Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective,head‐to‐head,placebo‐controlled trial

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? A previous trial found greater efficacy with the maximum available dose of fesoterodine 8 mg compared with the maximum available dose of tolterodine ER 4 mg and placebo for improving overactive bladder symptoms, and patient‐reported outcomes were demonstrated by a recent placebo‐controlled, head‐to‐head trial. The results of this trial, the largest to date to compare antimuscarinic efficacy, confirms the superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms, and further emphasize the clinical advantage of the availability of an additional 8‐mg dose over single‐dose tolterodine ER 4 mg.

OBJECTIVE

? To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo‐controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient‐reported outcomes.

MATERIALS AND METHODS

? In this 12‐week, double‐blind, double‐dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. ? Subjects completed 3‐day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12.

RESULTS

? A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). ? Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. ? Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively.

CONCLUSIONS

? In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self‐reported patient assessments of bladder‐related problems, urgency, symptom bother and health‐related quality of life. ? The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER.     

Efficacy of extended‐release tolterodine for the treatment of neurogenic detrusor overactivity and/or low‐compliance bladder

Objective: To evaluate the efficacy of extended‐release (ER) tolterodine 4 mg/day for the treatment of neurogenic detrusor overactivity (NDO) and/or low‐compliance bladder by assessing urodynamic parameters. Methods: Forty‐six patients (25 male, 21 female; mean age 57.6 ± 20.7 years) with NDO (n = 39) and/or low‐compliance bladder (n = 7) were included in this 12‐week single‐arm study. Twenty‐one patients (46%) were on clean intermittent catheterization and other patients could void on their own. A video urodynamic study was performed before and at 3 months after treatment. Changes in Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire–Short Form (ICIQ‐SF), and King's Health Questionnaire (KHQ) as well as changes in number of voids, amount of each void, and number of leaks in 24 h according to the 3‐day voiding diary were also evaluated before treatment and at weeks 4 and 12 after treatment. Results: Bladder capacity at first sensation and maximum cystometric capacity increased significantly, by an average of 36.8 mL (P = 0.0402) and 82.3 mL (P < 0.0001), respectively. Maximum cystometric capacity increased by more than 50 mL in 19 patients (49%) following treatment. Detrusor overactivity disappeared in three of 32 patients (9%), bladder capacity at first involuntary contraction increased significantly (P = 0.0009), and amplitude of detrusor overactivity decreased significantly (P = 0.0025). In patients with low‐compliance bladder, bladder compliance increased significantly (P = 0.0156). Overactive bladder symptom score, International Consultation on Incontinence Questionnaire–Short Form score, number of voids (per 24 h and night‐time), number of urgency episodes in 24 h, number and amount of leaks in 24 h, and amount of mean and maximum voided volumes all decreased significantly after treatment. Conclusion: Tolterodine is effective and well tolerated for the treatment of NDO and/or low‐compliance bladder in patients with neurogenic bladder.     

Mirabegron or tolterodine for the treatment of overactive bladder in Japan: Which drug is more cost‐effective as the first‐line treatment?

Objectives

To assess the cost‐effectiveness of mirabegron 50 mg relative to tolterodine extended release 4 mg for the treatment of overactive bladder if used as the first‐line treatment in Japan.

Methods

A Markov model was developed to simulate the cost‐effectiveness of the mirabegron first‐line treatment (and tolterodine second‐line) versus tolterodine first‐line treatment (and mirabegron second‐line) taken for 5 years from the randomized European‐Australian study (SCORPIO trial) and single technology appraisal assessment report by the National Institute for Health and Care Excellence. The incremental cost‐effectiveness ratio was calculated with utility value by quality‐adjusted life year with cost using the medical fee and the drug price tariff in 2016. For the study of transition of treatment status, our analytical model was established. The transition probabilities of severity states were calculated based on the probabilities for the mean numbers of incontinence episodes/day and micturition episodes/day in mirabegron‐treated and tolterodine‐treated patients in the single technology appraisal assessment report.

