Comparison of the efficacy and safety of tolterodine 2 mg and 4mg combined with an α-bIocker in men with lower urinary tract symptoms(LUTS) and overactive bladder : a randomized controlled trial

Comparison of the ef ficacy and safety of

tolterodine 2 mg and 4 mg combined with an a-blocker in men with lower urinary tract

symptoms (LUTS) and overactive bladder:

a randomized controlled trial

Tae Heon Kim*, Wonho Jung ^† , Yoon Seok Suh*, Soonhyun Yook ^‡ , Hyun Hwan Sung*

and Kyu-Sung Lee* ^‡

*Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,

Department of Urology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, and

Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea

Tae Heon Kim and Wonho Jung contributed equally to this work.

Objective

To evaluate the ef ficacy and safety of low-dose (2 mg) tolterodine extended release (ER) with an a-blocker compared with standard-dose (4 mg) tolterodine ER with an a-blocker for the treatment of men with residual storage symptoms after a-blocker monotherapy.

Patients and Methods

The study was a 12-week, single-blind, randomized, parallel- group, non-inferiority trial that included men with residual storage symptoms despite receiving at least 4 weeks of a- blocker treatment. Inclusion criteria were total International Prostate Symptom Score (IPSS) ≥12, IPSS quality-of-life item score ≥3, and ≥8 micturitions and ≥2 urgency episodes per 24 h. The primary outcome was change in the total IPSS score from baseline. Bladder diary variables, patient-reported outcomes and safety were also assessed.

Results

Patients were randomly assigned to addition of either 2 mg tolterodine ER (n = 47) or 4 mg tolterodine ER (n = 48) to

a-blocker therapy for 12 weeks. Patients in both treatment groups had a signi ficant improvement in total IPSS score ( 5.5 and 6.3, respectively), micturition per 24 h ( 1.3 and

1.7, respectively) and nocturia per night ( 0.4 and 0.4, respectively). Changes in IPSS, bladder diary variables, and patient-reported outcomes were not signi ficantly different between the treatment groups. All interventions were well tolerated by patients.

Conclusions

These results suggest that 12 weeks of low-dose tolterodine ER add-on therapy is similar to standard-dose tolterodine ER add-on therapy in terms of efficacy and safety for patients experiencing residual storage symptoms after receiving a- blocker monotherapy.

Keywords

benign prostatic hyperplasia, overactive bladder, anticholinergics

Introduction

In men, LUTS are associated with multifactorial aetiologies, including benign prostatic obstruction, overactive bladder (OAB) and nocturnal polyuria [1–3]. Among LUTS, storage symptoms including urgency with or without urgency urinary incontinence (UUI), usually associated with frequency and nocturia, are characterized as OAB [4]. Recent

epidemiological studies have reported that ~50–75% of men have storage symptoms, and that prevalence increases with

advancing age [5–7]. Furthermore, ~18–48% of men report coexisting storage and voiding symptoms. Storage symptoms are bothersome to patients, interfere with daily activities, and have a negative impact on quality of life (QoL) [8].

When symptom relief is insuf ficient after a-blocker monotherapy, patients with bothersome moderate to severe LUTS are recommended to undergo treatment with anticholinergic agents simultaneously or as an add-on [3].

Several studies have provided evidence that concomitant

treatment with anticholinergic drugs is effective and safe for the treatment of storage symptoms in men with LUTS or OAB, particularly when treatment response to a-blocker monotherapy is insufficient [9–11]. In clinical practice, ~70%

of men with voiding and storage symptoms require the addition of anticholinergics after 4 weeks of a-blocker monotherapy [12]; however, although a number of studies have shown that anticholinergics do not significantly increase post-void residual urine volume (PVR) or the incidence of acute urinary retention (AUR), many clinicians are still reluctant to prescribe standard-dose anticholinergic agents because of concerns about causing AUR and increasing PVR, especially in men with possible benign prostatic obstruction.

Moreover, many men discontinue use of anticholinergic agents, largely because of intolerable adverse events (AEs) including voiding difficulty. More recently, Lee et al. [13]

reported that three-quarters of men with benign prostatic obstruction and OAB discontinued standard-dose anticholinergics within 1 year, and aggravation of voiding symptoms was the most common AE leading to

discontinuation in clinical practice.

