Author's Accepted Manuscript

Effects of withdrawing alpha-1 blocker from the combination therapy with

alpha-1 blocker and 5-alpha-reductase inhibitor in patients with lower urinary
tract symptoms suggestive of benign prostatic hyperplasia: A prospective and
comparative trial using urodynamics

Yoshihisa Matsukawa , Shun Takai , Yasuhito Funahashi , Tsuyoshi Majima ,

Masashi Kato , Tokunori Yamamoto , Momokazu Gotoh

PII: S0022-5347(17)64714-1
DOI: 10.1016/j.juro.2017.05.031
Reference: JURO 14752

To appear in: The Journal of Urology

Accepted Date: 2 May 2017

Please cite this article as: Matsukawa Y, Takai S, Funahashi Y, Majima T, Kato M, Yamamoto T, Gotoh
M, Effects of withdrawing alpha-1 blocker from the combination therapy with alpha-1 blocker and 5-
alpha-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic
hyperplasia: A prospective and comparative trial using urodynamics, The Journal of Urology® (2017),
doi: 10.1016/j.juro.2017.05.031.

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 ACCEPTED MANUSCRIPT

Effects of withdrawing alpha-1 blocker from the combination therapy with alpha-1 blocker

and 5-alpha-reductase inhibitor in patients with lower urinary tract symptoms suggestive of

benign prostatic hyperplasia: A prospective and comparative trial using urodynamics

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Yoshihisa Matsukawa, Shun Takai, Yasuhito Funahashi, Tsuyoshi Majima, Masashi Kato, Tokunori

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Yamamoto and Momokazu Gotoh

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Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan

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Running head: α1 blocker withdrawal from combination therapy

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Address correspondence to: Yoshihisa Matsukawa, M.D.

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Department of Urology, Nagoya University Graduate School of Medicine

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65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

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Tel: +81 52 744 2985, Fax: +81 52 744 2319, E-mail: yoshi44@med.nagoya-u.ac.jp

Key words: α1 blocker; 5-alpha-reductase inhibitor; lower urinary tract symptoms; bladder outlet

obstruction; switch therapy.

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Word count:

Main text: 2483 words, Abstract: 246 words

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Acknowledgments

We thank all patients for participating and all trial investigators for their contribution to data

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acquisition and patient care.

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Abstract

Purpose: To compare the effects on lower urinary tract symptoms (LUTS) and bladder outlet

obstruction between combination therapy with α1 blocker and 5α-reductase inhibitor and a switch to

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5α-reductase inhibitor monotherapy, and determine the factors influencing changes in LUTS after α1

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blocker withdrawal.

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Materials and Methods: One-hundred and forty outpatients with LUTS suggestive of benign

prostatic hyperplasia received combination therapy with silodosin 8 mg/day and dutasteride 0.5

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mg/day for 12 months. 132 patients were randomized to continue combination therapy (CT group) or
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switched to dutasteride monotherapy through silodosin withdrawal (MT group). Parameter changes
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from before randomization to 12 months after randomization were assessed based on subjective
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symptoms and urodynamic findings for voiding and storage functions.

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Results: In efficacy analysis, 57 patients with CT and 60 with MT were included. The change in
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International Prostate Symptom Score after randomization was -0.7 and -0.6 in the CT and MT

groups, respectively. Bladder outlet obstruction index changed from 46.1 to 41.8 and 42.9 to 39.9 in
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the CT and MT groups, respectively. No significant differences in subjective symptoms and bladder

outlet obstruction were observed between the two groups. Meanwhile, storage functions decreased in

the MT group, and LUTS deteriorated significantly after the switch to dutasteride monotherapy in

patients with higher body mass index.

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Conclusions: α1 blocker withdrawal from combination therapy was reasonable and tolerable with

regard to the effect on LUTS and bladder outlet obstruction. However, the withdrawal must be

performed carefully for patients with high body mass index.

