P R O S T A T E 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 . 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) .
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 . 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@example.com / 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/)
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
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 ) 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-
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 .
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 . 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-
receptor antagonists alone. Athanasopoulos et al.  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.  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.  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
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,
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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.
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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-
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