To address these issues, low-dose anticholinergic agents are currently being used to maintain ef ficacy with minimal side effects. The use of flexible-dosing strategies is predicated on the concepts that the dose –response curve differs between

individual patients and that increasing dosage will result in increased ef ficacy [14]. Patients who are highly sensitive to the drug might experience sufficient efficacy on a lower dose but unacceptable side effects on a higher dose. If patients experience an insufficient treatment response at a low dose, increasing the dosage up to the point of acceptable tolerability will result in a better treatment response. In this respect, starting patients at a low dose is an effective strategy to avoid intolerable side effects. Despite clinicians’ awareness of this trade-off, little is known about the comparative efficacy and safety of low and standard doses for each anticholinergic agent;

therefore, we conducted a study to compare the ef ficacy and safety of low-dose (2 mg) and standard-dose (4 mg)

tolterodine extended release (ER) add-on therapy in men with residual storage symptoms after a-blocker monotherapy.

Patients and Methods

Study Design

This was a 12-week, randomized, single-blind, parallel-group, non-inferiority study conducted at our institution. Men aged

≥50 years with LUTS and residual storage symptoms despite at least 4 weeks of treatment with a-blocker were eligible for inclusion in the study. The inclusion criteria were as follows:

total IPSS ≥12; IPSS QoL item score ≥3; mean of ≥8 micturitions and ≥2 urgency episodes per 24 h in a 3-day bladder diary; and report of at least some moderate problems on the Patient Perception of Bladder Condition (PPBC)

questionnaire [15] at baseline. Exclusion criteria were: PVR

>150 mL; urethral or bladder neck stricture; history or suspicion of prostate cancer; neurological conditions that would affect bladder function; or current or recurrent UTI.

Patients who had received anticholinergics within the previous 2 weeks or 5a-reductase inhibitors within the previous 3 months were also excluded.

At baseline, eligible patients were randomized 1:1 to receive addition of either 2 mg of tolterodine ER (group A) or 4 mg of tolterodine ER (group B) to a-blocker treatment once daily for 12 weeks. We used block randomization to determine subject group assignments. All patients were required to maintain their existing a-blocker treatment regimen throughout the study. Patients were blinded to the dose of tolterodine ER prescribed, but the investigators were not blinded. Written informed consent was obtained from all patients before screening. The study protocol was approved by the appropriate institutional review board and registered at ClinicalTrials.gov with the identifier NCT00922506.

Outcome Assessment

Patients completed the IPSS (total, storage symptoms, voiding symptoms and QoL) and 3-day bladder diaries at baseline and after 4 and 12 weeks. In their bladder diaries the patients rated urgency sensations associated with each micturition episode using the five-point Urinary Sensation Scale (1 = no urgency; 5 = UUI) [16]. An urgency episode was defined as a score ≥3 on the Urinary Sensation Scale. The primary endpoint was mean change in total IPSS score from baseline to week 12. Other endpoints included change from baseline to week 12 in IPSS storage symptoms, IPSS voiding

symptoms, IPSS QoL, urgency episodes, micturitions, nocturia episodes and UUI episodes. Patients also completed the PPBC questionnaire and the Overactive Bladder questionnaire (OAB-q) [17] at baseline and week 12 in addition to a questionnaire regarding patient perceptions of treatment bene fit and satisfaction [18] at week 12.

Additionally, PVR and maximum urinary flow rate (Q max ) were measured at baseline and week 12 and all AEs that occurred within the study period were recorded.

Sample Size Determination

A sample size of 86 patients (43 patients per group) was required to detect a greater than four-point difference in reduction of total IPSS score with a 5% level of statistical signi ficance and 80% power. Accounting for a 20% dropout rate, the sample size was set at 108 patients.

Statistical Analysis

The primary and secondary endpoints were analysed on an

intention-to-treat basis. For missing data, we applied the last

observation carried forward method. Comparisons of continuous variables between the treatment groups were performed with a two-sample t-test or the Mann–Whitney test, as appropriate. Changes in ordinal variables between the treatment groups were compared using generalized estimating equation models. The significance levels for changes in continuous variables within each treatment group were assessed with the paired t-test or Wilcoxon ’s signed rank test as appropriate; generalized estimating equation models were used for ordinal variables. A P value <0.05 was taken to indicate statistical signi ficance. No adjustment was made for the primary and secondary endpoint comparisons. Statistical analyses were performed using SAS ^â software (SAS Institute Inc., Cary, NC, USA).

