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Antimuscarinics in men with lower urinary tract symptoms

suggestive of bladder outlet obstruction due to benign


prostatic hyperplasia
Christopher Chapple
Sheffield Teaching Hospitals, Sheffield, UK Purpose of review
Correspondence to Christopher Chapple, MD, This review will provide an update on the use of antimuscarinics, in combination with an
Sheffield Teaching Hospitals, Glossop Road, Sheffield a-blocker, in men with an overactive bladder and summarize the efficacy and safety of
S10 2JF, UK
Tel: +44 114 271 2559; fax: +44 114 279 7841; these drugs in this patient population.
e-mail: c.r.chapple@shef.ac.uk Recent findings
Current Opinion in Urology 2010, 20:43–48
Studies have included a number of antimuscarinic agents (tolterodine, oxybutynin,
propiverine, and solifenacin), with or without an a-blocker. These studies suggest that in
men with persistent storage symptoms (overactive bladder symptoms), clinically
meaningful improvements can be achieved by addition of an antimuscarinic therapy to
an a-blocker. Monotherapy with an antimuscarinic therapy alone in this patient group
has proven to be disappointing. Voiding difficulty and acute urinary retention are
infrequently reported across all studies, but several trials demonstrated an increase in
postvoid residual volume with anticholinergic therapy. It must, however, be borne in
mind that reported trials are of short duration (6–12 weeks) and include only men with
low postvoid residual volumes at baseline, and the results are, therefore, difficult to
unreservedly extrapolate to real-life clinical practice.
Summary
In a situation in which there are persistent urinary storage symptoms (overactive
bladder) following therapy with an a-blocker, the addition of an antimuscarinic therapy is
worth considering. A postvoid residual volume should be measured prior to
commencing antimuscarinic therapy to rule out baseline retention suggestive of poor
detrusor function, and patients should be kept under careful review, particularly, in the
early stages of having commenced therapy.

Keywords
antimuscarinics, benign prostatic hyperplasia, bladder outflow obstruction, lower
urinary tract symptoms, overactive bladder

Curr Opin Urol 20:43–48


ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0963-0643

in the development of LUTS include psychogenic dis-


Introduction orders, congestive heart failure, and polypharmacy [4].
The term lower urinary tract symptoms (LUTS) was LUTS should be considered in the subcategories of
introduced in an effort to counter any perception that storage (daytime frequency, urgency, nocturia, and urin-
there is a direct association between urinary symptoms ary incontinence), voiding (slow stream, splitting or
and the underlying pathophysiology affecting voiding [1]. spraying, intermittency, hesitancy, straining, and term-
Indeed, the phrase ‘the bladder is an unreliable witness’ inal dribble), and postmicturition symptoms (sensation of
was coined to acknowledge this important concept [2]. incomplete emptying and postmicturition dribble) [5]. It
Such misconceptions can lead to an inaccurate diagnosis is well recognized from the International Continence
and inappropriate or suboptimal management. Although Society (ICS) benign prostatic hyperplasia (BPH) study
there still exists a tendency to attribute all LUTS to and has been confirmed by the EpiLUTS study that
prostatic disease [3], LUTS may result from bladder although the prevalence of voiding symptoms is higher
neck, prostate, or bladder dysfunction [bladder outlet than that of storage symptoms, men are more bothered by
obstruction (BOO) secondary to prostatic enlargement storage symptoms including an overactive bladder (OAB)
and detrusor overactivity]. Other factors that may result [6,7].

0963-0643 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOU.0b013e3283330862

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
44 Benign prostatic hyperplasia

