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The medical management of refractory Overactive Bladder
Maturitas 74 (2013) 386–390
Contents lists available at SciVerse ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
The medical management of refractory Overactive Bladder Dudley Robinson ∗ , Ilias Giarenis, Linda Cardozo Department of Urogynaecology, Kings College Hospital, United Kingdom
a r t i c l e
i n f o
Article history: Received 11 January 2013 Accepted 14 January 2013
Keywords: Management Refractory Overactive Bladder Antimuscarinics
a b s t r a c t Overactive Bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Those women with refractory or intractable symptoms following initial conservative and antimuscarinic medication may benefit from further assessment and investigation of their symptoms prior to considering different approaches to drug therapy. This review is the first of two to cover the management of intractable OAB in women and provides a practical clinical approach to managing women with refractory OAB symptoms. This paper covers the investigation and medical management of this demanding patient group whilst the second paper will focus on the role of more invasive treatments such as Botulinum Toxin, neuromodulation and reconstructive surgery. © 2013 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Investigation of refractory OAB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical management of Overactive Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How effective is antimuscarinic medication? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How cost effective are antimuscarinic drugs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What are the treatment strategies after primary drug therapy failure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Make an accurate diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Use a holistic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Are there alternative routes of administration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Are there any alternatives to antimuscarinic drugs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Is there a role for vaginal oestrogen in post menopausal women? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative management strategies in refractory Overactive Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
386 387 387 387 387 387 387 387 388 388 388 388 389 389 389 389 389 389 389
1. Introduction Overactive Bladder (OAB) is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary
∗ Corresponding author. Tel.: +44 0203 299 3568. E-mail address: [email protected] (D. Robinson). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.01.012
incontinence, in the absence of urinary tract infection or other obvious pathology [1]. The aim of this review is to provide practical clinical advice regarding the investigation and management of women complaining of refractory lower urinary tract symptoms suggestive of OAB who have failed to improve using the primary approach of conservative measures and bladder retraining with, or without antimuscarinic therapy.
D. Robinson et al. / Maturitas 74 (2013) 386–390 Table 1 Drugs used in the treatment of overactive bladder.
Antimuscarinic drugs Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium
Level of evidence
Grade of recommendation
1 1 1 1 1 1 1
A A A A A A A
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per day, reduction in number of micturitions per day and reduction of urgency episodes per day [6]. Whilst these data confirm the efficacy of antimuscarinic drugs the evidence comparing drugs with one another is less robust. The available evidence would suggest that extended release oxybutynin and tolterodine have superior efficacy to the immediate release preparations [7]. In addition solifenacin has been shown to be non inferior to [8], and fesoterodine superior to [9,10] tolterodine extended release. 5. How cost effective are antimuscarinic drugs?
Ref. [3].
2. Investigation of refractory OAB Whilst Overactive Bladder (OAB) is a symptomatic diagnosis all patients require a basic assessment in order to confirm the diagnosis as to exclude any other underlying cause for lower urinary tract dysfunction. A midstream specimen of urine should be sent for microscopy, culture and sensitivity and a significant post void residual excluded either by ultrasound or catheterisation. In addition a frequency/volume chart is useful to support the diagnosis of OAB and can also be useful in excluding other causes of urinary symptoms such as nocturnal or global polyuria. For women who have failed on primary therapy urodynamic investigations are integral in order to make an accurate diagnosis prior to embarking on more invasive, or perhaps irreversible, therapy. Simple urodynamic investigations include uroflowmetry, filling cystometry and pressure/flow voiding studies. In addition those women with a neurological history, or who have had previous pelvic surgery, may benefit from videocystourethrography which allows simultaneous screening of the lower urinary tract during filling cystometry and voiding studies. Many women with intractable symptoms may also benefit from cystourethroscopy to exclude other causes for the symptoms associated with OAB such as a bladder tumour or calculus. In addition cystourethroscopy should be considered in all women complaining of haematuria and painful bladder syndrome. 