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Original Article
INTERNATIONAL
Prostate Int 2013;1(1):37-41 • http://dx.doi.org/10.12954/PI.12005
Efficacy and safety of low-dose anticholinergics to treat
men with lower urinary tract symptoms with overactive
bladder: a retrospective study based on real life practice
Kyung Kgi Park, Seung Hwan Lee1, Byung Ha Chung1, Su Jin Kim2, Cheol Kwak3, Hwan Cheol Son4,
Sae Woong Kim2, Ji Youl Lee2
Department of Urology, Jeju National University Hospital, Jeju National University Col ege of Medicine, Jeju, Korea
1Department of Urology, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea
2Department of Urology, Seoul St. Mary’s Hospital, The Catholic University of Korea Col ege of Medicine, Seoul, Korea
3Department of Urology, Seoul National University Col ege of Medicine, Seoul, Korea
4Department of Urology, SMG-SNU Boramae Medical Center, Seoul, Korea
Purpose: To investigate whether combination treatment using an α-blocker and 2 mg of tolterodine could improve the International
Prostate Symptom Score (IPSS) as much as α-blocker and 4 mg of tolterodine without voiding difficulties in real life practice.
Methods: We restrospectively recruited patients who were treated at four urology clinics between January 2006 and May 2008. A total
of 1,094 men with lower urinary tract symptoms/overactive bladder (LUTS/OAB) were assigned to one of three groups: an α-blocker
only group (group I, n=152), an α-blocker plus tolterodine 2 mg group (group I , n=520), and an α-blocker plus tolterodine 4 mg
group (group I I, n=574). Eligible patients were 50 years or older men who had a total IPSS of 8 or higher and a IPSS storage subscore
of 5 or higher and were fol owed up for 12 weeks.
Results: The total IPSS score and quality of life scores were significantly improved at week 12 in groups I and I I. The incidence of
acute urinary retention was similar between both combination treatment groups, but the incidence of voiding difficulty was much
lower in group I (2.1%) than group I I (10.8%) tolterodine.
Conclusions: Our results suggest that treatment of LUTS/OAB patients with an α-blocker plus tolterodine 2 mg is as effective as
α-blocker plus tolterodine 4 mg, and the incidence of voiding difficulty was in the low-dose anticholinergic is lower. These results
indicate that dose strength should be decided on a case-by-case basis to balance the efficacy and safety.
Keywords: Lower urinary tract symptoms, Adrenergic alpha-antagonist, Overactive urinary bladder, Cholinergic antagonists
INTRODUCTION
European countries [3]. Storage/OAB symptoms are bother-some to patients, interfere with daily activities, and have a Lower urinary tract symptoms (LUTS) and overactive blad- negative impact on patients’ quality of life (QoL) [4].
der (OAB) are highly prevalent in the adult population, and Generally, women patients who complain of OAB are the prevalence increases along with age [1,2]. OAB, which is treated with anticholinergics as a first-line drug [5]. However, defined by urgency, frequency, and nocturia, with or without in male OAB patients, muscarinic receptor antagonists are incontinence, affects 15.6% of men aged 40 years and older in not widely used because of the risk of urinary retention. Corresponding author: Ji Youl Lee
Department of Urology, Seoul St. Mary’s Hospital, The Catholic University of Korea Col ege of Medicine, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea
E-mail: [email protected] / Tel: +82-2-2258-6227 / Fax: +82-2-599-7839
Submitted: 24 November 2012 / Accepted after revision: 2 February 2013
Copyright 2013 Asian Pacific Prostate Society (APPS) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) http://p-international.org/
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
pISSN: 2287-8882 • eISSN: 2287-903X
Park, et al.  Efficacy and safety of low-dose anticholinergics in men with OAB PROSTATE INTERNATIONAL