Eleven and 16% of men in Europe and North America, BOO only who showed no improvement after treat-
respectively, have symptoms of OAB [8–10], and ment with doxazosin alone. In patients with detrusor
many men with BOO or benign prostatic obstruction overactivity along with BOO, symptoms improved in
(BPO) have concomitant detrusor overactivity and 35% of them after 12 weeks of treatment with dox-
OAB, which increase in prevalence with age [11–13]. azosin. The addition of tolterodine for 8 weeks
In 2009, however, men seeking treatment for bother- improved symptoms in 73% of 44 men with detrusor
some LUTS are more likely to be treated with medi- overactivity and BOO who showed no improvement
cations with benign prostatic disease in mind, typically after treatment with doxazosin alone. Two men
an a-blocker or 5-a reductase inhibitor. Neither drug on treatment with tolterodine along with doxazosin
class has any known direct effect on detrusor over- developed acute retention requiring catheterization
activity [14,15]. However, traditionally, the use of [19].
antimuscarinics in older men has generally been
avoided because of concerns about aggravating voiding In a prospective, double-blind trial, men aged 50–80
difficulties, increasing postvoid urinary volume (PVR) years with OAB symptoms for at least 6 months who
or precipitating acute urinary retention (AUR), particu- recorded at least one urgency episode per day and at
larly in men with BOO. Recently, there has been least eight micturitions per day in a 3-day diary and had
continuing and increased interest in the potential role urodynamically proven BOO (Abrams–Griffith score
of antimuscarinic treatment for men with persistent greater than 20) were randomly assigned in a ratio of
OAB symptoms after adequate treatment with an 2 : 1 to treatment with propiverine 20 mg once daily
a-blocker or a 5-a reductase inhibitor [16,17]. along with doxazosin 4 mg once daily (n ¼ 142) or
doxazosin 4 mg once daily alone (n ¼ 69) for 8 weeks,
and 198 (93.8%) completed the 8 weeks of treatment. A
Antimuscarinic monotherapy in men with greater percentage of men treated with propiverine
both storage lower urinary tract symptoms along with doxazosin than doxazosin alone reported
suggestive of bladder outlet obstruction being satisfied or very satisfied with treatment (81
In a prospective, randomized, controlled study, men with vs. 64%). Improvement in nocturia was statistically
urodynamically proven mild or moderate BOO and con- significant in both treatment groups (both P < 0.05
comitant detrusor overactivity were treated with tamsu- vs. baseline), but the difference between the groups
losin 0.4 mg for 1 week, then randomly assigned to was not significant. Postvoid residual urine was found
continue treatment with tamsulosin only (n ¼ 25) or tam- to be significantly increased only in the combination
sulosin along with tolterodine immediate release 2 mg group, but this was not accompanied by urinary reten-
twice daily (n ¼ 25). In the group treated with tamsulosin tion [20].
along with tolterodine, significant improvement was also
seen in maximum detrusor pressure during micturition A study of men with BOO and confirmed detrusor
and maximum involuntary contraction pressure (both overactivity on pressure flow urodynamics evaluated
P < 0.008). Significant improvement in health-related the safety of tolterodine vs. placebo in men with
quality of life (HRQL), as assessed using the individ- OAB and BOO. Men (older than 40 years) were
ual-completed Urolife BPH quality-of-life questionnaire, randomized to tolterodine (2 mg twice daily, n ¼ 149)
occurred only in men treated with tamsulosin along with or placebo (n ¼ 72) for 12 weeks. The primary end-
tolterodine (P ¼ 0.0003). No AUR was observed, and points were Qmax and pdetQmax, and the median treat-
tolterodine did not affect the quality of urine flow or ment differences were comparable. There were no
residual urine volume [18]. significant between-group differences in the incidence
of adverse events with urinary retention being reported
In another prospective investigation, men with urody- by one patient treated with placebo. These findings
namically confirmed BPO only (n ¼ 76) or urodynami- suggested that there was no evidence of clinically
cally confirmed BOO along with detrusor overactivity meaningful changes in voiding pressure and PVR or
(defined as involuntary detrusor contractions, n ¼ 68) urinary retention, and that antimuscarinics can be
were treated with doxazosin 2 mg for 12 weeks; men safely administered in men with BOO, provided that
who did not show improvement [a decrease in inter- those patients with an elevated residual are excluded.
national prostate symptom score (IPSS) of more than Conversely, no clinically significant improvement,
three points] were then treated with doxazosin along which could be attributed to relief of the detrusor
with tolterodine immediate release 2 mg twice daily for overactivity, was evident [14].
8 weeks. Among men with BPO only, symptom
improvement was observed in 79% of patients after A randomized, double-blind, placebo-controlled trial has
12 weeks of treatment with doxazosin. The addition of studied men aged at least 40 years meeting symptom
tolterodine improved symptoms in 38% of 16 men with research criteria for both OAB trials (8 micturitions per