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Introduction

Recently, a number of drugs are used for treating lower urinary tract symptoms suggestive of

benign prostatic hyperplasia (LUTS/BPH). However, α1-adrenoceptor antagonists (α1-blockers) and

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5-alpha-reductase inhibitors (5ARIs) play a central role in the treatment of LUTS/BPH. α1-blockers

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improve LUTS/BPH by relaxing the smooth muscle tone of the prostate and bladder neck. The

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action has been reported to be rapid in onset1, but tend to decrease in potency over the long term2, 3.

In contrast, 5ARI leads to improvement in LUTS and urinary flow by decreasing prostate size

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through inhibition of 5-AR. The onset of action of 5ARIs is slow, but the effect persists for longer
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periods of time4-6. Based on these factors, several countries recommend combination therapy using
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both α1-blockers and 5ARI from an early date in their guidelines for treating patients with a large
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prostate7-9. However, some questions remain to be elucidated, including how long combination
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therapy should be continued and whether the therapeutic effects decrease if combination therapy is
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changed to single-drug therapy.

The CombAT study showed that combination therapy with dutasteride and tamsulosin provided
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significantly greater benefits than monotherapy with either individual agent, as determined by

International Prostate Symptom Score (IPSS), in LUTS/BPH patients10. However, the change in

IPSS from 12 months after treatment in combination therapy group was found to be almost equal to

that in 5ARI monotherapy. Even if switching from combination therapy to 5ARI monotherapy at 12

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months after initial treatment was found to have no differences regarding subjective and objective

symptom improvement, the switch therapy still has many advantages for patients from the

perspective of adverse effects and medication costs. In this study, we withdrew the α1-blocker from

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combination therapy based on the drug profile, and examined the effects of the withdrawal on

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subjective symptoms and lower urinary tract function measured by a urodynamic study (UDS).

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The aims of the present study were: (i) to determine the effects of a switch to 5ARI monotherapy

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from combination therapy on LUTS and bladder outlet obstruction (BOO), and (ii) to determine the
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factors that influence any deleterious effects observed following the withdrawal of the α1 blocker

from combination therapy.

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Materials and Methods

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This was a single-center, randomized, prospective study, which was conducted in accordance
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with the ethical principles of the Declaration of Helsinki. The protocol was approved by the ethics
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committee of the Nagoya University Graduate School of Medicine (IRB approval number: 228012).

All participants provided written informed consent before enrolment.

The study included treatment-naive men who visited our hospital with a chief complaint of both

storage and voiding LUTS between May 2010 and December 2012. The inclusion criteria were as

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follows: Total IPSS ≥ 8; IPSS-QOL score ≥ 3; prostate volume ≥ 30 mL as determined by

transabdominal ultrasonography; maximum urinary flow rate (Qmax) < 15 mL/sec at voided volume

of ≥ 100 mL; post-void residual urine volume (PVR) < 150 mL; age ≥ 45 years. Patients were

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excluded if they received oral or surgical treatment for LUTS; or had neurogenic bladder

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dysfunction, bladder calculi, or active urinary tract infections; or had severe cardiac disease, renal

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dysfunction, or hepatic dysfunction. Prostate biopsy was performed in all patients who had

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prostate-specific antigen (PSA) levels > 4 ng/mL, and only cancer-free patients were included in the
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study.

Patients who satisfied all the inclusion and exclusion criteria received combination therapy using
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the α1-blocker silodosin (8 mg/day) and the 5ARI dutasteride (0.5 mg/day) for 12 months. At 12
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months after initial treatment, they were randomized by the independent central study center using a
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random number table to either continue combination therapy (CT group) or switch to dutasteride
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monotherapy through the withdrawal of silodosin (MT group). After patients received their newly
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assigned treatments for an additional 12 months, changes in subjective symptoms and objective
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findings were evaluated (Figure 1).

Sample size calculations were based on a primary outcome of IPSS change. The mean IPSS

change from 12 months to 24 months was 0.7 points in the dutasteride monotherapy group and 0.6

points in the combination therapy group, based on the CombAT study10. A standard deviation of this

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change was calculated as 2.9 points. The margin of clinical non-inferiority was fixed at 1.5 points. If

there was truly no difference in IPSS change between the CT and MT groups, then 107 participants

were required at one-sided significance level of 0.05 and a power of 80%. We expected

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approximately 25% attrition during the entire study period (after 24 months of study participation),

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and therefore randomized a total of 140 participants.

