Tadalafil once daily in the treatment of lower
urinary tract symptoms (LUTS) suggestive of
benign prostatic hyperplasia (BPH) in men
without erectile dysfunction
Gerald Brock, Gregory Broderick*, Claus G. Roehrborn†, Lei Xu‡, David Wong‡
and Lars Viktrup‡
St Joseph's Health Care London, University of Western Ontario, London, Canada, *Mayo Clinic, Jacksonville, FL, †UT
Southwestern Medical Center at Dallas, Dallas, TX, and ‡Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, IN, USA
Objectives
• To assess the safety and efficacy of tadalafil once daily on
lower urinary tract symptoms suggestive of clinical benign
prostatic hyperplasia (BPH-LUTS) in men without erectile
dysfunction (ED).
• To compare these with effects in men with ED.
Patients and Methods
• After a 4-week washout period and 4-week placebo run-in
period, 1089 men without ED (n = 338) and with ED
(n = 751) were randomly assigned to placebo or tadalafil
5 mg once daily for 12 weeks in three global clinical studies
with similar designs.
• In the pooled dataset, post hoc analyses of covariance
assessed the impact and severity of BPH-LUTS using the
International Prostate Symptom Score (IPSS) and the BPH
Impact Index (BII) and IPSS quality-of-life (IPSS-QoL)
subscores.
• Safety was assessed using treatment-emergent adverse
events.
• The treatment-by-ED-status interaction was used to assess
efficacy differences between the with/without ED
subgroups.
Introduction
Lower urinary tract symptoms suggestive of BPH
(BPH-LUTS), are increasingly common in aging men [1–3].
While the majority will experience coexisting erectile
dysfunction (ED) [4], many will have BPH-LUTS
without ED [5]. Irrespective of coexisting ED, men with
BPH-LUTS often report a diminished overall quality of
life [5].
BJU Int 2013; 112: 990–997
wileyonlinelibrary.com
Results
• Men without ED were similar in BPH-LUTS
severity/previous therapy to men with ED.
• Tadalafil significantly reduced BPH-LUTS from baseline
when compared with placebo in men without ED (IPSS −5.4
vs −3.3, P < 0.01; IPSS voiding subscore −3.5 vs −2.0,
P < 0.01; IPSS storage subscore −1.9 vs −1.3, P < 0.05).
• Tadalafil also significantly improved quality of life from
baseline when compared with placebo in men without ED
(IPSS-QoL −1.0 vs −0.7, BII −1.4 vs −1.0; both P < 0.05).
• Between-ED-subgroup interactions were not significant (all
P > 0.68).
• Tadalafil was safe and well tolerated.
Conclusion
• Tadalafil 5 mg once daily improved BPH-LUTS in men without
ED by a magnitude similar to that observed in men with ED.
• The adverse event profile in men without ED was consistent
with that observed in men with ED.
Keywords
lower urinary tract symptoms, LUTS, prostatic hyperplasia,
BPH, erectile dysfunction, phosphodiesterase type 5 inhibitors,
tadalafil
Phosphodiesterase type 5 (PDE5) inhibitors, especially tadalafil,
have been investigated for the treatment of BPH-LUTS and ED
coexisting with BPH-LUTS. Tadalafil 5 mg once daily was
approved in 2011 in the USA and in 2012 in the European
Union for the treatment of BPH-LUTS and ED with BPH-LUTS
and has achieved regulatory approval in other countries for the
treatment of men with one or both of these conditions.
Treatment with tadalafil may provide an alternative to current
recommendations such as α1-adrenergic blockers (α-blockers)
© 2013 The Authors
BJU International © 2013 BJU International | doi:10.1111/bju.12251
Published by John Wiley & Sons Ltd. www.bjui.org