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Antimuscarinics in men with LUTS Chapple 45

day, 3 urgency episodes per day with or without randomly assigned to treatment with terazosin alone
urgency urinary incontinence (UUI), self-reporting of (n ¼ 36) or terazosin along with tolterodine immediate
at least some moderate bladder-related problems, and release 2 mg twice daily (n ¼ 33) for 6 weeks. Improve-
BPO trials) [IPSS 12, quality of life (QOL) 3] (the ments in IPSS total and storage symptom subscale
TIMES study) [21]. Men with PVR of more than scores were significantly greater in the terazosin along
200 ml, Qmax of less than 5 ml/s at screening, or a history with tolterodine group compared with the terazosin
of AUR requiring catheterization were excluded. Patients alone group (P < 0.01). The differences about the peak
were treated for 12 weeks with tolterodine extended urinary flow rate and the residual urine from baseline
release 4 mg (n ¼ 217), tamsulosin 0.4 mg (n ¼ 215), tol- were not significantly contrasting in the two groups.
terodine extended release along with tamsulosin The incidence of adverse effects in the combination
(n ¼ 225), or placebo (n ¼ 222) once daily. The primary group was higher than that in the terazosin group.
endpoint was patient perception of treatment benefit at The most common adverse effect was mouth dryness
week 12. A total of 172 men (80%) receiving tolterodine [26].
extended release along with tamsulosin reported treat-
ment benefit by week 12 compared with 132 patients A prospective, noninterventional study assessed the
(62%) receiving placebo (P < 0.001), 146 (71%) receiving efficacy of tolterodine extended release in men
tamsulosin (P ¼ 0.06 vs. placebo), or 135 (65%) receiving (n ¼ 741) with OAB symptoms and Qmax of at least
tolterodine extended release (P ¼ 0.48 vs. placebo). Tol- 15 ml/s who either did not have suspected BOO or
terodine extended release along with tamsulosin also who had persistent storage symptoms, despite treatment
significantly decreased OAB symptom measures at week with an a-blocker of at least 6 weeks duration. The
12 compared with placebo, including urgency episodes patients were observed for 12 weeks in order to generate
without incontinence (3.33 vs. 2.54, P ¼ 0.03), 24-h real-life efficacy and safety data. Efficacy results were
frequency (2.54 vs. 1.41, P < 0.001), UUI (0.88 vs. not presented separately for men who were (42%) and
0.31, P ¼ 0.005), nocturnal frequency (0.59 vs. 0.39, were not (58%) taking a-blockers, except for IPSS scores,
P ¼ 002), daytime and nocturnal urgency episodes, and in which it was noted that results were similar for the two
frequency–urgency sum [the sum of urgency scale score groups. Mean PVR did not increase (25.4  26.5 vs.
(USS) ratings] [22]. Tolterodine extended release along 29.3  30.9 ml at baseline). AUR requiring catheteriza-
with tamsulosin significantly improved IPSS total (8.02 tion occurred in two patients and acute urinary tract
vs. placebo, 6.19, P ¼ 0.003), storage symptom subscale, infection (UTI) in four patients. Median IPSS total
and QOL score (1.61 vs. 1.17, P ¼ 0.003) vs. placebo at scores decreased from 17 to 10, IPSS QOL scores from
week 12, as well as scores for each IPSS storage question 4 to 2, and OAB-q symptom bother scores from 50.0 to
[23]. A significantly greater percentage of men taking 22.5, whereas OAB-q HRQL scores increased from 59.2
tolterodine extended release along with tamsulosin to 81.6 [27].
reported treatment satisfaction and willingness to con-
tinue and improve on the patient perception of bladder The efficacy of oxybutynin extended release along with
condition (PPBC) and urgency perception scale (UPS) vs. a-blocker was evaluated in a double-blind, placebo-con-
placebo at week 12. Improvements on the OAB-q symp- trolled trial of men aged at least 45 years with LUTS and
tom bother and HRQL scales and coping, concern, and OAB symptoms. Patients were eligible if they had IPSS
sleep domains at week 12 were significantly greater with total scores of at least 13, IPSS storage symptom scores of
tolterodine extended release along with tamsulosin than at least 8, Qmax of more than 8 ml/s over a minimum
with placebo [22]. All interventions were well tolerated, voided volume above 125 ml, and PVR of less than 150 ml
and the incidence of AUR requiring catheterization was on two occasions. All men were treated with tamsulosin
low (tolterodine extended release along with tamsulosin, 0.4 mg/day for 4 weeks, after which they were randomly
0.4%; tolterodine extended release, 0.5%; tamsulosin, assigned to 12 weeks of treatment with oxybutynin
0%; and placebo, 0%). Tolterodine extended release extended release 10 mg/day along with tamsulosin
along with tamsulosin was effective in patients, regard- (n ¼ 203) or placebo along with tamsulosin (n ¼ 206). At
less of whether their baseline prostate size or prostate- the end of treatment, improvement in the primary end-
specific antigen (PSA) level was above or below study point (total IPSS score) was significantly greater with the
medians [24,25]. combination of oxybutynin extended release along with
tamsulosin compared with placebo along with tamsulosin
An open study of men with LUTS, likely to be associ- after 8 weeks of treatment (P ¼ 0.03) and 12 (P ¼ 0.006)
ated with BPO, evaluated 191 patients treated with weeks of treatment. The incidence of postvoid residual
terazosin 2 mg once daily for 1 week. Those patients volume higher than 300 ml was 2.9% (6/209) in patients
with continued LUTS after the initial treatment were receiving combination therapy compared with 0.5% (1/
allocated randomly into two groups: those who contin- 209) in patients receiving tamsulosin alone (P ¼ 0.12)
ued to have symptoms after 1 week of terazosin were [28].

