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Article of the week: Both men and women with OAB find better relief with fesoterodine

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video by Dr. Ginsberg and colleagues.

If you only have time to read one article this week, it should be this one.

Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder

David Ginsberg, Tim Schneider*, Con Kelleher, Philip Van Kerrebroeck, Steven Swift§, Dana Creanga and Diane L. Martire**

Department of Urology, University of Southern California, Los Angeles, CA, §Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC, Consultant to Pfizer Inc, **Pfizer Inc, New York, NY, USA, *Praxisklinik Urologie Rhein/Ruhr, Mülheim, Germany, St. Thomas’ Hospital, London, UK, and Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands

OBJECTIVE

• To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men.

SUBJECTS AND METHODS

•  Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed.

• Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h.

• Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo.

• Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the ‘diary-dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary).

• The primary endpoint was the change from baseline to week 12 in UUI episodes.

RESULTS

• At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n= 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005).

• Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001).

• In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04).

• The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%).

• Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%).

CONCLUSION

• This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women.

• In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

 

Read Previous Articles of the Week

 

Editorial: Fesoterodine is superior to extended-release tolterodine for OAB

The treatment of overactive bladder (OAB) is still based on antimuscarinics, although the recent introduction of β3 agonists and botulinum toxin A has opened a window of new opportunities, the range of which is yet to be defined.

The clinical development of fesoterodine has taken the Urological community by surprise and raised levels of expectation. From a pharmacological standpoint fesoterodine is just a ‘smart drug’ because it is the pro-drug of 5-hydroxymethyl tolterodine (5-HMT) the active metabolite of tolterodine that is metabolised into 5-HMT by cytochrome P450 (CYP) enzymes, the activity of which is known to suffer significant genetic variability. Fesoterodine is transformed into 5-HMT by nonspecific esterase pathways. Pharmacokinetic studies of fesoterodine have shown highly predictable plasma levels of the 5-HMT after fesoterodine administration. Whether or not the better bioavailability offered by the esterase-related activation pathway translates into a larger clinic benefit for our patients with OAB was initially unclear. A phase II study showed a good safety profile and suggested that two different doses of fesoterodine could be proposed with a good balance between efficacy and adverse events. Results of the pivotal phase III study confirmed how the two different doses: 4 and 8 mg, tended to separate with a larger benefit observed with the larger dose, although a slightly larger incidence of adverse events was observed. As long as the comparison between 4 and 8 mg of fesoterodine was not part of the pre-planned analysis, the results of thepost hoc analysis had to be confirmed in a properly design prospective randomised trial.

The assumption that a higher drug dose brings a larger therapeutic effect is very often just wishful thinking and clinical pharmacology has often disproved such a belief. What is instead clear, from the paper of David Ginsberg et al., which pools data from two randomised trials (BJU Int 2010, BJU Int 2011), is that the flexible dosage available with fesoterodine brings a clinically relevant advantage in our daily practice.

The question is whether there is a real need for dose flexibility in the management of OAB. After a couple of decades in this area, I strongly believe that flexible dosing is crucial, in general, and even more so in functional urology. This is in fact an area where storage and voiding function needs to be rebalanced; a too weak or too strong effect may easily lead to a therapeutic failure. Reaching the right balance between therapeutic effect and adverse events is crucial while using antimuscarinics. If 40% of patients who withdraw from anticholinergic medications do so because of insufficient benefit, another large proportion (22%) discontinues treatment because of side-effects.

The question in real-life practice, provided treatment should be initiated with a 4 mg dose because of regulatory issues, is whether the dose should be upgraded and when, should this be left to the individual patient’s decision or should it be guided by the treating physician? There is no ‘golden’ rule and in my opinion is a matter of patient expectations. Most patients expect drugs to cure the conditions they are prescribed for, although we know this is rarely the case. When patients are properly informed about the effect of antimuscarinics treatment they will often choose their goal, some patients will look for reducing OAB symptoms while avoiding dry mouth and constipation as much as possible, others will want to become dry and accept higher levels of adverse events. Furthermore, because of body distribution, different doses of drugs may be required in a 45 kg lady and in a 90 kg man, although this may depend on the drug bioavailability at the target organ. The same applies to patients with normal detrusor contractility and patients with a weak bladder, such as patients with multiple sclerosis. The ‘one dose fits all’ approach does not seem to be the way to go.

The larger therapeutic effect achieved in the 8 mg fesoterodine group is obtained at the expense of almost doubling the incidence of dry mouth (from 15% to 28%), although the increase in the constipation rate is just 1%. Whether or not the observed differential improvement between tolterodine 4 mg and fesoterodine 8 mg is clinically relevant is matter for discussion for the investigators but looking at the parallel improvement in all patients reported outcomes, the difference seems to be of importance from the patient perspective.

The therapeutic area of storage disorders, e.g. OAB, is experiencing a number of paradigm changes, including the availability of flexible dosing of antimuscarinics, β3 agonists and botulinum toxin A. What once used to be a neglected area of functional urology is now an exciting area of basic and clinical research.

Andrea Tubaro and Cosimo De Nunzio*
Urology Unit, Department of Clinical and Molecular Medicine, Faculty of Health Sciences, Sapienza University, and *Urology Unit, Sant’Andrea Hospital, Rome, Italy

Read the full article

Video: Fesoterodine vs tolterodine in men and women with OAB

Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder

David Ginsberg, Tim Schneider*, Con Kelleher, Philip Van Kerrebroeck, Steven Swift§, Dana Creanga and Diane L. Martire**

Department of Urology, University of Southern California, Los Angeles, CA, §Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC, Consultant to Pfizer Inc, **Pfizer Inc, New York, NY, USA, *Praxisklinik Urologie Rhein/Ruhr, Mülheim, Germany, St. Thomas’ Hospital, London, UK, and Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands

OBJECTIVE

• To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men.

SUBJECTS AND METHODS

•  Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed.

• Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h.

• Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo.

• Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the ‘diary-dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary).

• The primary endpoint was the change from baseline to week 12 in UUI episodes.

RESULTS

• At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n= 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005).

• Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001).

• In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04).

• The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%).

• Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%).

CONCLUSION

• This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women.

• In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

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