as monotherapy for the management of bothersome BPH-LUTS
or in combination with 5α-reductase inhibitors (5-ARIs) [6].
Commonly reported adverse events (AEs) associated with
α-blockers include orthostatic hypotension, dizziness, asthenia,
nasopharyngitis and abnormal ejaculation [7,8]. Ejaculatory
dysfunction, characterized by Hellstrom and Sikka [9] as
decreased ejaculate volume and anejaculation, occurs in 10 and
30% of men taking tamsulosin and silodosin, respectively
[10,11]. Common AEs associated with 5-ARIs include decreased
libido, decreased ejaculate volume and ED [7,8,12,13]. Reports
of persistent sexual dysfunction (including libido, ejaculation
and orgasm disorders) after drug discontinuation or male
infertility and/or poor semen quality that normalized or
improved after drug discontinuation resulted recently in a
revision of the finasteride US package insert [14,15].
While PDE5-inhibitors successfully improve ED, the
approval of tadalafil once daily for the treatment of
BPH-LUTS supports the additional effects of tadalafil on
other key structures of the lower urinary tract. Several
studies have confirmed the efficacy and tolerability of
tadalafil in the treatment of men with BPH-LUTS,
irrespective of ED [16–19]; however, sample sizes in
individual studies in men with BPH-LUTS but without ED
have been too small to fully understand the impact of
tadalafil in this subpopulation. Thus, the focus of this
integrated analysis of international studies in men with
BPH-LUTS [17–19] was to further evaluate the efficacy and
safety of tadalafil 5 mg once daily vs placebo on BPH-LUTS
in a large sample of men without ED and to compare these
effects with those found in men with ED.
Materials and Methods
Study Design and Participants
The present integrated analysis comprised three randomized,
double-blind, placebo-controlled, 12-week studies with similar
inclusion and exclusion criteria performed at centres in
Argentina, Australia, Austria, Belgium, France, Canada,
Germany, Greece, Italy, Mexico, the Netherlands, Poland,
Spain, Sweden and the USA. Men were eligible to participate if
they were ≥45 years of age with a history of LUTS secondary
to BPH for >6 months, an IPSS ≥13, and maximum urinary
flow rate (Qmax) 4–15 mL/s. ED reflected a clinical diagnosis by
the investigator after a physical examination and a functional
inquiry confirming a consistent change in the quality of
erection adversely affecting satisfaction with sexual
intercourse, but this was not a required inclusion criterion.
Exclusion criteria included PSA >10.0 ng/mL (or PSA ≥4.0 to
≤10.0 ng/mL if malignancy had not been excluded), postvoid
residual urine volume ≥300 mL at screening, and the use of
finasteride within the previous 3 months or dutasteride within
the previous 6 months or 12 months, respectively. Additional
exclusion criteria were as described previously [17–19].
Tadalafil treatment of BPH-LUTS in men without ED
A 4-week washout period preceded a 4-week placebo lead-in
period before the baseline visit. At baseline, patients were
randomly assigned either to tadalafil 5 mg once daily or
placebo for a 12-week treatment period. Additional study
design details were as reported previously [18].
The studies were conducted in accordance with the
Declaration of Helsinki and were approved by the institutional
review boards at each site. All participants provided written
informed consent before undergoing any study procedure or
receiving study therapy.
Measures
The primary efficacy measure of BPH-LUTS severity was
assessed by the mean change in total IPSS from baseline to
endpoint (12 weeks or last measurement). The IPSS is a
validated, seven-part, self-administered questionnaire. Higher
scores are indicative of greater symptom severity.
Secondary efficacy measures included IPSS obstructive
(voiding) and irritative (storage) subscores, the BPH Impact
Index (BII), and the IPSS quality-of-life (IPSS-QoL)
subscore. Safety measures included patient-reported
treatment-emergent AEs (TEAEs). Other efficacy and safety
parameters have been reported previously in the individual
studies [18–20].
Statistical Analysis
The efficacy analysis population included all randomized
patients who started double-blind study medication with
either tadalafil 5 mg or placebo once daily. The demographic
and safety summaries were based on randomized patients.
We used ANCOVA to assess the least squares (LS) mean change
in total IPSS from baseline to endpoint (12 weeks or last
non-missing measurement). Model terms were included for
baseline, treatment, region, protocol, ED history indicator and
treatment-by-ED-status interaction. Baseline-by-treatment and
treatment-by-region interactions were included if P < 0.10.
Similar to the analysis for total IPSS, secondary analyses were
conducted using ANCOVA to evaluate LS mean change from
baseline to endpoint (12 weeks or last non-missing
measurement) for tadalafil 5 mg compared with placebo for
IPSS voiding and storage, BII and IPSS-QoL subscores.
To determine whether treatment response patterns across
therapies (tadalafil or placebo) were different for men with
or without ED, a treatment-by-ED-status interaction was
assessed in the ANCOVA model described above. P values for
treatment-by-ED-status interaction were reported regardless
of their statistical significance. Insignificant interaction
P values were indicative of similar treatment effects across the
two ED status subgroups.
© 2013 The Authors
BJU International © 2013 BJU International 991
Brock et al.