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46 Benign prostatic hyperplasia

A double-blind study evaluated men aged at least PSA of less than 1.41 ng/ml, and number of daytime
40 years with LUTS suggestive of OAB (8 micturitions micturitions and urgency episodes in men with PSA of
per day, 1 urgency episode per day) and self-report of at at least 1.41 ng/ml vs. placebo along with an a-blocker
least some moderate bladder-related problems on the [30].
PPBC. Despite being on a stable dose of a-blocker for
at least 1 month, these men were randomly assigned to In a prospective study, men aged at least 50 years with
12 weeks of treatment with tolterodine extended release LUTS and OAB symptoms (8 micturitions per day, 1
4 mg (n ¼ 329) or placebo (n ¼ 323), both given once daily, urgency episode per day with or without UUI, and 1
(the ADAM study) [29]. Men with PVR of more than nocturia episode per day), who had an IPSS of at least 8
200 ml at screening, poor detrusor function or clinically and PVR of 50 ml or less, were randomly assigned to
relevant BOO based on the investigator’s judgment of treatment with propiverine 20 mg once daily (n ¼ 23),
flow rate, and residual urine assessments at screening, or a naftopidil 50 mg once daily (n ¼ 20), or a combination
previous history of AUR requiring catheterization were of propiverine 20 mg and naftopidil 50 mg once daily
excluded. All patients in both groups were already being (n ¼ 23) for 4 weeks [30]. The combination of propiverine
treated with an a-blocker for at least 1 month (tamsulosin and naftopidil significantly improved total IPSS, storage
and alfuzosin were the most commonly used) and con- symptom subscale, and QOL scores from baseline. Com-
tinued taking this medication throughout the study. The bination treatment also significantly improved IPSS item
primary endpoint was the percentage of patients report- scores for frequency, urgency, nocturia, incomplete emp-
ing an improvement on the PPBC at week 12; PPBC tying, and weak stream from baseline. Significant
improvement from baseline to week 12 was reported by improvements in urgency episodes were noted in each
63.6 and 61.6% of patients receiving tolterodine extended group. Although more outcomes were significantly
release along with a-blocker and placebo along with a- improved vs. baseline in the propiverine along with
blocker, respectively; this treatment difference, which naftopidil than in the propiverine or naftopidil alone
was the primary endpoint, was not statistically significant groups, there were no significant differences between
(P > 0.6699). At week 12, patients receiving tolterodine the treatment groups. Postvoid residual urine volume
extended release along with an a-blocker had signifi- increased significantly in propiverine alone group and
cantly greater improvements vs. placebo along with an a- the combination group. One patient in the propiverine
blocker in 24-h micturitions (1.8 vs. 1.2, P ¼ 0.0079) alone group required catheterization owing to AUR and
and daytime micturitions (1.3 vs. 0.8, P ¼ 0.0123), 24- another stopped medication because of difficulty in void-
h urgency episodes (2.9 vs. 1.8, P ¼ 0.0010), daytime ing [31].
urgency episodes (2.2 vs. 1.4, P ¼ 0.0017), and noc-
turnal urgency episodes (0.5 vs. 0.3, P ¼ 0.0378);
frequency–urgency sum (7.8 vs. 5.1, P ¼ 0.0065), Conclusion
IPSS storage subscale (2.6 vs. 2.1, P ¼ 0.0370), and Review of studies of antimuscarinic use in men used as a
OAB-q symptom bother scale (17.9 vs. 14.4, treatment for storage symptoms (OAB) alone by the
P ¼ 0.0086) and coping domain (15.4 vs. 12.4, International Consultation on Incontinence suggests that