Results

Of 98 men screened, 95 were randomized to receive

treatment (group A, n = 47; group B, n = 48) and participate in the safety analysis. Eighty-seven of these men (91.6%) were included in the efficacy analysis. Patient disposition is shown in Fig. 1. Baseline demographic and clinical characteristics were similar in group A and group B (Table 1; all P > 0.05).

Tamsulosin was the most frequently used a-blocker in both group A (62.8%, 27/43 patients) and group B (54.5%, 24/44 patients), followed by alfuzosin (23.3 and 20.5%, respectively), doxazosin (4.7 and 13.6%, respectively), and others (9.3 and 11.3%, respectively). The mean duration of a-blocker treatment before randomization was 9.1  19.9 months.

Table 2 shows changes in the IPSS and bladder diary from baseline to weeks 4 and 12 of treatment. The total IPSS scores for both groups were significantly improved by week 12 ( 5.5 and 6.3; P < 0.001 in each group). The IPSS

Screened ( n=98)

Randomized ( n=95)

Excluded ( n=3) - Did not meet inclusion

criteria ( n=3)

α-blocker plus tolterodine 2mg ( n=47)

Discontinued ( n=7) Lost to follow-up ( n=1) Withdrew consent ( n=2)

Adverse event ( n=4)

Complete the study ( n= 40)

α-blocker plus tolterodine 4mg ( n=48)

Discontinued ( n=9) Lost to follow-up ( n=1) Withdrew consent ( n=4)

Adverse event ( n=4)

Complete the study ( n= 39) Fig. 1 Patient disposition.

Table 1 Baseline demographic and clinical characteristics.

Group A ( n = 43) Group B ( n = 44)

Age, years 65.6  8.0 64.0  7.5

PSA, ng/mL 1.3  0.9 2.3  4.3

Prostate volume, mL 30.3  7.9 31.0  13.3

Q

, mL/s 14.9  8.3 14.8  6.3

Volume voided/

micturition, mL

191.0  105.8 185.6  83.3 Post-void residual

urine volume, mL

30.9  29.0 26.3  17.9

Bladder diary

Micturition/24 h 10.8  2.1 11.6  3.4

Nocturia episodes/24 h (n)

1.9  0.9 (35) 1.8  1.1 (43) Urgency

episodes/24 h

7.2  3.2 8.2  4.5

UUI

episodes/24 h (n)

1.6  1.1 (6) 3.9  8.6 (9) IPSS

Total score 19.3  5.5 20.6  6.

Storage symptoms score

9.2  2.4 9.9  2.4

Voiding symptoms score

10.1  4.5 10.8  5.5

QoL score 4.3  0.8 4.3  0.8

PPBC response, n (%)

No problems at all 0 0

Some very minor problems

0 0

Some minor problems

0 0

Some moderate problems

22 (51.2) 28 (63.6)

Severe problems 19 (44.2) 14 (31.8)

Many severe problems

2 (4.7) 2 (4.5)

Group A = a-blocker + 2 mg tolterodine; group B = a-blocker + 4 mg tolterodine.

Q

, maximum urinary flow rate; UUI, urgency urinary incontinence; PPBC, Patient Perception of Bladder Condition. Data are mean 

, unless otherwise indicated.

Baseline dermographic and clinical characteristics in two groups were similar.

storage symptom scores, voiding symptom scores and QoL scores for both groups also improved between baseline and week 12; however, differences in mean change from baseline to week 12 for total IPSS score, IPSS storage symptom score, voiding symptom score and QoL score between groups A and B were not significant (Fig. 2A; all P > 0.05). Significant improvement in micturition and nocturia episodes was noted in both groups at week 12 (all P < 0.05). The number of urgency and UUI episodes were significantly reduced in group B at week 12 (P = 0.002 and P = 0.012, respectively).

Although the absolute number of urgency and UUI episodes was reduced in group A at week 12, the differences from baseline were not signi ficant (P = 0.099 and P = 0.375, respectively). There were no signi ficant intergroup differences regarding changes in the number of urgency episodes, micturition, nocturia events and UUI episodes (Table 2, Fig. 2B; all P > 0.05).