3. Medical management of Overactive Bladder Whilst a conservative approach is justified initially drug therapy remains integral in the management of women with OAB and there are a number of different agents available. Traditionally tolerability, compliance and persistence have limited the usefulness of many of the antimuscarinic agents although with the introduction of newer bladder selective drugs, once daily dosing and differing routes of administration it is possible that persistence with therapy may increase [2]. There are now a number of different licensed antimuscarinic drugs available on the market within the UK. These have all been reviewed by the International Consultation on Incontinence [3] (Table 1) and all have Level 1 evidence [4] and a Grade A recommendation [5]. 4. How effective is antimuscarinic medication? The most recent systematic review and meta-analysis of 83 studies, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium), supports the efficacy of antimuscarinic therapy in the management of OAB. Overall there was a significantly higher return to continence favouring active treatment over placebo; the pooled RR across different studies and different drugs being 1.3–3.5 (p < 0.01). Antimuscarinic therapy was also shown to be statistically significantly more effective in reduction of incontinence episodes
The cost effectiveness of all antimuscarinic therapies has recently been assessed within the UK National Health Service (NHS). Overall solifenacin was associated with the highest Quality Adjusted Life Year (QALY) gain in terms of urinary urgency, frequency and incontinence. Solifenacin was found to be dominant to fesoterodine, tolterodine and propiverine in terms of cost effectiveness although not to oxybutynin for frequency and incontinence [11]. Furthermore a cost utility analysis comparing solifenacin and tolterodine has found that solifenacin was less expensive and more effective than tolterodine; one year costs being £509 with solifenacin as compared to £526 for tolterodine [12]. 6. What are the treatment strategies after primary drug therapy failure? After conservative therapy antimuscarinic agents are the most commonly used agents in the management of OAB although compliance and persistence rates continue to be poor. Lack of efficacy has been shown to be the primary reason why patients stop therapy whilst intolerable side effects are the second most common. Should efficacy be the main reason for stopping therapy then it would seem appropriate to try an alternative drug whilst if adverse effects are the main reason for discontinuation then an alternative route of administration may be useful. Before resorting to more invasive treatment options in the management of OAB there are several different treatment approaches that should be considered. 6.1. Make an accurate diagnosis OAB is a symptom complex rather than a urodynamic diagnosis and there are many different causes of frequency and urgency. Consequently those patients who fail on primary therapy may benefit from further investigation with urodynamic studies in addition to excluding other gynaecological, urological and medical causes of lower urinary tract symptoms. 6.2. Use a holistic approach There is considerable evidence to show that combination therapy with medication and conservative measures lead to a greater improvement in patient symptoms. Equally improving patient awareness and education should lead to an improvement in compliance with medication. Antimuscarinic therapy may be a useful addition to non drug therapy in the management of patients with OAB. In a Cochrane review of 13 trials including 1770 patients symptomatic improvement was more common amongst those on antimuscarinic therapy compared to bladder retraining (RR 0.73; 95%CI: 0.59–0.90) and combination treatment was also associated with more improvement than bladder training alone (RR 0.55; 95%CI: 0.32–0.93). Similarly there was a trend towards greater improvement with a combination of antimuscarinic therapy with bladder retraining
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Table 2 Drugs used in the treatment of overactive bladder.