Recently, several randomized trial have revealed that mus- an α-blocker plus tolterodine 2 mg group (group II, n=520), carinic receptor antagonists are effective and safe to be used and an α-blocker plus tolterodine 4 mg group (group III, n =574). Four urologists treated their patients based on the Despite these reports, however, physicians have been reluc- personal preferences. When subjects experienced grade 3 ur- tant to use muscarinic receptor antagonists in real life practice, gency (voiding cannot be delayed for more than 15 minutes, mainly because they often encounter patients who experi- proposed by De Wachter and Wyndaele [9]) at least once a ence mild to moderate voiding difficulty after treatment with day through 3 days of voiding diary, we subscribed combi- nation drugs (α-blocker plus tolterodine). Of these, subjects Herein, we investigated whether combination treatment who had less than 100 mL of PVR were assigned to group III, using an α-blocker and 2 mg of tolterodine improved the stor- subjects with greater than 100 mL of PVR in group II. The re- age subscore of the international prostate symptom score as much as a combination of α-blocker and 4 mg of tolterodine Serum PSA levels, maximal flow rate (Qmax) according to without voiding difficulty in men with LUTS/OAB symptoms uroflowmetry (Urodyn 1000, Medtronics, Minneapolis, MN, USA) PVR (BladderScan BVI 3000, Verathon Inc., Bothell, WA, USA), and prostate volume (Pro Focus Ultra View type 2202, MATERIALS AND METHODS
BK medical Aps, Peabody, MA, USA) at baseline were evalu-ated in all patients. Total IPSS score and QoL score were assessed at baseline Patients were retrospectively recruited from those who were and at week 12, and are reported as changes from baseline treated at four urology clinics in Korea between January 2006 values. Patients were asked about adverse events at every and May 2008. A total of 1,094 men with benign prostatic hy- visit, and all adverse events were recorded. Voiding difficulty perplasia (BPH) and OAB were included in this study. was defined as an adverse event if the subject complained of Eligible patients were men who were 50 years or older, new bladder emptying symptoms after 2 weeks of receiving had an International Prostate Symptom Score (IPSS) of 8 or higher and an IPSS storage subscore of 5 or higher, and were followed up for 12 weeks with the same drugs. The exclusion criteria were as follows: men with clinically Based on the characteristics of the data, mean±standard devi- significant bladder outlet obstruction (BOO; defined as a post- ations were calculated. The paired t-test was used to compare voided residual volume (PVR) >200 mL and a maximal uri- data before and after the 12-week treatment for each group. nary flow rate <5 mL/sec), serum prostate-specific antigen One-way analysis of variance was used to compare data among (PSA) of more than 10 ng/mL with risk of prostate cancer, his- the three groups. When significance was detected, Scheffe’s tory of some neurologic condition affecting bladder function test was used to ascertain intergroup significance. Values of (e.g., multiple sclerosis, spinal cord injury, Parkinson’s dis- P=0.05 were considered significant. ease), prostate cancer, prior surgery of the prostate or blad-der, acute urinary retention (AUR) requiring catheterization, BOO due to causes other than BPH, history of treatment with a drug affecting voiding function such as an α-blocker within Patients demographic and baseline clinical characteristics are 2 weeks, anticholinergics within 1 month, or a 5α reductase summarized in Table 1. The mean subject age was 65.1 years inhibitor within 3 months. Of patients who were prescribed old (range, 40 to 75 years). There were no significant differ- tolterodine 2 mg at baseline, 141 patients were also excluded ences in age, prostate volume, PSA levels, or the mean Qmax as the dose was increased to 4 mg during the 12-week period of treatment because of no improvement in storage symptoms. The total IPSS score, IPSS voiding & storage subscores, The Institutional Review Board of our institution approved and QoL score were significantly improved at week 12 after therapy compared to baseline in all three groups (Fig. 1). IPSS subscores for storage symptom and urgency were only significantly improved in the combination therapy groups All subjects were divided into three groups according to the even though group III was more effective in terms of urgency physician’s preference: an α-blocker group (group I, n=152), compared to group II (Figs. 1, 2). However, there was no sig- PROSTATE INTERNATIONAL
nificant difference in the change in IPSS storage subscores symptoms such as dry mouth and voiding difficulty. More and QoL between groups II and III (Fig. 2).
group III patients complained of adverse events than those in Patients in the combination therapy groups experienced group II. However, the incidence of AUR was not significantly different among the three groups (Table 2).