The PPBC and OAB-q outcomes were similar in group A and group B, although changes in PPBC and OAB-q were

numerically greater in group B than in group A at week 12 (Fig. 3A,B; all P > 0.05). With regard to treatment benefit

Table 2 Outcome measures among treatment groups in IPSS and bladder diary variables. Variables Group A (n = 43) Group B (n = 44) P

Baseline Week 4 P * Week12 P * Baseline Week 4 P * Week12 P * IPSS Total 19.3  5.5 15.2  6.0 < 0.001 13.8  6.9 < 0.001 20.6  6.7 15.7  7.3 < 0.001 14.3  6.1 < 0.001 0.531 Storage 9.2  2.4 6.8  2.9 < 0.001 6.2  3.2 < 0.001 9.9  2.4 7.1  3.0 < 0.001 6.8  2.5 < 0.001 0.857 Voiding 10.1  4.5 8.4  4.4 0.014 7.6  4.9 0.001 10.8  5.5 8.6  4.8 0.006 7.6  4.2 < 0.001 0.383 QoL 4.3  0.8 4.0  1.2 0.248 3.6  1.4 0.002 4.3  0.8 3.7  1.2 < 0.001 3.7  1.0 < 0.001 0.923 Bladder diary Urgency/24 h (n ) 7.2  3.2 (43) 5.6  3.5 (43) 0.006 5.8  4.7 (43) 0.099 8.2  4.5 (43) 6.2  4.7 (43) 0.003 6.0  4.2 (43) 0.002 0.574 Micturition/24 h (n ) 10.8  2.1 (43) 9.2  2.5 (43) < 0.001 9.5  2.8 (43) < 0.001 11.6  3.4 (43) 10.0  2.8 (43) < 0.001 10.0  2.4 (43) < 0.001 0.598 Nocturia/24 h (n ) 1.9  0.9 (35) 1.7  1.1 (35) 0.154 1.5  0.9 (35) 0.032 1.8  1.1 (43) 1.7  1.6 (43) 0.854 1.4  1.0 (43) 0.008 0.807 UUI/24 h (n ) 1.6  1.1 (6) 1.1  1.9 (6) 1.000 0.9  1.2 (6) 0.375 3.9  8.6 (9) 0.7  2.0 (9) 0.012 0.0  0.0 (9) 0.012 0.589 Data are mean 

. Group A = a-blocker + 2 m g tolterodine; Group B = a-blocker + 4 m g tolterodine. QoL, quality of life; UUI, urgency urinary incontinence. *Vs baseline.

Difference in change from baseline to week 12 between group A and group B.

0 (A)

(B)

Storage score Total

score

Group A -0.7*

-3.0*

-5.5*

-6.3*

-0.7*

-3.2*

-3.1*

-2.5*

†

†

†

†

†

†

†

Group B Voiding

score QoL

score

-1 -2 -3 -4 -5 -6 -7

Urgency Frequency Nocturia 0

-0.5 -1 -1.5 -1.4

-2.3*

-1.7*

-1.3*

-0.4* -0.4*

-2 -2.5 -3

Group A

Group B

Fig. 2 Changes in (A) IPSS and (B) bladder diary from baseline to

12 weeks of treatment. Group A = a-blocker + 2 mg tolterodine; group

B = a-blocker + 4 mg tolterodine. *P < 0.05 vs baseline;

No signi ficant

differences between groups. QoL, quality of life.

and satisfaction, 97.6% of patients (41/42) in group A and 97.7% of patients (43/44) in group B reported their treatment to be beneficial, and 85.7% of patients (36/42) in group A and 86.4% of patients (38/44) in group B were satisfied with their treatment at week 12. There were no significant differences between the two treatment groups regarding

patient perceptions of treatment benefit and satisfaction at week 12 (Fig. 3C; all P > 0.05).

Table 3 shows data for mean change in PVR and Q _max from baseline to week 12. The difference between group A and group B regarding mean increase in PVR from baseline was 0% 7.0%

Percentage of patients 20%

40%

60%

80%

100%

34.9%

37.2%

20.9%

*

≥ 2 point improvement 1 point improvement No change

Deterioration

2.3%

29.5%

34.1%

34.1%

Group A ( n=43)

* *

*

0 0

5 -5

10

-10

15

-15 -13.5 -13.9

Mean change from baseline

Mean change from baseline

20

15.1

10.2 12.5 13.5

11.7

7.7 8.6 9.5

9.6

11.3 *

*

*

Group B ( n=44) Symptom bother

Total HRQL Concern Coping Sleep Social interaction

Group A ( n=42) 0%

20%

40%

60%

80%

100%

2.4% 2.3%

73.8%

23.8%

Very satisfied

Much A little satisfied

A little dissatisfied Very dissatisfied Little

No

68.2%

29.5%

59.5%

7.1%

7.1% 6.8%

6.8%

68.2%

18.2%

26.2%

Group B ( n=44) Group A

( n=43)

Group B ( n=44)

Benefit

Group A ( n=42)

Group B ( n=44) Satisfaction

Percentage of patients

* *

(A)

(B)

(C) Fig. 3 Patient-reported outcomes at week 12.