Drugs acting on membrane channels Calcium channel antagonists Potassium channel openers Drugs with mixed actions Flavoxate Alpha-antagonists Alfuzosin Doxazosin Prazosin Terazosin Tamsulosin Beta agonists Terbutaline Salbutamol Antidepressants Imipramine Duloxetine Prostaglandin synthesis inhibitors Indomethacin Flurbiprofen Vasopressin analogues Desmopressin
Level of evidence
Grade of recommendation
2 2
D D
2
D
3 3 3 3 3
C C C C C
3 3
C C
3 2
C C
2 2
C C
1
A
compared to antimuscarinic therapy alone (RR 0.81; 95%CI: 0.61–1.06) although this was not statistically significant [13]. 6.3. Are there alternative routes of administration? A different route of administration may offer advantages in those women who find antimuscarinic medication helpful although complain of troublesome side effects. The oxybutynin transdermal delivery system has been developed and compared with extended release tolterodine in 361 patients with mixed urinary incontinence. Both agents significantly reduced incontinence episodes, increased volume voided and lead to an improvement in quality of life when compared to placebo and there was no significant difference in efficacy between the oxybutynin patch and extended release tolterodine. The most common adverse event in the oxybutynin patch arm was application site pruritis in 14% although the incidence of dry mouth was reduced to 4.1% compared to 7.3% in the tolterodine arm [14]. Whilst application site reactions may limit the usefulness of the oxybutynin transdermal patch an oxybutynin gel has now been launched in North America and would appear to be associated with similar efficacy but a lower incidence of skin reactions [15,16]. 6.4. Are there any alternatives to antimuscarinic drugs? Many other drugs are used in the treatment of patients with OAB although the levels of evidence supporting their usage varies [14] (Table 2). Using an alternative treatment approach may be helpful to groups of patients with troublesome OAB symptoms that have not responded to conventional antimuscarinic therapy. Desmopressin, a synthetic vasopressin analogue has been used primarily in the treatment of nocturia and nocturnal enuresis in children [17] and adults [18] although has also been reported for the treatment of daytime urinary incontinence [19]. In addition newer agents remain under evaluation. Although the use of calcium blocking agents and potassium channel opening drugs showed initial promise neither have proved to be useful in the clinical setting [20,21]. Consequently the search for novel agents to treat OAB continues and has recently focused on the use of neurokinin antagonists [22], vitamin D analogues [23] and -adrenoceptor agonists [24]. Mirabegron is the first selective 3-adrenoreceptor agonist to undergo phase III clinical trials and is soon to be launched in
Europe although already available in Japan and the USA. Two recently reported phase III randomised controlled trials, including 3306 patients, have shown that mirabegron is statistically significantly more effective in reduction of incontinence episodes per day and reduction in number of micturitions per day compared to placebo [25,26]. The overall incidence of side effects was similar to tolterodine extended release 4 mg a day, but the incidence of dry mouth was lower (2.8% vs. 10.1%). Future studies are currently planned to explore the potential synergistic effect of selective 3-adrenoreceptor agonists with antimuscarinic agents in the treatment of OAB. 6.5. Is there a role for vaginal oestrogen in post menopausal women? More recently there has been some evidence regarding the synergistic use of vaginal oestrogen therapy with antimuscarinic therapy in the management of postmenopausal women with OAB although the results are contradictory. A 12 week prospective randomised trial comparing tolterodine 2 mg bd and vaginal conjugated oestrogen cream versus tolterodine 2 mg bd alone has been reported in 80 post menopausal women complaining of OAB [27]. Overall those women receiving combination therapy had a significantly greater improvement in mean daytime frequency and voided volume as compared to the tolterodine arm. These objective observations were also supported by a significantly greater improvement in QoL in the combination therapy group. Whilst there was a trend to improvement in symptoms of nocturia, urgency and urgency incontinence these findings were not significantly different between the groups. However these finding have not been replicated in a 12 week prospective study of 229 post menopausal women treated with either tolterodine extended release (ER) 4 mg od or tolterodine ER 4 mg and vaginal oestriol [28]. Overall there were no significant differences between the two treatment groups in terms of efficacy which was assessed subjectively. Interestingly however those women who were subsequently found to have a urodynamic diagnosis of detrusor overactivity were found to have an overall poorer outcome in terms of efficacy suggesting that some of the improvement in symptoms may simply be due to improving urogenital atrophy. More recently a 12 week prospective randomised trial comparing the oestradiol releasing vaginal ring and oral oxybutynin 5 mg bd has been reported in 59 postmenopausal women with OAB. [29] Those women who received oxybutynin had a mean decrease of 3.0 voids per day as compared to a decrease of 4.5 voids per day in women using the oestradiol ring although the difference between the groups was not significant. In addition there was a significant improvement in QoL in both groups although again no difference between groups. The authors concluded that low dose topical vaginal oestrogens were as effective as oxybutynin in reducing micturition frequency in postmenopausal women with OAB. It remains unclear why the results of these three studies are contradictory. This may be due to the difference in the patient populations; one study included women with detrusor overactivity whilst the other two simply recruited OAB patients. In addition the different oestrogen preparations investigated may also have a significant effect on efficacy as conjugated oestrogens are absorbed systemically and therefore may have a greater effect on the lower urinary tract. 7. Alternative management strategies in refractory Overactive Bladder Whilst the majority of patients with OAB will gain benefit from medical therapy there are a number of patients who will complain