Results

The 5‐year expected effect per patient was 3.860 quality‐adjusted life years for first‐line mirabegron and 3.839 quality‐adjusted life years for first‐line tolterodine. The 5‐year expected cost per patient was ¥526 191 for first‐line mirabegron, and ¥472 390 for first‐line tolterodine. The incremental cost‐effectiveness ratio was ¥2 565 927/quality‐adjusted life year. This value was below the willingness‐to‐pay threshold of ¥5 million/quality‐adjusted life year. In more severe states, the incremental cost‐effectiveness ratio exceeded ¥5 million.

Conclusions

First‐line mirabegron appears to be more cost‐effective than first‐line tolterodine. In patients with severe symptoms, first‐line mirabegron is not economically preferable.

     

不同α受体阻滞剂联合M受体阻滞剂治疗BPH下尿路症状的尿流动力学研究

目的:比较多沙唑嗪联合托特罗定与坦索罗辛联合托特罗定治疗良性前列腺增生(BPH)下尿路症状(LUTS)的尿流动力学变化的研究。方法:选取诊断明确的BPH患者50例,采用随机非双盲方法平均分为A、B两组,A组患者服用多沙唑嗪联合酒石酸托特罗定缓释剂、B组患者服用坦索罗辛联合酒石酸托特罗定缓释剂联合治疗12周,于治疗前后对潴尿期与排尿期的相关尿流动力学指标,如最大尿流率(Qmax)、膀胱剩余尿量、最大膀胱容量、排尿开始时膀胱压、膀胱顺应性等进行比较。结果:两组在治疗前的各项指标无统计学意义。服药治疗12周后,两组Qmax、排尿开始时膀胱压、膀胱顺应性均较治疗前有明显改善。而剩余尿量和最大膀胱容量较治疗前无明显变化。治疗后两组间比较,A组Qmax、排尿开始时膀胱压、膀胱顺应性均优于B组(P0.05),而两治疗组之间的剩余尿量及最大膀胱容量差异无统计学意义(P0.05)。结论:α受体阻滞剂联合M受体阻滞剂治疗BPH能明显提高Qmax,降低排尿开始时膀胱压力,改善膀胱顺应性,且多沙唑嗪联合应用M受体阻滞剂优于坦索罗辛联合应用M受体阻滞剂。     

Efficacy and tolerability of tolterodine extended-release in continent patients with overactive bladder and nocturia

OBJECTIVE: To evaluate the clinical efficacy and tolerability of tolterodine extended-release (ER) in continent patients with overactive bladder (OAB) and nocturia. PATIENTS AND METHODS: A post hoc analysis was conducted of data from a 12-week, double-blind study of 850 patients randomized to tolterodine ER (4 mg once daily) or placebo, taken within 4 h of going to bed. Patients with a mean of > or = 8 voids/24 h were enrolled, including a mean of > or = 2.5 voids/night. Patients completed 7-day voiding diaries, and for each void an urgency rating was assessed using a 5-point scale (1, none; 5, urgency incontinence); 24-h voids were categorized by urgency rating: total (1-5), non-OAB (1-2), OAB (3-4), and severe OAB (4-5) voids. All adverse events were recorded. RESULTS: The post hoc analysis included 513 patients (243 placebo; 270 tolterodine ER; 58% men) who were continent at baseline; 47% of 24-h voids were classed as non-OAB, and 12% as severe OAB. After 12 weeks of treatment, tolterodine ER significantly reduced mean urgency rating and 24-h OAB, severe OAB, and total voids vs placebo. Tolterodine ER did not affect normal, non-OAB voids, and there were no significant adverse events related to voiding. Other than dry mouth (tolterodine ER, 9% vs placebo, 2%), all the adverse events were reported in <3% of patients; <2% of patients receiving tolterodine ER withdrew because of adverse events. CONCLUSIONS: In continent patients with OAB, tolterodine ER significantly improved urgency rating and reduced 24-h OAB, severe OAB, and total voids, suggesting that it is an effective and well-tolerated treatment option for this subpopulation. More studies are needed to better understand the clinical efficacy of tolterodine ER in this under evaluated group of OAB patients without incontinence.     

