente em todos os estudos incluídos. O estudo que permitiria o maior número de comparações seria o de Amarenco et al. 2015, pois incluiu a solifenacina em 5 e 10 mg, além da oxibutinina e o placebo. No entanto, o estudo não forneceu o valor da diferença entre os braços, quanto ao ganho em qualidade de vida (I-QoL), entre início e fim do estudo. Realizamos os testes estatísticos para essa diferença não relatada e vimos que todas, sem exceção, foram não significativas. Sendo assim, devido ao alto risco de viés do estudo de Amarenco et al. 2015, à falta de estudos que avaliassem a darifenacina e à ausência do desfecho I-QoL em alguns estudos, não seria plausível realizar uma análise econômica utilizando desfechos substitutos ou não significativos (estatística e clinicamente). AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário adotou a perspectiva do SUS e um horizonte temporal de cinco anos (2020-2024). O custo dos tratamentos medicamentosos limitou-se ao valor de aquisição dos medicamentos, (oxibutinina, tolterodina, solifenacina, darifenacina e mirabegrona) obtidos do Banco de Preços em Saúde. Dada a ausência de dados específicos para indivíduos com bexiga neurogênica, foram consideradas as quatro principais causas de bexiga neurogênica: doença de Parkinson (DP), esclerose múltipla (EM), acidente vascular cerebral (AVC) e danos na coluna vertebral (DCV). As porcentagens de uso dos agentes antimuscarínicos foram obtidas de uma publicação do Sistema de Saúde Inglês (NHS). Com isso, a estimativa de impacto orçamentário neste cenário decorrente da incorporação dos antimuscarínicos e mirabegrona seria de R$ 2.095.249.966,02 bilhões no primeiro ano de incorporação. Após cinco anos de incorporação esse valor seria de R$ 10.679.375.762,42 bilhões de reais. Cenários alternativos foram elaborados, considerando a incorporação de apenas um dos medicamentos. Nestes cenários as estimativas de impacto orçamentário, decorrentes da incorporação de cada um dos antimuscarínicos e mirabegrona, após cinco anos de incorporação, variaram de R$ 3.486.573.869,54 a R$ 20.415.826.991,67 bilhões de reais, sendo a oxibutinina e a tolterodina, respectivamente, os cenários de menor e maior custo. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: foram realizadas buscas no ClinicalTrials.gov e Cortellis™, a fim de localizar potenciais medicamentos para o tratamento de pacientes adultos com bexiga neurogênica. Não foram encontrados medicamentos nas fases de desenvolvimento clínico, contudo foi detectado a fesoterodina em estudo para pacientes pediátricos com incontinência urinária de causa neurológica. CONSIDERAÇÕES GERAIS: Os antimuscarínicos disponíveis atualmente no Brasil são: oxibutinina, tolterodina, solifenacina e darifenacina. No entanto, há pouca evidência científica sobre a eficácia e segurança desses medicamentos e qual seria o ideal para o tratamento de disfunção de armazenamento em pacientes neurogênicos adultos. A qualidade metodológica dos estudos encontrados foi baixa e não existem comparações diretas que englobem os quatro antimuscarínicos aqui considerados (darifenacina, oxibutinina, tolterodina e solifenacina). RECOMENDAÇÃO PRELIMINAR: pelo exposto, a Conitec, em sua 82ª reunião ordinária, no dia 09 de outubro de 2019, recomendou a não incorporação no SUS dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da bexiga neurogênica. Além do aspecto financeiro, considerou-se, primordialmente, a ausência de benefício clínico significante e baixa qualidade da evidência analisada. CONSULTA PÚBLICA: Foram recebidas nove contribuições de experiência ou opinião, sendo sete discordantes da recomendação preliminar, uma não discordou nem concordou e uma foi excluída por não ter conteúdo analisável. A Conitec entendeu que não houve argumentação suficiente para alterara sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 85º reunião ordinária, no dia 04 de fevereiro de 2020, deliberaram, por unanimidade, por recomendar a não incorporação no SUS dos antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica. DECISÃO: não incorporar os antimuscarínicos (oxibutinina, tolterodina, solifenacina e darifenacina) para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 9, publicada no Diário Oficial da União nº 49, seção 1, página 187, em 12 de março de 2020.

Effectiveness of Combined Behavioral and Drug Therapy for Overactive Bladder Symptoms in Men: A Randomized Clinical Trial.