D. Robinson et al. / Maturitas 74 (2013) 386–390
of persistent or refractory symptoms. In general these patients should be referred to secondary or tertiary care for further investigation and management. Once alternative pathology has been excluded they may benefit from more invasive therapy such as intravesical Botulinum Toxin, neuromodulation or perhaps ultimately reconstructive surgery. 8. Conclusions Overactive Bladder is a common and distressing condition, which is known to have a significant effect on QoL. The clinical diagnosis of OAB is often one of exclusion although urodynamic investigations are helpful in those women with refractory or unusual symptoms. The majority of women will benefit from conservative measures in the first instance although many will eventually require drug therapy. Whilst antimuscarinic drugs are currently integral in the medical management of OAB new drugs remain under development and 3 agonists may offer an alternative mode of treatment for those women who have persistent symptoms or intolerable adverse effects. In addition a different approach to drug therapy, by tailoring medication to the individual patient, may also improve compliance and acceptability. For those women with refractory symptoms who fail to derive sufficient benefit with medical therapy alternative treatment approaches with Botulinum Toxin and neuromodulation now offer effective alternatives to reconstructive surgery. 9. Practice points • Overactive Bladder is a common condition, known to affect Quality of Life (QoL) and the prevalence increases with age. • All women require basic assessment to exclude urinary tract infection and voiding dysfunction. Urodynamic investigations may be useful in women with refractory symptoms. • Conservative measures should be used as first line therapy prior to starting antimuscarinic therapy. • Lack of efficacy and intolerable adverse effects are the two main reasons why women stop antimuscarinic therapy. • Alternative delivery mechanisms may be appropriate in women with troublesome side effects. • A different approach to drug treatment may be useful in women who complain of lack of efficacy with antimuscarinic agents. • Vaginal oestrogens may be useful in post menopausal women with OAB symptoms. Contributors The contributors are the authors who all participated in the writing and editing of the paper. Competing interest Robinson: Consultant – Astellas, Pfizer, Allergan; Research – Astellas, Pfizer, Allergan. Giarenis: none. Cardozo: Consultant – Astellas, Pfizer, Allergan, Taevo; Research – Astellas, Pfizer. Funding Nono. Provenance and peer review Commissioned and externally peer reviewed.
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Contents lists available at SciVerse ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
The medical management of refractory Overactive Bladder Dudley Robinson ∗ , Ilias Giarenis, Linda Cardozo Department of Urogynaecology, Kings College Hospital, United Kingdom
a r t i c l e
i n f o
Article history: Received 11 January 2013 Accepted 14 January 2013
Keywords: Management Refractory Overactive Bladder Antimuscarinics
a b s t r a c t Overactive Bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Those women with refractory or intractable symptoms following initial conservative and antimuscarinic medication may benefit from further assessment and investigation of their symptoms prior to considering different approaches to drug therapy. This review is the first of two to cover the management of intractable OAB in women and provides a practical clinical approach to managing women with refractory OAB symptoms. This paper covers the investigation and medical management of this demanding patient group whilst the second paper will focus on the role of more invasive treatments such as Botulinum Toxin, neuromodulation and reconstructive surgery. © 2013 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Investigation of refractory OAB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical management of Overactive Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How effective is antimuscarinic medication? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How cost effective are antimuscarinic drugs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What are the treatment strategies after primary drug therapy failure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Make an accurate diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Use a holistic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Are there alternative routes of administration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Are there any alternatives to antimuscarinic drugs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Is there a role for vaginal oestrogen in post menopausal women? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative management strategies in refractory Overactive Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
386 387 387 387 387 387 387 387 388 388 388 388 389 389 389 389 389 389 389
1. Introduction Overactive Bladder (OAB) is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary
∗ Corresponding author. Tel.: +44 0203 299 3568. E-mail address: [email protected] (D. Robinson). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.01.012
incontinence, in the absence of urinary tract infection or other obvious pathology [1]. The aim of this review is to provide practical clinical advice regarding the investigation and management of women complaining of refractory lower urinary tract symptoms suggestive of OAB who have failed to improve using the primary approach of conservative measures and bladder retraining with, or without antimuscarinic therapy.