Table 1. Subject characteristics of the α-blocker-only group
α-blocker tolterodine tolterodine P-value* Prostate volumea) (g) 29.4±12.4 30.8±18.3 30.9±17.3 Fig. 2. Comparison of International Prostate Symptom Score
(IPSS) scores on urgency according to treatment regimen. Al subjects were assigned to one of three groups: an α-blocker Values are presented as mean±standard deviation.
group (group I), an α-blocker plus tolterodine 2 mg group PSA, prostate-specific antigen; Qmax, maximal urine flow.
(group I ), and an α-blocker plus tolterodine 4 mg group (group a)Measured by transrectal ultrasound. b)Measured by uroflowmetry. I I). Significant difference between baseline results and those *P<0.05 among the three groups by analysis of variance, no statistical measured at 12 weeks. There were no significant change in the difference between the tolterodine 2 mg and 4 mg combination thera- urgency score between baseline and 12 weeks between groups Fig. 1. Comparison of the efficacy of the three regimens. Al subjects were assigned to one of three groups: an α-blocker group
(group I), an α-blocker plus tolterodine 2 mg group (group I ), and an α-blocker plus tolterodine 4 mg group (group I I). Al groups showed a significant difference in baseline scores and scores at 12 weeks. IPSS, International Prostate Symptom Score.
Park, et al.  Efficacy and safety of low-dose anticholinergics in men with OAB PROSTATE INTERNATIONAL
Table 2. No. of patients that experienced adverse events ac-
In a meta-analysis of randomized controlled trials which used anticholinergics to treat OAB, most anticholinergics were safe and effective except oxybutynin which significantly increased the risk of AUR compared with placebo [12].
Despite the evidence that anticholinergics can safely and effectively treat OAB symptoms in men, only 40% of men with OAB symptoms who received drug treatment were pre- scribed anticholinergics [13]. Recent studies suggest that a Values are presented as number (%). AUR, acute urinary retention.
combination of antimuscarinic and α1-receptor antagonist may more effectively reduce male LUTS than the use of α1- DISCUSSION
receptor antagonists alone. Athanasopoulos et al. [8] used a combination of tamsulosin The combination therapy with 2 mg of tolterodine and an 0.2 mg and tolterodine 2 mg to treat 50 patients with BOO and α-blocker was effective and had a lower rate of adverse events detrusor overactivity, and reported improvement in QoL and than the one combining 4 mg tolterodine and an α-blocker. bladder volume. Furthermore, no AUR occurred in any of the Therefore, the combination therapy with 2 mg of tolterodine is reasonable for patients with LUTS and mild to moderate A few randomized controlled trials have demonstrated that anticholinergics are a safe option in patients with mild to Alpha1-adrenergic antagonists are widely used to treat LUTS because of their rapid effects and safety. In patients with However, previous studies of the safety of medications fo- LUTS accompanied by OAB, however, monotherapy with an cused on the rate of urinary retention or increased residual volume rather than voiding difficulty as a subjective symptom Therefore, it would be logical to assume that adding an anti- after treatment. Based on our clinical experience, however, cholinergic would helpful for the management of these symp- patients who take anticholinergics may complain of voiding toms. However, anticholinergics decrease bladder contractility difficulty without urinary retention or increased residual by blocking acetylcholine binding at muscarinic receptors in volume. In this study, only 5 subjects who were treated with the bladder. These effects do not inhibit overactive detrusor combination therapies complained of AUR during the study contraction. However, they may theoretically exacerbate void- period. However, 14.6 times more subjects (n =73) com- ing symptoms, residual urine volume or, even worse, provoke plained of voiding difficulty in combination therapy groups. These showed the high prevalence of voiding difficulty com- Abrams et al. [6] randomly treated 221 men with urody- pared to previous studies [7,14,15]. This could be attributed to namically verified (BOO) with oral tolterodine 2 mg for 12 the fact that we included mild to moderate symptoms of void- weeks. Changes from baseline urodynamics in the patients ing difficulty. Actually, AUR frequently occurs in subjects with treated with tolterodine were statistically equivalent to those severe voiding difficulty. Although it may not be considered who received a placebo. The median increase in PVR was as a serious issue to many other investigators, we believe that significantly greater in the tolerodine group (25 mL) than the subjective symptoms should not be neglected.