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To evaluate changes in subjective symptoms, the IPSS, IPSS-QOL, and overactive bladder

symptom scores (OABSS)11 were assessed at baseline, 12 months (before randomization), and 24

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months (after randomization). The patients also underwent UDS, including uroflowmetry,

cystometrogram (CMG), and pressure flow study (PFS) for the evaluation of objective findings at
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baseline, 12 months, and 24 months after the initial treatment. First desire to void (FDV), maximum
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cystometric capacity (MCC), and detrusor overactivity (DO) were assessed as parameters of storage
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function, and Qmax, PVR, detrusor pressure at Qmax (PdetQmax), and bladder outlet obstruction
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index (BOOI) were evaluated as parameters of voiding function.

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Additionally, we divided MT group patients into two groups according to IPSS change after
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switching to monotherapy. Patients with IPSS improvement or same were classified as the IPSS

better/same group, while patients with worsening IPSS values were classified as IPSS worse group.

We compared the backgrounds of the two groups and evaluated factors that may have influenced this

change in subjective symptoms.

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CMG and PFS were performed according to the standard methods defined by the International

Continence Society12. UDS data were de-identified and analyzed independently by our research

group members who were not involved in conducting UDS. Patients were excluded from the

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analysis if they discontinued the treatment owing to adverse reactions and urinary retention, or if

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urodynamic assessment data were not collected during 24 months of treatment. As for adherence to

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therapy, we continued the study for patients who complain only the worsening of subjective

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symptoms or hope a treatment change for selfish personal ends, under informed consent.
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All statistical values are represented as mean ± standard deviation. The Wilcoxon rank-sum test,

Student-t test, and chi-square test were performed to evaluate changes in subjective symptoms and
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objective findings obtained by UDS. All tests were two-sided, and a p value < 0.05 was considered
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statistically significant.
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Results
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Of 140 patients who met the entry criteria, 132 patients completed combination therapy with
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dutasteride and silodosin for 12 months. At this time point, we randomly divided the 132 remaining

patients into the CT and MT groups (66 patients each). Of the 66 patients in the CT group, 3 (4.5%)

discontinued treatment owing to adverse reactions, including breast pain (n = 1), postural

hypotension (n = 1), and dizziness (n = 1). Two patients (3.0%) discontinued treatment owing to

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breast pain (n = 1) and anthema (n = 1) in the MT group. One patient in each groups showed urinary

retention during the study period. No significant difference in the incidence of adverse effects was

found between the two groups. UDS was not performed after randomization in 5 patients in the CT

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group and 3 patients in the MT group. As a result, the final analysis included 57 patients in the CT

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group and 60 patients in the CT group, shown separately as CONSORT flow diagram (Figure 2).

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Patient characteristics at baseline were shown in Table 1; no significant difference was detected in

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subjective and objective parameters between the two groups.
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Changes in prostate volume, PSA, subjective symptoms, and objective findings are summarized

in Table 2 and 3. The prostate size decreased by 29.5% in the CT and 32.9% in the MT group after
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24 months. A significant decrease was observed in total IPSS, IPSS-QOL score, and OABSS at 12
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months (before randomization) in both groups. After randomization, mean IPSS and OABSS
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changed from 11.1 to 10.4 and from 3.7 to 3.4, respectively, in the CT group, and from 10.8 to 10.2
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and from 3.5 to 3.3, respectively, in the MT group (Figure 3a). No significant differences in the
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change of IPSS and OABSS, including the other subjective parameters, were observed between
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these two groups (Table 2). Evaluation of voiding function indicated that both groups showed

significant improvements in Qmax, PVR, PdetQmax, and BOOI after 12 months. After

randomization, BOOI changed from 46.1 to 41.8 and from 42.9 to 39.9 for the CT and MT groups,

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respectively (Figure 3b). There was no significant difference in the improvement of parameters

relevant to voiding function between these two groups (Table 3).

As for storage function, FDV and MCC significantly improved in both groups at 12 months.