D. Robinson et al. / Maturitas 74 (2013) 386–390 Table 1 Drugs used in the treatment of overactive bladder.
Antimuscarinic drugs Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium
Level of evidence
Grade of recommendation
1 1 1 1 1 1 1
A A A A A A A
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per day, reduction in number of micturitions per day and reduction of urgency episodes per day [6]. Whilst these data confirm the efficacy of antimuscarinic drugs the evidence comparing drugs with one another is less robust. The available evidence would suggest that extended release oxybutynin and tolterodine have superior efficacy to the immediate release preparations [7]. In addition solifenacin has been shown to be non inferior to [8], and fesoterodine superior to [9,10] tolterodine extended release. 5. How cost effective are antimuscarinic drugs?
Ref. [3].
2. Investigation of refractory OAB Whilst Overactive Bladder (OAB) is a symptomatic diagnosis all patients require a basic assessment in order to confirm the diagnosis as to exclude any other underlying cause for lower urinary tract dysfunction. A midstream specimen of urine should be sent for microscopy, culture and sensitivity and a significant post void residual excluded either by ultrasound or catheterisation. In addition a frequency/volume chart is useful to support the diagnosis of OAB and can also be useful in excluding other causes of urinary symptoms such as nocturnal or global polyuria. For women who have failed on primary therapy urodynamic investigations are integral in order to make an accurate diagnosis prior to embarking on more invasive, or perhaps irreversible, therapy. Simple urodynamic investigations include uroflowmetry, filling cystometry and pressure/flow voiding studies. In addition those women with a neurological history, or who have had previous pelvic surgery, may benefit from videocystourethrography which allows simultaneous screening of the lower urinary tract during filling cystometry and voiding studies. Many women with intractable symptoms may also benefit from cystourethroscopy to exclude other causes for the symptoms associated with OAB such as a bladder tumour or calculus. In addition cystourethroscopy should be considered in all women complaining of haematuria and painful bladder syndrome. 3. Medical management of Overactive Bladder Whilst a conservative approach is justified initially drug therapy remains integral in the management of women with OAB and there are a number of different agents available. Traditionally tolerability, compliance and persistence have limited the usefulness of many of the antimuscarinic agents although with the introduction of newer bladder selective drugs, once daily dosing and differing routes of administration it is possible that persistence with therapy may increase [2]. There are now a number of different licensed antimuscarinic drugs available on the market within the UK. These have all been reviewed by the International Consultation on Incontinence [3] (Table 1) and all have Level 1 evidence [4] and a Grade A recommendation [5]. 4. How effective is antimuscarinic medication? The most recent systematic review and meta-analysis of 83 studies, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium), supports the efficacy of antimuscarinic therapy in the management of OAB. Overall there was a significantly higher return to continence favouring active treatment over placebo; the pooled RR across different studies and different drugs being 1.3–3.5 (p < 0.01). Antimuscarinic therapy was also shown to be statistically significantly more effective in reduction of incontinence episodes
The cost effectiveness of all antimuscarinic therapies has recently been assessed within the UK National Health Service (NHS). Overall solifenacin was associated with the highest Quality Adjusted Life Year (QALY) gain in terms of urinary urgency, frequency and incontinence. Solifenacin was found to be dominant to fesoterodine, tolterodine and propiverine in terms of cost effectiveness although not to oxybutynin for frequency and incontinence [11]. Furthermore a cost utility analysis comparing solifenacin and tolterodine has found that solifenacin was less expensive and more effective than tolterodine; one year costs being £509 with solifenacin as compared to £526 for tolterodine [12]. 6. What are the treatment strategies after primary drug therapy failure? After conservative therapy antimuscarinic agents are the most commonly used agents in the management of OAB although compliance and persistence rates continue to be poor. Lack of efficacy has been shown to be the primary reason why patients stop therapy whilst intolerable side effects are the second most common. Should efficacy be the main reason for stopping therapy then it would seem appropriate to try an alternative drug whilst if adverse effects are the main reason for discontinuation then an alternative route of administration may be useful. Before resorting to more invasive treatment options in the management of OAB there are several different treatment approaches that should be considered. 6.1. Make an accurate diagnosis OAB is a symptom complex rather than a urodynamic diagnosis and there are many different causes of frequency and urgency. Consequently those patients who fail on primary therapy may benefit from further investigation with urodynamic studies in addition to excluding other gynaecological, urological and medical causes of lower urinary tract symptoms. 6.2. Use a holistic approach There is considerable evidence to show that combination therapy with medication and conservative measures lead to a greater improvement in patient symptoms. Equally improving patient awareness and education should lead to an improvement in compliance with medication. Antimuscarinic therapy may be a useful addition to non drug therapy in the management of patients with OAB. In a Cochrane review of 13 trials including 1770 patients symptomatic improvement was more common amongst those on antimuscarinic therapy compared to bladder retraining (RR 0.73; 95%CI: 0.59–0.90) and combination treatment was also associated with more improvement than bladder training alone (RR 0.55; 95%CI: 0.32–0.93). Similarly there was a trend towards greater improvement with a combination of antimuscarinic therapy with bladder retraining
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Table 2 Drugs used in the treatment of overactive bladder.