P ¼ 0.0491). The number of UUI episodes decreased these agents appear to be effective and well tolerated
in both groups; the between-group difference was not [32].
statistically significant (but only 16% of patients reported
UUI at baseline). Significantly greater improvement was Previous meta-analyses of the data from both random-
seen with tolterodine extended release along with an a- ized, controlled trials and observational studies updated
blocker compared with placebo along with an a-blocker here, including men with LUTS suggestive of BPO due
on the IPSS storage symptom subscale and the OAB-q to BPH (and including both storage and voiding LUTS),
symptom bother scale and coping domain (P < 0.05 for all have been reported [17,33].
comparisons). AUR requiring catheterization occurred in
less than 1% of either group. There were no clinically These studies have included a number of antimuscarinic
meaningful changes in postvoid residual volume or maxi- agents (tolterodine, oxybutynin, propiverine, and solife-
mum urinary flow rate. A post-hoc analysis of data from nacin), with or without an a-blocker. These studies
the ADAM trial, in which results were stratified by suggest that in men with persistent storage symptoms
median baseline serum PSA level (<1.41 and 1.41 ng/ (OAB symptoms), clinically meaningful improvements
ml), found that tolterodine extended release along with can be achieved by addition of an antimuscarinic therapy
an a-blocker was effective in men with higher or lower to an a-blocker. Monotherapy with an antimuscarinic
baseline PSA levels. After 12 weeks of treatment, tolter- therapy alone in this patient group has proven to be
odine extended release along with an a-blocker signifi- disappointing. Voiding difficulty and AUR are infre-
cantly decreased the number of micturitions per 24 h, quently reported across all studies. A careful review
daytime micturitions, and urgency episodes in men with reveals that small, not clinically significant, changes were

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antimuscarinics in men with LUTS Chapple 47

seen in objective measures of urinary function, and 14 Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability
 of tolterodine for the treatment of overactive bladder in men with
several trials demonstrated an increase in postvoid bladder outlet obstruction. J Urol 2006; 175 (3 Pt 1):999–1004;
residual volume with anticholinergic therapy. It must, discussion.
The first large, randomized study in this field looking at the safety of antimuscarinic
however, be borne in mind that reported trials are of short therapy in men with urodynamically proven BOO.
duration (6–12 weeks) and include only men with low 15 Chapple CR, Roehrborn CG. A shifted paradigm for the further understand-
postvoid residual volumes at baseline. Therefore, before ing, evaluation, and treatment of lower urinary tract symptoms in men: focus on
the bladder. Eur Urol 2006; 49:651–658.
starting the therapy, a postvoid residual volume should be
16 Armitage J, Emberton M. The role of anticholinergic drugs in men with lower
measured to rule out baseline retention suggestive of urinary tract symptoms. Curr Opin Urol 2008; 18:11–15.
poor detrusor function. 17 Gallegos PJ, Frazee LA. Anticholinergic therapy for lower urinary tract
symptoms associated with benign prostatic hyperplasia. Pharmacotherapy
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18 Athanasopoulos A, Gyftopoulos K, Giannitsas K, et al. Combination treat-
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
48 Benign prostatic hyperplasia