Importance: First-line behavioral and drug therapies for overactive bladder (OAB) symptoms in men are effective but not usually curative. Objective: To determine whether combining behavioral and drug therapies improves outcomes compared with each therapy alone for OAB in men and to compare 3 sequences for implementing combined therapy. Design, Setting, and Participants: In this 3-site, 2-stage, 3-arm randomized clinical trial, participants were randomized to 6 weeks of behavioral therapy alone, drug therapy alone, or combined therapy followed by step-up to 6 weeks of combined therapy for all groups. Participants were recruited from 3 outpatient clinics and included community-dwelling men 40 years or older with urinary urgency and 9 or more voids per 24 hours. Data were collected from July 2010 to July 2015 and analyzed from April 2016 to September 2019. Interventions: Behavioral therapy consisted of pelvic floor muscle training with urge suppression strategies and delayed voiding. Drug therapy included an antimuscarinic (sustained-release tolterodine, 4 mg) plus an α-blocker (tamsulosin, 0.4 mg). Main Outcomes and Measures: Seven-day bladder diaries completed before and after each 6-week treatment stage were used to calculate reduction in frequency of urination (primary outcome) and other symptoms (ie, urgency, urgency incontinence, and nocturia). Other secondary outcomes included validated patient global ratings of improvement and satisfaction, Overactive Bladder Questionnaire score, and International Prostate Symptom Score. Results: Of the 204 included men, 133 (65.2%) were white, and the mean (SD) age was 64.1 (11.1) years. A total of 21 men discontinued treatment and 183 completed treatment. Mean (SD) voids per 24 hours decreased significantly in all 3 groups from baseline to 6-week follow-up (behavioral therapy: 11.7 [2.4] vs 8.8 [2.1]; change, 2.9 [2.4]; percentage change, 24.7%; P < .001; drug therapy: 11.8 [2.5] vs 10.3 [2.7]; change, 1.5 [2.3]; percentage change, 12.7%; P < .001; combined therapy: 11.8 [2.4] vs 8.2 [2.3]; change, 3.6 [2.1]; percentage change, 30.5%; P < .001). Intention-to-treat analyses indicated that posttreatment mean (SD) voiding frequencies were significantly lower in those receiving combined therapy compared with drug therapy alone (8.2 [2.3] vs 10.3 [2.7]; P < .001) but not significantly lower compared with those receiving behavioral therapy alone (8.2 [2.3] vs 8.8 [2.1]; P = .19) and were lower for behavioral therapy alone compared with drug therapy alone (8.8 [2.1] vs 10.3 [2.7]; P < .001). At 12-week follow-up, after all groups had received combined therapy, improvements in mean (SD) voids per 24 hours were also greatest for those receiving initial combined therapy compared with baseline (behavioral therapy: 11.7 [2.4] vs 8.0 [2.2]; change, 3.7 [2.3]; percentage change, 31.6%; P < .001; drug therapy: 11.8 [2.5] vs 8.6 [2.3]; change, 3.2 [2.5]; percentage change, 27.1%; P < .001; combined therapy: 11.8 [2.4] vs 8.0 [2.2]; change, 3.8 [2.1]; percentage change, 32.2%; P < .001), but there were no statistically significant group differences on primary or secondary measures. Conclusions and Relevance: Combining behavioral and drug therapy yields greater improvements in OAB symptoms than drug therapy alone but not behavioral therapy alone. When using a stepped approach, it is reasonable to begin with behavioral therapy alone. Trial Registration: ClinicalTrials.gov identifier: NCT01175382.

Hypnotherapy or medications: a randomized noninferiority trial in urgency urinary incontinent women.