Drugs acting on membrane channels Calcium channel antagonists Potassium channel openers Drugs with mixed actions Flavoxate Alpha-antagonists Alfuzosin Doxazosin Prazosin Terazosin Tamsulosin Beta agonists Terbutaline Salbutamol Antidepressants Imipramine Duloxetine Prostaglandin synthesis inhibitors Indomethacin Flurbiprofen Vasopressin analogues Desmopressin
Level of evidence
Grade of recommendation
2 2
D D
2
D
3 3 3 3 3
C C C C C
3 3
C C
3 2
C C
2 2
C C
1
A
compared to antimuscarinic therapy alone (RR 0.81; 95%CI: 0.61–1.06) although this was not statistically significant [13]. 6.3. Are there alternative routes of administration? A different route of administration may offer advantages in those women who find antimuscarinic medication helpful although complain of troublesome side effects. The oxybutynin transdermal delivery system has been developed and compared with extended release tolterodine in 361 patients with mixed urinary incontinence. Both agents significantly reduced incontinence episodes, increased volume voided and lead to an improvement in quality of life when compared to placebo and there was no significant difference in efficacy between the oxybutynin patch and extended release tolterodine. The most common adverse event in the oxybutynin patch arm was application site pruritis in 14% although the incidence of dry mouth was reduced to 4.1% compared to 7.3% in the tolterodine arm [14]. Whilst application site reactions may limit the usefulness of the oxybutynin transdermal patch an oxybutynin gel has now been launched in North America and would appear to be associated with similar efficacy but a lower incidence of skin reactions [15,16]. 6.4. Are there any alternatives to antimuscarinic drugs? Many other drugs are used in the treatment of patients with OAB although the levels of evidence supporting their usage varies [14] (Table 2). Using an alternative treatment approach may be helpful to groups of patients with troublesome OAB symptoms that have not responded to conventional antimuscarinic therapy. Desmopressin, a synthetic vasopressin analogue has been used primarily in the treatment of nocturia and nocturnal enuresis in children [17] and adults [18] although has also been reported for the treatment of daytime urinary incontinence [19]. In addition newer agents remain under evaluation. Although the use of calcium blocking agents and potassium channel opening drugs showed initial promise neither have proved to be useful in the clinical setting [20,21]. Consequently the search for novel agents to treat OAB continues and has recently focused on the use of neurokinin antagonists [22], vitamin D analogues [23] and -adrenoceptor agonists [24]. Mirabegron is the first selective 3-adrenoreceptor agonist to undergo phase III clinical trials and is soon to be launched in
Europe although already available in Japan and the USA. Two recently reported phase III randomised controlled trials, including 3306 patients, have shown that mirabegron is statistically significantly more effective in reduction of incontinence episodes per day and reduction in number of micturitions per day compared to placebo [25,26]. The overall incidence of side effects was similar to tolterodine extended release 4 mg a day, but the incidence of dry mouth was lower (2.8% vs. 10.1%). Future studies are currently planned to explore the potential synergistic effect of selective 3-adrenoreceptor agonists with antimuscarinic agents in the treatment of OAB. 6.5. Is there a role for vaginal oestrogen in post menopausal women? More recently there has been some evidence regarding the synergistic use of vaginal oestrogen therapy with antimuscarinic therapy in the management of postmenopausal women with OAB although the results are contradictory. A 12 week prospective randomised trial comparing tolterodine 2 mg bd and vaginal conjugated oestrogen cream versus tolterodine 2 mg bd alone has been reported in 80 post menopausal women complaining of OAB [27]. Overall those women receiving combination therapy had a significantly greater improvement in mean daytime frequency and voided volume as compared to the tolterodine arm. These objective observations were also supported by a significantly greater improvement in QoL in the combination therapy group. Whilst there was a trend to improvement in symptoms of nocturia, urgency and urgency incontinence these findings were not significantly different between the groups. However these finding have not been replicated in a 12 week prospective study of 229 post menopausal women treated with either tolterodine