Efficacy and tolerability of tolterodine extended-release in men with overactive bladder and urgency urinary incontinence

A group of authors from the USA evaluated the efficacy and tolerability of tolterodine extended-release on objective and subjective endpoints in men with an overactive bladder. They found that it significantly reduced incontinent episodes and improved patient perception of treatment benefit in men with an overactive bladder OBJECTIVE: To evaluate the efficacy and tolerability of tolterodine extended-release (ER) on objective and subjective endpoints in men with overactive bladder (OAB) and urgency urinary incontinence (UI). PATIENTS AND METHODS This was a post hoc analysis of data collected from men with OAB enrolled in a 12-week, double-blind, placebo-controlled trial of tolterodine ER (4 mg once daily; tolterodine ER registration trial) and included men with urinary frequency (> or =8 micturitions/24 h) and urgency UI (> or =5 episodes/week). UI episodes were assessed using 7-day bladder diaries. Patient perception of treatment benefit was evaluated after 12 weeks. Adverse events (AEs) were recorded throughout the study. RESULTS: In all, 163 men with OAB (placebo, 86; tolterodine ER, 77; mean age 65 years) were evaluated. Baseline demographics and clinical characteristics were similar for the two treatment groups. Compared with placebo, tolterodine ER significantly reduced weekly UI episodes (median % change, -71% vs - 40%, P < 0.05; mean numeric change, - 11.9 vs -5.9, P = 0.02). Men receiving tolterodine ER had fewer micturitions/24 h, but this was not a significant difference from placebo (median % change, -12% vs - 4%, P = 0.22). Significantly more men treated with tolterodine-ER (63%) than placebo-treated men (46%) reported a benefit of treatment after 12 weeks (P = 0.04). The most commonly reported AEs associated with tolterodine-ER vs placebo were dry mouth (16% vs 7%), constipation (4% vs 9%), dyspepsia (4% vs 1%), dizziness (5% vs 1%), and somnolence (3% vs 1%). One of the men receiving tolterodine ER had symptoms suggestive of urinary retention that led to his withdrawal from the study. None of the men had acute urinary retention requiring catheterization. CONCLUSION: In men with OAB and urgency UI, tolterodine ER was well tolerated and significantly reduced episodes of urgency UI, and improved patient perception of treatment benefit.     

生物反馈／电刺激联合托特罗定治疗女性膀胱过度活动症

目的：评价生物反馈／电刺激联合托特罗定治疗女性膀胱过度活动症（OAB）的疗效。方法：60例女性OAB患者采用生物反馈／电刺激（20天）联合口服托特罗定（4周）进行治疗,结束后3个月评价疗效并追踪观察。结果：60例女性OAB患者中,治愈32例（53．3％）,有效22例（36．7％）,无效6例（10．0％）,总有效率达90％。54例获6个月追踪观察,无复发。结论：生物反馈／电刺激联合托特罗定是治疗女性OAB的一种有效方法。     

Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder in Japanese patients

AIM: To evaluate the long-term safety, tolerability and efficacy of extended-release (ER) tolterodine in Japanese patients completing 12-week treatment in a randomized, double-blind trial comparing tolterodine ER 4 mg once daily, oxybutynin 3 mg three times daily or placebo in patients with overactive bladder. METHODS: Of 293 Japanese patients completing the 12-week study, 188 continued in the open-label trial and received tolterodine ER 4 mg once daily for 12 months, irrespective of previous treatment. The primary objective was to assess the safety of tolterodine ER for up to 52 weeks of treatment and at post-treatment follow-up. Secondary endpoints included changes in micturition diary variables, patient perception of bladder condition and urgency and treatment benefit. RESULTS: Overall, 77% of patients completed 12 months of open-label treatment. Tolterodine ER was well tolerated and the most common adverse event was dry mouth (33.5%). In general, there was no increase in adverse event frequency with long-term treatment compared with short-term treatment. The efficacy of tolterodine ER was maintained over the 12-month period. The complete analysis showed a median reduction in incontinence episodes/week (-92.9%; mean reduction, -77.2%), a mean reduction in micturitions/24 h (-21.3%) and a mean increase in volume voided per micturition (19.6%). Of patients completing the 12-month study, 78.6% reported improvement in patient perception of bladder condition, 52.4% reported improvement in perception of urgency and 89.7% reported treatment benefit. CONCLUSIONS: Favorable safety, tolerability and efficacy of once-daily tolterodine ER was maintained over 12 months in a Japanese overactive bladder patient population.