(A) Patient perception of bladder condition,

(B) Overactive Bladder questionnaire, and (C)

patient perceptions of treatment bene fit and

satisfaction. Group A = a-blocker + 2 mg

tolterodine; group B = a-blocker + 4 mg

tolterodine. *No significant differences

between groups (P > 0.05).

significant (0.5 vs 43.6 mL; P = 0.025). The intergroup difference for change in Q _max was not significant (P = 0.421).

Treatment-emergent AEs were reported by 46.8% of patients (22/47) in group A and 47.9% of patients (23/48) in group B.

The most common AE in both treatment groups was dry mouth, reported by 27.7% in group A (13/47) and 31.3% in group B (15/48). There was no AUR in either group. Four patients in each treatment group discontinued treatment because of an AE. AEs are summarized in Table 4.

Discussion

This study shows that low-dose tolterodine ER add-on therapy is not inferior to standard-dose tolterodine ER add- on therapy in patients with residual storage symptoms after a-blocker monotherapy. The within-group improvements in

total IPSS score at week 12 (primary endpoint) were

significant for both groups (both P < 0.001). Moreover, ~70%

of patients in both groups showed an improvement in total IPSS score by ≥4 points at week 12 (69.8% in group A [30/

44] and 70.5% [31/44] in group B). A four-point decrease in the total IPSS score has been shown to be a minimally important difference, i.e. the lowest amount of change that a patient would perceive as meaningful or bene ficial [19].

Changes in total IPSS score, IPSS subscore and QoL score before and after treatment were all similar in the two groups.

The differences between the two groups in terms of mean change in urgency, micturition, nocturia and UUI episodes per 24 h at week 12 were also nonsignificant.

Safety and tolerability outcomes in the present study showed that both treatment doses were well tolerated. Treatment- emergent AEs were of mild or moderate intensity in both treatment groups. Overall, 8.5% of patients (4/47) in group A and 8.3% of patients (4/48) in group B discontinued

treatment because of an AE; only one patient in each treatment group discontinued because of voiding dif ficulty.

Although no cases of AUR were reported in either treatment group, the patients in group B had a significantly higher PVR than those in group A.

Only a few studies have investigated the efficacy, safety and tolerability of low-dose anticholinergics combined with a- blockers for treatment of voiding and storage symptoms in men (Table 5 [20 –23]). Bae et al. [20] reported that total IPSS score and storage symptom score were signi ficantly improved in patients receiving combined alfuzosin and low- dose propiverine (10 mg) compared with those receiving alfuzosin monotherapy. The ASSIST (add-on therapy of solifenacin succinate in men for BPH with OAB symptoms treated by tamsulosin hydrochloride) study [21] reported a significant reduction in IPSS storage score when patients were treated with tamsulosin and low-dose (2.5 mg) or standard- dose (5 mg) solifenacin add-on compared with patients treated with tamsulosin monotherapy. Additionally, the urgency score in the Overactive Bladder Symptom Scores (OABSS) questionnaire and the number of micturitions per 24 h improved significantly, even when comparing the

Table 3 Effect of treatment on post-void residual urine volume and maximum urinary flow rate.

Group A ( n = 43) Group B ( n = 44) P

Baseline 12 weeks Baseline 12 weeks

n 40 40 38 38

PVR 30.9  29.0 31.5  26.1 26.3  17.9 69.8  136.2

Change – 0.5  32.0 – 43.6  139.0* 0.025

n 40 40 38 38

Q

14.9  8.3 14.3  8.0 14.8  6.3 15.3  7.5

Change – 0.6  4.8 – 0.5  7.5 0.421

Group A, a-blocker + 2 mg tolterodine; group B = a-blocker + 4 mg tolterodine. PVR, post-void residual urine volume; Q

, maximum urinary flow rate. *P < 0.05 vs baseline.