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Although the additional improvement in bladder capacity was observed in the CT group at 24

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months, bladder capacity tended to decrease in the MT. DO also improved significantly in both

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groups, in terms of rate of patients with disappearance of DO in CMG. After randomization, further

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DO improvement was observed in the CT group, while the rate of patients with DO increased from
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28.3% to 33.3% in the MT group (Table 3).

Additionally, after randomization, IPSS worsened in 15 patients (26.3%) in the CT group and in
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23 patients (38.3%) in the MT group, although there was no significant difference in the
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deterioration rate between the two groups (p=0.11) (Figure 4). In these 23 patients with deteriorated
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IPSS in the MT group, mean total-IPSS, IPSS-voiding, IPSS-storage and OABSS increased
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significantly by 3.3, 2.1, 1.2 and 0.5, respectively, compared with those before α1-blocker
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withdrawal. In addition, BOO and storage functions worsened (BOOI changed from 41.0 to 42.2,
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and MCC changed from 326 mL to 298 mL). When comparing the patients showing worsened IPSS

after the switch to monotherapy and those who did not, body weight and body-mass index (BMI)

were significantly larger in the patients with worsening IPSS, although no differences in the degree

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of severity of either subjective or objective parameters in the lower urinary tract were observed.

(Table 4)

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Discussion

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This is the first study to evaluate the long-term effect of α1-blocker withdrawal from α1-blocker

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and 5ARI combination therapy in LUTS/BPH patients based on subjective symptoms and

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urodynamic findings. Barkin et al. reported in the SMART-1 study that switching to 5ARI
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monotherapy after 24 weeks of dutasteride and tamsulosin combination therapy was well tolerated

and efficacious in LUTS patients13. Harkaway et al. also reported the discontinuation of the
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α1-blocker after 9 to 12 months of finasteride and doxazosin combination therapy didn’t deteriorate
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LUTS14. However, the evaluation period after the switch to monotherapy in the two studies was
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only 4 and 12 weeks. Additionally, objective efficacy was not evaluated. We showed here the
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long-term evaluation of both subjective and objective changes in CT and MT group patients. In this
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study, IPSS improved by 0.7 in the CT group and 0.6 in the MT group after randomization. This
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change was almost the same as that observed in the CombAT study, and was therefore thought to be

reasonable10. Furthermore, this similar long-term improvement between CT and MT groups was

observed in not only subjective symptoms but also in objective metrics such as urinary flow rate and

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BOO. These findings will lead to new therapeutic approaches for patients continuing α1-blocker and

5ARI combination therapy for LUTS/BPH.

In the SMART-1 study, a small increase in IPSS was observed in patients where α1-blocker was

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withdrawn after 24 weeks of combination therapy13. In our study, mean IPSS and BOO improved

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steadily after switching to dutasteride monotherapy. Regarding this discrepancy, we believe that the

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switch time point in the SMART-1 study at 24 weeks was too early, and that the effect of 5ARI to

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improve LUTS had not attained its maximum. We previously reported that a significant decrease in
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IPSS and BOO started at 2 months after administration of dutasteride and further improvement was

observed until 12 months15. In our study, since the protocol was switched to dutasteride
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monotherapy after 12 months of combination therapy, relief of mechanical obstructions by

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dutasteride was thought to be sufficient at this point, and compensated the possible effects brought
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by silodosin withdrawal. However, the withdrawal of silodosin led to the worsening of storage
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functions, which was counter-intuitive with the changes of subjective symptoms and BOO. In fact,
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35 (58.3%) of 60 patients in the MT group showed decreased MCC, and the incidence of DO
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increased by 17.6% after the withdrawal of silodosin, although they were not statistically significant.

The detailed mechanism is still incompletely understood, but the influence on bladder blood flow

(BBF) by the withdrawal of α1-blocker, which has been reported to increase BBF and improve

storage function16, 17, may be involved in the decrease of storage function.

