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Article of the Week: Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an alpha-blocker

Every Week the Editor-in-Chief selects an 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 from Dr. Tae Heon Kimdiscussing his paper. 

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

Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an alpha-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial

Tae Heon Kim*, Wonho Jung†, Yoon Seok Suh*, Soonhyun Yook‡, Hyun Hwan Sung* and Kyu-Sung Lee*‡
*Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, †Department of Urology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, and ‡Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea Tae Heon Kim and Wonho Jung contributed equally to this work.

 

Objective
To evaluate the efficacy and safety of low-dose (2 mg) tolterodine extended release (ER) with an a-blocker compared with standard-dose (4 mg) tolterodine ER with an α-blocker for the treatment of men with residual storage symptoms after α-blocker monotherapy.
Patients and Methods
The study was a 12-week, single-blind, randomized, parallel group, non-inferiority trial that included men with residual storage symptoms despite receiving at least 4 weeks of α-blocker
treatment. Inclusion criteria were total International Prostate Symptom Score (IPSS) ≥12, IPSS quality-of-life item score ≥3, and ≥8 micturitions and ≥2 urgency episodes per 24 h. The primary outcome was change in the total IPSS score from baseline. Bladder diary variables, patient-reported
outcomes and safety were also assessed.
feb-2-aotw-f1
Results
Patients were randomly assigned to addition of either 2 mg tolterodine ER (n = 47) or 4 mg tolterodine ER (n = 48) to α-blocker therapy for 12 weeks. Patients in both treatment groups had a significant improvement in total IPSS score (5.5 and 6.3, respectively), micturition per 24 h (1.3 and
1.7, respectively) and nocturia per night (0.4 and 0.4, respectively). Changes in IPSS, bladder diary variables, and patient-reported outcomes were not significantly different between the treatment groups. All interventions were well tolerated by patients.
Conclusions
These results suggest that 12 weeks of low-dose tolterodine ER add-on therapy is similar to standard-dose tolterodine ER add-on therapy in terms of efficacy and safety for patients experiencing residual storage symptoms after receiving α-blocker monotherapy.

 

Editorial: Should we start with low-dose anti-cholinergics when alpha-blockers alone fail?

Kim et al. [1] asked the question whether we should start by treating men who have persistent storage LUTS despite α-blocker monotherapy, with a low-dose anti-cholinergic as opposed to the standard dose (given the potentially increased risk of side-effects such as acute urinary retention and high discontinuation rates with the standard dose). It is a valid question, for we know that discontinuation rates with standard doses of anti-cholinergics can be as high as 50% in the first 3 months due to a combination of ineffectiveness and side-effects [2]. However, the problem lies in the multifactorial nature of the causes of storage vs voiding LUTS, and the difficulty in assessing and distinguishing them accurately with our current tools.

The authors have conducted a randomised controlled trial of 2 mg vs 4 mg tolterodine added to the participants’ on-going α-blocker regime and selected reduction in total IPSS as their primary outcome measure. They have also assessed IPSS sub-scores, 3-day bladder diary variables, and the Patient Perception of Bladder Condition (PPBC) and Overactive Bladder (OAB-q) questionnaires, as secondary outcomes. As would be expected of a peer-reviewed publication the trial has been seemingly well conducted and fairly well reported. Recruitment met the requirement set by the power calculation based on a clinically significant difference of a 4-point drop in total IPSS, and the authors concluded that 2 mg tolterodine is not inferior to the 4 mg dose in achieving a significant reduction in total IPSS at 12 weeks. They also report no difference in patient perception of treatment benefit or satisfaction at this time point.

These results are interesting, especially considering some of the details of the study. First of all, patients were not on the same α-blocker at baseline; the most common was tamsulosin (62.8%), but alfuzosin, doxazosin, and others were also being used. This in itself may not be a problem because all patients continued on the same α-blocker through the study, and in fact this better represents real-world practice. However, the mean (sd) duration of α-blocker therapy at baseline was 9.1 (19.9) months. We know that α-blocker therapy can improve IPSS by up to 30–40% [3], but the pertinent question for this study is whether these patients had achieved this level of improvement initially then stabilised and improved no further, or whether they had no improvement at all? It could conceivably make a difference to participants approach to the IPSS if they were previously familiar with it and, more importantly, aware of their results. The Hawthorne effect, also known as the observer effect, and the related Heisenberg uncertainty principle, are factors that we must necessarily encounter in clinical trials but we sometimes fail to account for.