†

P values for comparisons between group A and group B.

Table 4 Treatment-emergent adverse events.

Group A ( N = 47) n (%)

Group B ( N = 48) n (%)

Any event 22 (46.8) 23 (47.9)

Gastrointestinal disorders

Dry mouth 13 (27.7) 15 (31.3)

Constipation 1 (2.1) 3 (6.3)

Abdominal discomfort 2 (4.3) 1 (2.1)

Dyspepsia 0 1 (2.1)

Nausea 1 (2.1) 0

Diarrhoea 1 (2.1) 0

Eye disorder

Dry eye 3 (6.4) 3 (6.3)

Blurred vision 0 1 (2.1)

Nervous system disorders

Dizziness 0 3 (6.3)

Headache 2 (4.3) 0

Dizziness postural 1 (2.1) 0

Somnolence 1 (2.1) 1 (2.1)

Urinary and reproductive system disorders

Slow stream 3 (6.4) 3 (6.3)

AUR 0 0

Retrograde ejaculation 0 1 (2.1)

Discontinuation because of AE 4 (8.5) 4 (8.3)

AUR, acute urinary retention; AE, adverse event. Group A = a-blocker + 2 mg

tolterodine; group B = a-blocker + 4 mg tolterodine.

low-dose solifenacin add-on group with the tamsulosin monotherapy group. In the TAABO study (trial of combination treatment of an alpha-blocker plus an anticholinergic for BPH with OAB) [22], patients who received tamsulosin with 10 mg of propiverine had

significantly fewer micturitions and urgency episodes per 24 h and lower IPSS storage symptom scores compared with patients who received tamsulosin monotherapy. Moreover, tamsulosin combined with 10 mg of propiverine was equally effective or slightly more effective than tamsulosin combined with 20 mg of propiverine. Similarly, Cho et al. [23] reported that alfuzosin combined with 10 mg or 20 mg of propiverine signi ficantly reduced OABSS compared with alfuzosin monotherapy. The improvements in total IPSS score and storage and voiding symptom scores were not signi ficantly different between the groups receiving alfuzosin combined with 10 mg of propiverine and the group receiving alfuzosin combined with 20 mg of propiverine. Safety and tolerability outcomes from these studies show that a combination of low- dose anticholinergic and an a-blocker is well tolerated and has a low rate of discontinuation. No patients in such groups experienced AUR. As noted above, these findings provide evidence that low-dose anticholinergic drugs in combination therapy are effective and safe for men with voiding and storage symptoms, which is consistent with the findings in the present study.

In contrast to previous studies, the present study included an assessment of patient-reported outcomes, including the PPBC questionnaire, the OAB-q and patient perceptions of

treatment benefit and satisfaction. The IPSS, bladder diary and OABSS are conventionally used to evaluate the efficacy of anticholinergics. These tools provide clinicians with objective and quantitative information about symptom improvement;

however, these improvements do not always correlate with patient perceptions or clinical significance. Patient-reported outcomes are typically used to fill the assessment gap between clinicians and patients [24]. The present study showed that patients who received an a-blocker combined with low-dose anticholinergics perceived improved bladder-related problems and improved health-related QoL after treatment. The majority of patients reported that the treatment was bene ficial and had a satisfactory outcome. These results were similar to those in patients who received an a-blocker with standard- dose anticholinergics.

Although urinary frequency and urgency are the two most important storage symptoms, it is well known that these symptoms are dif ficult to precisely define or to characterize for research or clinical purposes. In the present study, patients with ≥8 micturitions and ≥2 urgency episodes per 24 h before randomization were considered to have moderate to severe storage symptoms, and these criteria were used to determine suitability for inclusion. By contrast, nocturia is a multifactorial symptom and actually occurs more often as a

Table 5 a -blocker and low-dose anticholinergics combination trial characteristics and subjective outcome measures. Trial No. of patients Drug (dose) Duration, months Primary endpoint Change from baseline in primary endpoint a -blocker monotherapy Lower-dose combination Standard-dose combination Bae et al. [20] 209 Alfuzosin (10 mg) Propiverine (10 mg) 2 Change in IPSS storage symptom 3.4 4.0 Signi ficant vs a-blocker NA ASSIST [21] 638 Tamsulosin (0.2 mg) Solifenacin (2.5 mg) Solifenacin (5 mg) 3 Change in urgency episodes per 24 h 1.9 2.2 2.4 Signi ficant vs a-blocker TABBO [22] 214 Tamsulosin (0.2 mg) Propiverine (10 mg) Propiverine (20 mg)