BACKGROUND: Urgency urinary incontinence afflicts many adults, and most commonly affects women. Medications, a standard treatment, may be poorly tolerated, with poor adherence. This warrants investigation of alternative interventions. Mind-body therapies such as hypnotherapy may offer additional treatment options for individuals with urgency urinary incontinence. OBJECTIVE: To evaluate hypnotherapy's efficacy compared to medications in treating women with urgency urinary incontinence. MATERIALS AND METHODS: This investigator-masked, noninferiority trial compared hypnotherapy to medications at an academic center in the southwestern United States, and randomized women with non-neurogenic urgency urinary incontinence to weekly hypnotherapy sessions for 2 months (and continued self-hypnosis thereafter) or to medication and weekly counseling for 2 months (and medication alone thereafter). The primary outcome was the between-group comparison of percent change in urgency incontinence on a 3-day bladder diary at 2 months. Important secondary outcomes were between-group comparisons of percent change in urgency incontinence at 6 and 12 months. Outcomes were analyzed based on noninferiority margins of 5% for between group differences (P < 0.025) (that is, for between group difference in percentage change in urgency incontinence, if the lower bound of the 95% confidence interval was greater than -5%, noninferiority would be proved). RESULTS: A total of 152 women were randomized to treatment between April 2013 and October 2016. Of these women, 142 (70 hypnotherapy, 72 medications) had 3-day diary information at 2 months and were included in the primary outcome analysis. Secondary outcomes were analyzed for women with diary data at the 6-month and then 12-month time points (138 women [67 hypnotherapy, 71 medications] at 6 months, 140 women [69 hypnotherapy, 71 medications] at 12 months. There were no differences between groups' urgency incontinence episodes at baseline: median (quartile 1, quartile 3) for hypnotherapy was 8 (4, 14) and medication was 7 (4, 11) (P = .165). For the primary outcome, although both interventions showed improvement, hypnotherapy did not prove noninferior to medication at 2 months. Hypnotherapy's median percent improvement was 73.0% (95% confidence interval, 60.0-88˖9%), whereas medication's improvement was 88.6% (95% confidence interval, 78.6-100.0%). The median difference in percent change between groups was 0% (95% confidence interval, -16.7% to 0.0%); because the lower margin of the confidence interval did not meet the predetermined noninferiority margin of greater than -5%, hypnotherapy did not prove noninferior to medication. In contrast, hypnotherapy was noninferior to medication for the secondary outcomes at 6 months (hypnotherapy, 85.7% improvement, 95% confidence interval, 75.0-100%; medications, 83.3% improvement, 95% confidence interval, 64.7-100%; median difference in percent change between groups of 0%, 95% confidence interval, 0.0-6.7%) and 12 months (hypnotherapy, 85.7% improvement, 95% confidence interval, 66.7-94.4%; medications, 80% improvement, 95% confidence interval, 54.5-100%; median difference in percent change between groups of 0%, 95% confidence interval, -4.2% to -9.5%). CONCLUSION: Both hypnotherapy and medications were associated with substantially improved urgency urinary incontinence at all follow-up. The study did not prove the noninferiority of hypnotherapy compared to medications at 2 months, the study's primary outcome. Hypnotherapy proved noninferior to medications at longer-term follow-up of 6 and 12 months. Hypnotherapy is a promising, alternative treatment for women with UUI.

Safety and Efficacy of Mirabegron: Analysis of a Large Integrated Clinical Trial Database of Patients with Overactive Bladder Receiving Mirabegron, Antimuscarinics, or Placebo.

BACKGROUND: Mirabegron, a ß3-adrenoreceptor agonist, is an alternative drug to antimuscarinics for overactive bladder (OAB) symptoms. OBJECTIVE: To summarise safety and efficacy reporting of mirabegron treatment for OAB symptoms. DESIGN, SETTING, AND PARTICIPANTS: Pooled data analysed from 10 phase 2-4, double-blind, 12-wk mirabegron monotherapy studies in adults with OAB who had received one or more doses of study drug. INTERVENTION: Mirabegron: 25 and 50mg; antimuscarinics: solifenacin (2.5, 5, and 10mg) and tolterodine extended release (4mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline OAB-related characteristics, intrinsic and extrinsic factors, and analyses by age (<65 vs ≥65yr and <75 vs ≥75yr) and sex were assessed. Solifenacin 2.5 and 10mg groups were not included in the efficacy analyses (small patient numbers). Safety was evaluated using the proportion of treatment-emergent adverse events. Efficacy variables were derived from bladder diaries (baseline and week 12). RESULTS AND LIMITATIONS: Baseline hypertension and diabetes were more frequent across treatment groups in the older versus younger age groups and in men versus women. Within sexes, frequencies were similar between treatment groups. Some differences were observed in baseline characteristics, including type of incontinence and medical history between sexes. No previously unreported safety concerns were identified. Improvements in efficacy (mean number of incontinence episodes/24h, micturitions/24h, urgency episodes/24h, volume voided/micturition, and nocturia episodes) versus placebo were observed in all treatment groups. Significant treatment-by-subgroup interactions included change from baseline in the mean number of incontinence episodes/24h by age (<65 vs ≥65yr), nocturia by age (<65 vs ≥65yr and <75 vs ≥75yr), and urgency episodes by previous OAB medication. CONCLUSIONS: Data from this integrated database of 10 mirabegron studies reaffirm the safety and efficacy profiles of mirabegron, solifenacin, and tolterodine in adults of different age groups and sexes. PATIENT SUMMARY: Overactive bladder is a complex of symptoms including a compelling desire to pass urine that leads to increased frequency, which may lead to a degree of incontinence if you do not reach the toilet in time and may wake you from sleep. We pooled data from 10 different studies of mirabegron in patients with overactive bladder symptoms, and looked at the effect in the total number of patients who received the treatment, as well as in different age groups and between men and women. No new safety concerns were identified, and mirabegron improved the symptoms of overactive bladder.