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Twenty-three patients (38.3%) in the MT group demonstrated worsening of IPSS after

randomization, and not only IPSS, but also BOO and storage function deteriorated in these

individuals. Comparing these patients with those with IPSS better/same after switching to

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dutasteride monotherapy, body weight and BMI were found to be significant factors influencing the

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therapeutic effects after the withdrawal of silodosoin. These findings indicate new potential criteria

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for deciding to switch medical treatment course in patients with LUTS/BPH. It is still not fully

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understood why BMI and body weight were the significant factors leading to deterioration of
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subjective symptoms after the withdrawal of silodosin. However, it has been reported that IPSS

improvement was greater in high-BMI groups when clinical efficacy of α1-blocker was compared
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between normal and obese patients18, 19. Conversely, patients with high BMI were considered more
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susceptible to subjective symptom deterioration after withdrawal of α1-blocker, as α1-blockers have

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been reported to improve sympathetic nervous tone and impaired pelvic blood circulation16, 17, 20,
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which were thought to lead to obesity-induced LUTS21-23. Consequently, the attenuation of these
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actions by the withdrawal of silodosin may lead to the deleterious IPSS changes in high BMI
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patients.

The present study has several limitations. First, this was an open-label and not a

placebo-controlled study. Therefore, placebo effects cannot be completely excluded in terms of

subjective symptom changes as well as UDS evaluation. However, we thought these effects did not

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significantly affect the objectivity of the present study in a major manner. Another limitation was

that the follow-up period of the present study was still only 24 months. In the CombAT study, the

effect on subjective symptoms for each medical treatment was evaluated for 4 years10. Since

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pharmacotherapy for LUTS should generally be continued for a much longer period, the long-term

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efficacy and safety of monotherapy switching in comparison to those of combination therapy need to

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be further clarified in future studies.

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Conclusions

Although silodosin was withdrawn from combination therapy with silodosin and dutasteride for
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LUTS/BPH after 12 months, no significant differences were observed in the improvement of

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subjective symptoms and BOO between the patients continuing combination therapy and those who
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were switched to dutasteride monotherapy. However, LUTS significantly deteriorated after the
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switch to dutasteride monotherapy in patients with higher BMI. Therefore, withdrawal must be
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carefully performed for these patients.

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References

1. Djavan B, Chapple C, Milani S, MarbergerM. State of the art on the efficacy and tolerability of

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alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of

benign prostatic hyperplasia. Urology 2004;64:1081–8.

2. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin,

PT
finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.

N Engl J Med 2003;349:2387–98.

RI
3. Masumori N, Hashimoto J, Itoh N, et al. Short-term efficacy and long-term

SC
compliance/treatment failure of the alpha1 blocker naftopidil for patients with lower urinary

tract symptoms suggestive of benign prostatic hyperplasia. Scand J Urol Nephrol. 2007; 41:

422-9.
U
AN
4. Rittmaster RS, Norman RW, Thomas LN, Rowden G. Evidence for atrophy and apoptosis in
M

the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81:814–9.

D

5. NaslundMJ, Miner M. A review of the clinical efficacy and safety of 5a-reductase inhibitors
TE

for the enlarged prostate. Clin Ther 2007; 29:17–25.

EP

6. Tsukamoto T, Endo Y, Narita M. Efficacy and safety of dutasteride in Japanese men with
C

benign prostatic hyperplasia. Int J Urol. 2009;16:745

AC

7. American Urological Association Education and Research, Inc. Guideline on the management

of benign prostatic hyperplasia (BPH). Linthicum, MD: American Urological Association

Education and Research, Inc.; 2010.

16
 ACCEPTED MANUSCRIPT

8. Homma Y, Gotoh M, Yokoyama O, et al. Outline of JUA clinical guidelines for benign

prostatic hyperplasia. Int J Urol. 2011; 18: 741-56.

9. Oelke M, Bachmann A, Descazeaud A, et al. EAU Guidelines on the treatment and follow-up

PT
of non-neurogenic male lower urinary tract symptoms, incl. benign prostatic obstruction

(BPO). Eur Urol 2013; 64: 118-40.

RI
SC
10. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride

and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia:

U
4-year results from the CombAT study. Eur Urol. 2010;57:123
AN
11. Homma Y, Yoshida M, Seki N, et al. Symptom assessment tool for overactive bladder

syndrome--overactive bladder symptom score. Urology. 2006; 68: 318-23.

M

12. Schäfer W, Abrams P, Liao L, et al. Good urodynamic practices: uroflowmetry, filling
D

cystometry, and pressure-flow studies. Neurourol Urodyn. 2002; 21:261-74.