placebo group (0 mL). AUR was reported in one patient in Because we think previous studies did not well reflect real life practice in respect of safety of regimen, in this study, we Kaplan et al. [11] treated 39 men who did not respond to investigated the optimal combination dose of anticholiner- α-blocker therapy for 5.7 months with tolterodine 4 mg mono- gics and α-blocker to minimize urinary or nonurinary side therapy for 6 months. They concluded that monotherapy with effects and maintain the efficacy of the combination therapy. 4 mg of tolterodine induced a significant increase in the Qmax We found that 2 mg of tolterodine and an α-blocker regimen of patients and decreased PVR, in contrast to the results re- was effective in patients with OAB and resulted in much less voiding difficulty and dry mouth symptoms than combina- These contradicting safety findings indicate that large, tion therapy with tolterodine 4 mg Therefore, we suggest that placebo-controlled studies in men with OAB symptoms and a combination therapy of an α-blocker and tolterodine 2 mg other LUTS are needed to confirm the efficacy and safety of is a feasible regimen in male patients with mild-to-moderate PROSTATE INTERNATIONAL
OAB and patients who present severe storage symptoms and want to minimize dry mouth symptom and voiding difficulty. 5. Andersson KE, Wein AJ. Pharmacologic management of stor- There were some limitations in this study. First, our analy- age and emptying failure. In: Wein AJ Kavoussi LR, Novick sis was based on the results of an open-label, retrospective, AC, Partin AW, Peters CA, editors. Campbell-Walsh urology. observational study without a placebo control, which limits 9th ed. Philadelphia: Saunders; 2007. p. 2091-123.
interpretation of the data. However, the study included a large 6. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety number of subjects, which allowed analysis of multiple sub- and tolerability of tolterodine for the treatment of overac- groups. Furthermore, as patients were treated and data were tive bladder in men with bladder outlet obstruction. J Urol recorded under real-life conditions, the findings are likely to 7. Lee KS, Choo MS, Kim DY, Kim JC, Kim HJ, Min KS, et al. A second limitation of this study was that the follow-up pe- Combination treatment with propiverine hydrochloride plus riod was relatively short compared to other studies. However, doxazosin controlled release gastrointestinal therapeutic we believe that a period of 12 weeks is reasonable to evaluate system formulation for overactive bladder and coexisting the efficacy and safety of a drug regimen. benign prostatic obstruction: a prospective, randomized, In conclusion, our results suggest that treatment of LUTS/ controlled multicenter study. J Urol 2005;174:1334-8.
OAB patients with an α-blocker plus tolterodine 2 mg resulted 8. Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, in less side effects and was as effective as treatment of LUTS/ Perimenis P, Barbalias G. Combination treatment with an OAB patients with an α-blocker and tolterodine 4 mg. How- alpha-blocker plus an anticholinergic for bladder outlet ob- ever, the combination of tolterodine 4 mg with an α-blocker struction: a prospective, randomized, controlled study. J Urol resulted in greater improvement in urgency symptoms than other regimens evaluated in this study. Therefore, we suggest 9. De Wachter S, Wyndaele JJ. Frequency-volume charts: a tool that the combination therapy for the treatment of LUTS/OAB to evaluate bladder sensation. Neurourol Urodyn 2003;22: 10. Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. CONFLICT OF INTEREST
Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overac- No potential conflict of interest relevant to this article was re- tive bladder. BJU Int 2004;94:817-20.
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