29 Chapple C, Herschorn S, Abrams P, et al. Tolterodine treatment improves vs. 14.4, P ¼ 0.0086) and coping domain (15.4 vs. 12.4, P ¼ 0.0491). The
 storage symptoms suggestive of overactive bladder in men treated with alpha- number of UUI episodes decreased in both groups; the between-group difference
blockers. Eur Urol 2009; 56:534–543. was not statistically significant (but only 16% of patients reported UUI at baseline).
A double-blind study evaluated men aged at least 40 years with LUTS suggestive Significantly greater improvement was seen with tolterodine extended release
of OAB (8 micturitions per day, 1 urgency episode per day, and self-report of at along with an a-blocker compared with placebo along with an a-blocker on the
least some moderate bladder-related problems on the PPBC) Despite being on a IPSS storage symptom subscale and the OAB-q symptom bother scale and
stable dose of a-blocker for at least 1 month, these men were randomly assigned to coping domain (P < 0.05 for all comparisons).
12 weeks of treatment with tolterodine extended release 4 mg (n ¼ 329) or
30 Chapple CR, Herschorn S, Abrams P, et al. Tolterodine extended release
placebo (n ¼ 323), both given once daily (the ADAM study). All patients in both
improves overactive bladder symptoms in men treated with alpha-blockers
groups were already being treated with an a-blocker for at least 1 month
irrespective of baseline serum prostate-specific antigen level [abstract]. Eur
(tamsulosin and alfuzosin were the most commonly used) and continued taking
Urol Suppl 2009; 8:166.
this medication throughout the study. The primary endpoint was the percentage of
patients reporting improvement on the PPBC at week 12; PPBC improvement 31 Yokoyama T, Uematsu K, Watanabe T, et al. Naftopidil and propiverine hydro-
from baseline to week 12 was reported by 63.6 and 61.6% of patients receiving chloride for treatment of male lower urinary tract symptoms suggestive of benign
tolterodine extended release along with an a-blocker and placebo along with an prostatic hyperplasia and concomitant overactive bladder: a prospective ran-
a-blocker, respectively; this treatment difference, which was the primary endpoint, domized controlled study. Scand J Urol Nephrol 2009; 43:307–314.
was not statistically significant (P > 0.6699). At week 12, patients receiving 32 Andersson KE, Chapple CR, Cardozo L, et al. Pharmacological treatment of
tolterodine extended release along with an a-blocker had significantly greater overactive bladder: report from the International Consultation on Inconti-
improvements vs. placebo along with an a-blocker in 24-h micturitions (1.8 vs. nence. Curr Opin Urol 2009; 19:380–394.
1.2, P ¼ 0.0079) and daytime micturitions (1.3 vs. 0.8, P ¼ 0.0123), 24-h
urgency episodes (2.9 vs. 1.8, P ¼ 0.0010), daytime urgency episodes (2.2 33 Blake-James BT, Rashidian A, Ikeda Y, Emberton M. The role of anticholi-
vs. 1.4, P ¼ 0.0017), and nocturnal urgency episodes (0.5 vs. 0.3, nergics in men with lower urinary tract symptoms suggestive of benign
P ¼ 0.0378), frequency–urgency sum (7.8 vs. 5.1, P ¼ 0.0065), IPSS storage prostatic hyperplasia: a systematic review and meta-analysis. BJU Int
subscale (2.6 vs. 2.1, P ¼ 0.0370), and OAB-q symptom bother scale (17.9 2007; 99:85–96.

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