Tag Archive for: OAB

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May Editorial: The Current Hot Topics in Functional Urology

BJUI-May-2015-cover_smallFor some time, the challenge represented by managing the overactive bladder (OAB) has been dominant in functional urology research. The introduction of new therapies has galvanised the area, with mirabegron showing strong promise for many patients as a monotherapy. In addition, the potential for combined therapy using mirabegron with established antimuscarinics has recently been reported for urgency urinary incontinence [1]. Now that the place of onabotulinum-A injections in refractory cases is firmly established, management options have clearly taken a step forward in recent years. However, there remain people for whom even the more comprehensive current options are inadequate or intolerable. The need for basic science research remains a priority, in the hope of translation into clinical options. In this month’s BJUI, Aizawa et al. [2] report responses in an animal model to an inhibitor of fatty acid amide hydrolase, showing how exploiting the endocannabinoid pathway might be a translational focus for entirely new approaches in OAB. They consider an issue that is very important in developing clinical options, which is that the systems regulating bladder function are also fundamental in other organs, such as the CNS. As the compound they studied does not cross the blood–brain barrier, the potential generation of CNS adverse effects is reduced, which would be important for its potential as a new therapy.

OAB is a symptom syndrome based on storage-type LUTS [3]. Increasingly the field of functional urology is recognising the large number of people who present with voiding and post-micturition LUTS yet do not have BOO. Currently, there are no satisfactory treatment options for affected people and the symptoms can have considerable impact. Frustratingly, current diagnostic methods rely on urodynamic testing to establish whether the presence of detrusor underactivity explains voiding LUTS in an individual patient. Recently, the profession has established a move towards using symptoms to categorise the clinical need in patients [4]. Accordingly, the International Continence Society has established a working group to generate terminology for underactive bladder (UAB), which will report this year, including a symptom-based definition. A symptomatic diagnosis would be very helpful to enable therapy development to proceed without the need for urodynamic testing. Also, in this month’s BJUI, Kajbafzadeh et al. [5] report a clinical trial in UAB using transcutaneous interferential electrical stimulation in children. The treatment was delivered in the context of the rather laborious process currently required for managing this difficult problem, namely diet and fluid manipulation, scheduled voiding, toilet training, and pelvic floor and abdominal muscles relaxation training. The electrical stimulation was demonstrably beneficial, and included responses for the highly troublesome symptom of nocturnal enuresis. The comparatively straightforward nature of this therapeutic approach potentially makes it a valuable tool for dealing with a notoriously difficult problem.

Marcus J. Drake, Senior Lecturer
School of Clinical Sciences, University of Bristol, Bristol, UK

 

References

 

 

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.
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