TE

13. Barkin J, Guimara˜es M, Jacobi G, et al. Alpha-blocker therapy can be withdrawn in the
EP

majority of men following initial combination therapy with the dual 5a-reductase inhibitor

dutasteride. Eur Urol 2003; 44: 461–6.

C
AC

14. Baldwin KC, Ginsberg PC, Roehrborn CG, et al. Discontinuation of alpha-blockade after

initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and

clinical evidence of benign prostatic hyperplasia. Urology. 2001; 58: 203-9.

15. Matsukawa Y, Gotoh M, Kato M, et al. Effects of dutasteride on storage and voiding

symptoms in male patients with lower urinary tract symptoms as a result of benign prostatic

17
 ACCEPTED MANUSCRIPT

obstruction: the 1-year outcomes from a prospective urodynamic study. Int J Urol. 2014; 21:

826-30.

16. Goi Y, Tomiyama Y, Nomiya M, et al. Effects of silodosin, a selective α1A-adrenoceptor

PT
antagonist, on bladder blood flow and bladder function in a rat model of atherosclerosis

induced chronic bladder ischemia without bladder outlet obstruction. J Urol. 2013; 190:

RI
1116-22.

SC
17. Okutsu H, Matsumoto S, Ohtake A, et al. Effect of tamsulosin on bladder blood flow and

bladder function in a rat model of bladder over distention/emptying induced bladder

overactivity. J Urol. 2011; 186: 2470-7.

U
AN
18. Lee SH, Oh CY, Park KK, et al. Comparison of the clinical efficacy of medical treatment of
M

symptomatic benign prostatic hyperplasia between normal and obese patients. Asian J Androl.

2011; 13: 728-31.

D
TE

19. Kim JH, Choi H, Sun HY, et al. BMC Urol. Measuring the improvement in health-related

quality of life using King's health questionnaire in non-obese and obese patients with lower
EP

urinary tract symptoms after alpha-adrenergic medication: a preliminary study. BMC Urol.

2014; 14: 60.

C
AC

20. Oelke M, Höfner K, Berges RR, et al. Drug therapy of benign prostatic hyperplasia syndrome

with alpha 1-receptor blockers. Basic principles and clinical results. Urologe A. 2002; 41:

425-41.

21. Kasturi S, Russell S, McVary KT. Metabolic syndrome and lower urinary tract symptoms

secondary to benign prostatic hyperplasia. Curr Urol Rep. 2006; 7: 288-92.

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22. McVary K. Lower urinary tract symptoms and sexual dysfunction: epidemiology and

pathophysiology. BJU Int. 2006; 97: 23-8.

PT
23. Pomian A, Lisik W, Kosieradzki M, et al. Obesity and Pelvic Floor Disorders: A Review of the

Literature. Med Sci Monit. 2016; 22: 1880-6.

RI
U SC
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Figure legends

Figure 1.
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Title: Study flow chart

Figure 2.
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CONSORT diagram
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Figure 3.
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Title: Changes of total IPSS score and BOOI in CT and MT group during the study periods

Legends to figures:
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(a) Change of IPSS between the two groups

(b) Change of BOOI between the two groups

Figure 4.

Title: Proportions of patients with IPSS better/same and IPSS worse after randomization in CT and

MT group

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Legends to figure:

The changes of total-IPSS at 12 months after randomization were divided into two groups: IPSS

better/same and IPSS worse. The proportions of patients whose IPSS-total deteriorated, IPSS worse,

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were 24 % in CT group and 38 % in MT group.

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Table1. Background between the two groups at baseline

CTgroup MT group
p
Mean ± S.D. Mean ± S.D.