extended release (ER) 4 mg od or tolterodine ER 4 mg and vaginal oestriol [28]. Overall there were no significant differences between the two treatment groups in terms of efficacy which was assessed subjectively. Interestingly however those women who were subsequently found to have a urodynamic diagnosis of detrusor overactivity were found to have an overall poorer outcome in terms of efficacy suggesting that some of the improvement in symptoms may simply be due to improving urogenital atrophy. More recently a 12 week prospective randomised trial comparing the oestradiol releasing vaginal ring and oral oxybutynin 5 mg bd has been reported in 59 postmenopausal women with OAB. [29] Those women who received oxybutynin had a mean decrease of 3.0 voids per day as compared to a decrease of 4.5 voids per day in women using the oestradiol ring although the difference between the groups was not significant. In addition there was a significant improvement in QoL in both groups although again no difference between groups. The authors concluded that low dose topical vaginal oestrogens were as effective as oxybutynin in reducing micturition frequency in postmenopausal women with OAB. It remains unclear why the results of these three studies are contradictory. This may be due to the difference in the patient populations; one study included women with detrusor overactivity whilst the other two simply recruited OAB patients. In addition the different oestrogen preparations investigated may also have a significant effect on efficacy as conjugated oestrogens are absorbed systemically and therefore may have a greater effect on the lower urinary tract. 7. Alternative management strategies in refractory Overactive Bladder Whilst the majority of patients with OAB will gain benefit from medical therapy there are a number of patients who will complain
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of persistent or refractory symptoms. In general these patients should be referred to secondary or tertiary care for further investigation and management. Once alternative pathology has been excluded they may benefit from more invasive therapy such as intravesical Botulinum Toxin, neuromodulation or perhaps ultimately reconstructive surgery. 8. Conclusions Overactive Bladder is a common and distressing condition, which is known to have a significant effect on QoL. The clinical diagnosis of OAB is often one of exclusion although urodynamic investigations are helpful in those women with refractory or unusual symptoms. The majority of women will benefit from conservative measures in the first instance although many will eventually require drug therapy. Whilst antimuscarinic drugs are currently integral in the medical management of OAB new drugs remain under development and 3 agonists may offer an alternative mode of treatment for those women who have persistent symptoms or intolerable adverse effects. In addition a different approach to drug therapy, by tailoring medication to the individual patient, may also improve compliance and acceptability. For those women with refractory symptoms who fail to derive sufficient benefit with medical therapy alternative treatment approaches with Botulinum Toxin and neuromodulation now offer effective alternatives to reconstructive surgery. 9. Practice points • Overactive Bladder is a common condition, known to affect Quality of Life (QoL) and the prevalence increases with age. • All women require basic assessment to exclude urinary tract infection and voiding dysfunction. Urodynamic investigations may be useful in women with refractory symptoms. • Conservative measures should be used as first line therapy prior to starting antimuscarinic therapy. • Lack of efficacy and intolerable adverse effects are the two main reasons why women stop antimuscarinic therapy. • Alternative delivery mechanisms may be appropriate in women with troublesome side effects. • A different approach to drug treatment may be useful in women who complain of lack of efficacy with antimuscarinic agents. • Vaginal oestrogens may be useful in post menopausal women with OAB symptoms. Contributors The contributors are the authors who all participated in the writing and editing of the paper. Competing interest Robinson: Consultant – Astellas, Pfizer, Allergan; Research – Astellas, Pfizer, Allergan. Giarenis: none. Cardozo: Consultant – Astellas, Pfizer, Allergan, Taevo; Research – Astellas, Pfizer. Funding Nono. Provenance and peer review Commissioned and externally peer reviewed.
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