Another aspect of the study that warrants consideration is the choice of primary outcome itself. This is a particular bug-bear of mine and indeed has been commented on by many authors including in the European Association of Urology (EAU) guideline on urinary incontinence in relation to anti-muscarinics [4]. Outcomes that lend themselves to easier power calculations and statistically significant results have almost evolved to be ‘un’-naturally selected for the purpose of clinical trial primary outcome measures. Drug trials are especially notorious for this. Here again, the choice of the total IPSS to assess whether an anti-muscarinic will help improve persistent storage LUTS is a case in point. Not least because it renders the significance of all the secondary outcomes dependant on the same power calculation. It is no doubt convenient, but is it appropriate? It is easy to point the finger at trialists for this, but the business-like, ‘bottom-line’ nature of medical publishing and research today is equally, if not more, to blame.

Finally, I would like to call the reader’s attention to the difference in baseline urgency and urgency urinary incontinence (UUI) episodes. The author’s state there was no statistically significant difference, but one might argue that when assessing improvement in storage LUTS, a group with a mean (sd) baseline number of UUI episodes of 3.9 (8.6) may perceive improvement quite differently compared with a group with a baseline of 1.6 (1.1). This has borne out in the difference in the bladder diary outcome of UUI/24 h; significant improvement in the first group (who were wetter at baseline and got 4 mg tolterodine) but no difference in the latter group (comparatively drier and got 2 mg tolterodine). But almost paradoxically this does not seem to have made a difference to the patient-reported outcome measures. One possible explanation for this could be the relatively few patients who were incontinent at baseline.Overall this paper gives us a lot of food for thought. The direct result – should we indeed start men with persistent storage LUTS on low-dose anti-cholinergics rather than standard dose, and then titrate upwards? But it also challenges us to consider whether we simply accept researcher’s and sponsor’s decisions on outcome measures. What do you think? Do we simply sit back and accept what is put before us because statistics scares us a little? Or, as researchers and consumers of medical literature, do we struggle to make the hard choices, risk our results being rejected by the top journals, and stand up for good science?

Conflicts of Interest

The author has received a travel grant to attend an international conference from Ferring pharmaceuticals.

 

Arjun K. Nambiar
Clinical Research Registrar
Department of Urology, Morriston Hospital, Abertawe Bro Morgannwg (ABM) University Local Health Board, Swansea, SA6 6NL, UK

 

References

 

1 Kim TH, Jung W, Suh YS, Yook S, Sung HH, Lee KS. Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an a-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial. BJU Int 2015; 117:  307–15
2 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.4. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17-Urinary-Incontinence_LR.pdf. Accessed September 2015
3 Gravas S, Bach T, Bachmann A et al. Guidelines on Non-Neurogenic Male LUTS Including Benign Prostatic Obstruction, Section 3C.2. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/11-Male-LUTS_LR.pdf. Accessed September 2015
4 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.1. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17- Urinary-Incontinence_LR.pdf. Accessed September 2015

 

Video: Tolterodine combined with an alpha-blocker in men with LUTS and OAB

Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an α-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial

Tae Heon Kim*, Wonho Jung†, Yoon Seok Suh*, Soonhyun Yook‡, Hyun Hwan Sung*
and Kyu-Sung Lee*‡
*Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, †Department of Urology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, and ‡Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea Tae Heon Kim and Wonho Jung contributed equally to this work.

 

Objective
To evaluate the efficacy and safety of low-dose (2 mg) tolterodine extended release (ER) with an a-blocker compared with standard-dose (4 mg) tolterodine ER with an α-blocker for the treatment of men with residual storage symptoms after α-blocker monotherapy.
Patients and Methods
The study was a 12-week, single-blind, randomized, parallel group, non-inferiority trial that included men with residual storage symptoms despite receiving at least 4 weeks of α-blocker
treatment. Inclusion criteria were total International Prostate Symptom Score (IPSS) ≥12, IPSS quality-of-life item score ≥3, and ≥8 micturitions and ≥2 urgency episodes per 24 h. The primary outcome was change in the total IPSS score from baseline. Bladder diary variables, patient-reported
outcomes and safety were also assessed.
Results
Patients were randomly assigned to addition of either 2 mg tolterodine ER (n = 47) or 4 mg tolterodine ER (n = 48) to α-blocker therapy for 12 weeks. Patients in both treatment groups had a significant improvement in total IPSS score (5.5 and 6.3, respectively), micturition per 24 h (1.3 and
1.7, respectively) and nocturia per night (0.4 and 0.4, respectively). Changes in IPSS, bladder diary variables, and patient-reported outcomes were not significantly different between the treatment groups. All interventions were well tolerated by patients.
Conclusions
These results suggest that 12 weeks of low-dose tolterodine ER add-on therapy is similar to standard-dose tolterodine ER add-on therapy in terms of efficacy and safety for patients experiencing residual storage symptoms after receiving α-blocker monotherapy.

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

Read the full article
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

Read the full article
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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