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n 57 60

Age (years) 70.1±7.4 69.1±7.1 0.50

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Prostate volume （mL）
） 57.0±19.4 57.1±17.4 0.95

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PSA (ng/mL) 4.9 ±4.4 4.9 ±3.8 0.96

IPSS-total 17.4± 5.5 17.2±5.6 0.83

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QOL 4.7 ±0.8 4.7 ±0.7 0.93
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OABSS 5.2±2.2 5.1±2.0 0.65

FDV (mL) 140±60 133±50 0.46

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MCC (mL) 267±97 265±70 0.88

Qmax (mL/s) 7.6±2.5 7.8±3.2 0.67

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PVR (mL) 80±70 67±61 0.26

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PdetQmax (cmH20）
） 82.9±21.8 81.5±22.6 0.70

BOOI 67.7±24.4 65.9±23.7 0.65

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prevalence of DO 28/57 (49.1%) 33/60 (55.0%) 0.33

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Table2. Changes in subjective symptoms between the two groups

CT group p (intra- MT group p p

group) (intra-group) (inter-group)

mean±SD mean±SD

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(difference in mean (difference in mean

change from baseline change from baseline

and12 months) and 12 months)

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N 57 60

Prostate Vol (mL)

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baseline 57.0±19.4 57.1±17.4 0.95

12 months 43.0±15.6 (-14.0) <0.001 41.6±14.3 (-15.5) <0.001 0.61

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24 months 40.2±14.8 (-16.8, -2.8) <0.001 38.3±13.5 (-18.8, -3.3) <0.001 0.45

PSA (ng/mL)
AN
baseline 4.9 ±4.4 4.9 ±3.8 0.96

12 months 2.2 ±2.0 (-2.7) <0.001 2.1 ±1.7 (-2.8) <0.001 0.70

24 months 2.1 ±1.9 (-2.8, -0.1) <0.001 2.0 ±1.9 (-2.9, -0.1) <0.001 0.70
M

IPSS

baseline 17.4± 5.5 17.2±5.6 0.83

D

12 months 11.1 ±4.8 (-6.3) <0.001 10.8±4.8 (-6.4) <0.001 0.70

TE

24 months 10.4±5.4 (-7.0, -0.7)) <0.001 10.2±5.3 (-7.0, -0.6) <0.001 0.79

IPSS-voiding

baseline 10.4±3.6 10.6±3.9 0.74

EP

12 months 6.4±3.5 (-4.0) <0.001 6.4±3.5 (-4.2) <0.001 0.98

24 months 6.0±3.7 (-4.4, -0.4) <0.001 6.1±3.7 (-4.5, -0.3) <0.001 0.88

IPSS-storage
C

baseline 7.0±2.6 6.6±2.4 0.36

AC

12 months 4.7±2.1 (-2.3) <0.001 4.4±2.1 (-2.2) <0.001 0.38

24 months 4.4±2.2 (-2.6, -0.3) <0.001 4.1±2.4 (-2.5, -0.3) <0.001 0.39

IPSS-QOL

baseline 4.7 ±0.8 4.7 ±0.7 0.93

12 months 3.1±1.2 (-1.6) <0.001 2.9 ±1.1 (-1.8) <0.001 0.37

24 months 2.9±1.2 (-1.8, -0.2) <0.001 2.8±1.1 (-1.9, -0.1) <0.001 0.66

OABSS
baseline 5.2±2.2 5.1±2.0 0.65
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12 months 3.7±1.9 (-1.5) <0.001 3.5±1.7 (-1.6) <0.001 0.54

24 months 3.4±1.9 (-1.8, -0.3) <0.001 3.3±2.1 (-1.8, -0.2) <0.001 0.83

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Table3. Changes in objective findings between the two groups

CT group p (intra- MT group p p

group) (intra-group) (inter-group)

mean±SD mean±SD

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(difference in mean (difference in mean

change from baseline change from baseline

and 12 months) and 12 months)

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N 57 60

FDV (mL)