3 Change in micturition episodes per 24 h 0.8 1.9* Signi ficant vs a-blocker 1.2 Cho et al. [23] 150 Alfuzosin (10 mg) Propiverine (10 mg) Propiverine (20 mg) 2 Change in OABSS 0.7 2.5 Signi ficant vs a-blocker 4.3 Signi ficant vs a-blocker Present study 95 Any a-blocker Tolterodine (2 mg) Tolterodine (4 mg)

3 Change in IPSS total score NA 5.5* 6.3 NA, not assessed; ASSIST, Add-on therapy of Solifenacin Succinate in men for BPH with OAB symptoms treated by Tamsulosin; OAB, overactive bladder; TA ABO, Trial of combination treatment of an a-blocker plus an Anticholinergic for BPH with OAB; OABSS = Overactive Bladder Symptom Scores. *P > 0.05 vs standard-dose combination.

consequence of processes unrelated to lower urinary tract dysfunction [25]. Additional methods are needed to determine whether the patient is awakened by OAB symptoms or by something else; therefore, we did not consider the number of nocturia episodes per night as an inclusion criterion in this study.

The present study has several limitations. Although the number of patients recruited provided suf ficient statistical power to the study, the sample size was still relatively small.

Second, the investigators were not blinded to patient assignment and this might have caused some bias. We believe, however, that our single-blinded study design did not significantly affect the results because outcome measurements were assessed by the patients themselves, who were blinded to the treatment arms. Third, this study was not a placebo- controlled study, which might have affected the results of within-group comparisons. Nevertheless, as we focused on comparisons between the different dosages of add-on anticholinergics, the intergroup comparisons might not have been affected. Fourth, participants in this study were taking a variety of different types of a-blocker. The human lower urinary tract contains a 1 -adrenergic receptors (ARs), and three subtypes of ARs have been identi fied in the prostate ( a 1A , a 1B , and a 1D ), with ~70% being the a 1A subtype [26].

Functional studies suggest that a 1 -ARs play an important role in mediating prostate muscle contraction [27]. Activation of these receptors and the subsequent increase in prostatic smooth muscle tone with urethral constriction and impaired urine flow are thought to be major contributors to the pathophysiology of LUTS. All available a-blockers have activity at all receptors and are thought to have the greatest influence on prostatic smooth muscle tone [28]. Alfuzosin and doxazosin are second-generation a 1 -blockers, whereas tamsulosin is a third-generation a 1 -blocker and more selective for all subtypes. Furthermore, tamsulosin has 2.5- to 12-fold greater selectivity for the a 1A -ARs than for the a 1B -ARs [29].

The treatment response in the present study might therefore have been affected by differences in a 1 -AR subtype selectivity against various types of a-blockers; however, we were primarily concerned with evaluating the additional bene fits of addition of anticholinergics to an a-blocker, so the type of a- blocker used probably had little effect on the results. Finally, one of the main limitations of this study was its short (12- week) treatment duration; a longer follow-up is necessary to confirm that the results are maintained over an extended treatment duration.

In conclusion, low-dose tolterodine ER add-on therapy was not inferior to standard-dose tolterodine ER add-on therapy in men experiencing residual storage symptoms after receiving a-blocker monotherapy. Moreover, this treatment contributed to improvements in patient-reported outcomes.

Based on the present results, low-dose anticholinergics may be considered as the starting dose for relief of residual storage

symptoms in men with LUTS who have not received symptom relief from a-blocker monotherapy.

Conflict of Interest

None declared.

Acknowledgements

This work was supported by the Clinical Research Design Program grant at Samsung Medical Center, #CRS 1097231.

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Correspondence: Kyu-Sung Lee, Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 135-710, Korea.

e-mail: [email protected]

Abbreviations: ER, extended release; OAB, overactive bladder;

UUI, urgency urinary incontinence; PVR, post-void residual urine volume; QoL, quality of life; AUR, acute urinary retention; AE, adverse event; PPBC, Patient Perception of Bladder Condition; OAB-q, Overactive Bladder questionnaire;

Q _max , maximum urinary flow rate; OABSS, Overactive

Bladder Symptom Scores; AR, adrenergic receptor.