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baseline 140±60 133±50

12 months 175±61 (+35) 0.003 180±60 (+47) <0.001 0.64

U
24 months 177±64 (+37, +2) 0.002 173±61 (+40, -7) <0.001 0.70

MCC (mL)
AN
baseline 267±97 265±70

12 months 301±90 (+34) 0.04 302±86 (+37) 0.01 0.95

24 months 312±98 (+45, +11) 0.01 282±83 (+17, -20) 0.22 0.07
M

Qmax (mL/s)

baseline 7.6±2.5 7.8±3.2

D

12 months 9.5±3.1 (+1.9) 0.002 9.6±3.7 (+1.8) 0.007 0.85

TE

24 months 10.0±3.2 (+2.4, +0.5) <0.001 9.9±3.8 (+2.1, +0.3) 0.002 0.83

PdetQmax (cmH2O)
baseline 82.9±21.8 81.5±22.6
EP

12 months 65.1±14.5 (-17.8) <0.001 62.1±18.9 (-19.4) <0.001 0.33

24 months 61.8±16.2 (-21.1, -3.3) <0.001 59.7±18.4 (-21.8, -2.4) <0.001 0.49

PVR (mL)
C

baseline 80±70 67±61

AC

12 months 39±35 (-41) <0.001 37±33 (-30) <0.001 0.72

24 months 43±43 (-37, +4) <0.001 41±51 (-26, +4) 0.01 0.86

BOOI
baseline 67.7±24.4 65.9±23.7

12 months 46.1±18.3 (-21.6) <0.001 42.9±22.3 (-23.0) <0.001 0.38

24 months 41.8±20.4 (-25.9, -4.3) <0.001 39.9±21.4 (-26.0, -3.0) <0.001 0.62
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DO case,
Disappearing rate (%)
baseline 28/57 33/60 0.33

12 months 17/57 (39.3%) 0.02 17/60 (48.4%) 0.002 0.51

24 months 15/57 (46.4%) 0.009 20/60 (39.4%) 0.01 0.27

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Table4. Background before randomization (after 12months’ treatment of combination therapy

with silodosin and dutasteride) in the MT group between IPSS worse and IPSS better/same
after switch to dutasteride monotherapy

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IPSS better/same IPSS worse
p
Mean ± S.D. Mean ± S.D.

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n 37 23

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Age (years) 68.4±8.0 71.3±5.1 0.14

Prostate volume （mL）

） 40.2±11.2 43.9±18.2 0.33

PSA (ng/mL) 2.4 ±1.6 1.7±1.8 0.15

IPSS-total

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10.7± 5.1 11.0±4.4 0.80

IPSS-voiding 6.5± 3.9 6.3± 5.1 0.93

RI
IPSS-storage 4.2± 1.8 4.7± 5.1 0.48

OABSS 3.0±1.0 3.6±1.8 0.40

SC
MCC (mL) 290±92 322±73 0.17

Qmax (mL/s) 9.5±3.7 9.8±3.9 0.52

PVR (mL) 31±31

U 45±35 0.12
AN
BOOI 44.4±23.0 40.3±21.5 0.50
M

Height (cm) 165.4±4.1 165.3±4.0 0.94

Weight (kg) 62.6±7.1 68.8±7.2 0.002

D

BMI 22.8±2.2 25.2±2.5 <0.001

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Manuscript title: Effects of withdrawing alpha-1 blocker from the combination therapy
with alpha-1 blocker and 5-alpha-reductase inhibitor in patients with lower urinary tract
symptoms suggestive of benign prostatic hyperplasia: A prospective and comparative
trial using urodynamics

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Authors: Yoshihisa Matsukawa, Shun Takai, Yasuhito Funahashi, Tsuyoshi Majima,
Masashi Kato, Tokunori Yamamoto and Momokazu Gotoh

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Key of Definitions for Abbreviations

LUTS, lower urinary tract symptoms

U
BPH, benign prostatic hyperplasia
AN
LUTS/BPH, LUTS suggestive of BPH
OAB, overactive bladder
IPSS, International Prostate Symptom Score
M

OABSS, Overactive Bladder Symptom Score

QOL, quality of life
D

α1-blocker, α1-adrenergic receptor blocker

5ARIs, 5α-reductase inhibitors
TE

UDS, urodynamic study

CMG, cystometrogram
PFS, pressure flow study
EP

FDV, first desire to void

MCC, maximum cystometric capacity
C

DO, detrusor overactivity

Qmax, maximum urinary flow rate
AC

PdetQmax, detrusor pressure at maximum flow rate

PVR, post-void residual urine volume
BOO, bladder outlet obstruction
BOOI, bladder outlet obstruction index
PSA, prostate specific antigen
BMI, body-mass index