Results Significant improvements in changes from baseline were

A total of 1092 men entered the studies and were randomly
assigned to treatment groups. Of these, 1089 reported their
ED status: 338/1089 (31%) reported no history of ED, and
751/1089 (69%) reported a history of ED. Of the 1089 patients,
971 (89%) completed the study (placebo, n = 485; tadalafil,
n = 486).
The sample of men without ED was similar to the sample of
men with ED in age, body mass index, PSA level, sexual
activity and previous α-blocker therapy (Table 1). Previous
PDE5 therapy was reported by 1% of men without ED (3/338)
and 30% of men with ED (224/751). Men without ED reported
a lower incidence of comorbid conditions than men with ED
(Table 1): diabetes mellitus (7% [23/338 patients] vs 15%
[115/751 patients]), cardiovascular disease (41% [139/338
patients] vs 50% [373/751 patients]), and hypertension (35%
[119/338 patients] vs 43% [326/751 patients]).
In men without ED, treatment with tadalafil 5 mg resulted in a
significant improvement in total IPSS mean change from
baseline (–5.4) compared with placebo (–3.3; treatment
difference, –2.1, P < 0.01 [Table 2; Fig. 1]). Significant
improvements in changes from baseline were observed
compared with placebo in IPSS subscores (voiding, –3.5 vs
–2.0, P < 0.01; storage, –1.9 vs –1.3, P < 0.05, respectively) and
quality of life (BII, –1.4 vs –1.0; IPSS-QoL, –1.0 vs –0.7; both
P < 0.05 [Table 2; Figs 1,2]).
In men with ED, treatment with tadalafil 5 mg resulted in a
significant improvement in total IPSS mean change from
baseline to endpoint (–5.7) compared with placebo (–3.3;
treatment difference, –2.3, P < 0.001 [Table 2; Fig. 1]).
observed compared with placebo in IPSS subscores (voiding,
–3.5 vs –1.9; storage, –2.2 vs –1.3, both P < 0.001) and quality
of life (BII, –1.6 vs –0.9; IPSS-QoL, –1.1 vs –0.7; both
P < 0.001 [Table 2; Figs 1,2]).
Improvement in BPH-LUTS was similar between men without
ED and with ED, as P values for treatment-by-ED-status
interactions were insignificant for total IPSS (P = 0.73), IPSS
voiding subscore (P = 0.69), IPSS storage subscore (P = 0.78),
BII (P = 0.81), and IPSS-QoL (P = 0.89).
Common TEAEs reported by men without ED and with ED
were similar (Table 3). Of 338 men without ED, 91 (26.9%)
reported at least one TEAE; 53 (15.7%) were treated with
tadalafil and 38 (11.2%) with placebo. Headache (n = 7),
dyspepsia (n = 6), and nasopharyngitis (n = 6) were the most
commonly reported TEAEs in men without ED treated with
tadalafil; and nasopharyngitis (n = 4) and back pain (n = 3)
were the most commonly reported with placebo. Of the 751
men with ED, 174 (23.2%), reported at least one TEAE; 96
(12.8%) were treated with tadalafil and 78 (10.4%) with
placebo. Headache (n = 10), dyspepsia (n = 9), and
hypertension (n = 9) were the most commonly reported
TEAEs in men with ED treated with tadalafil; and
nasopharyngitis (n = 9) and headache (n = 7) were the most
commonly reported with placebo.
Discussion
In men without ED, tadalafil 5 mg once daily significantly
reduced BPH-LUTS and improved quality of life; these
changes were similar to those observed in men with ED. The

Table 1 Demographics and baseline characteristics for all randomly assigned patients without and with ED.

Patients without ED Patients with ED

Placebo, Tadalafil 5 mg, Total, Placebo, Tadalafil 5 mg, Total,

N = 171 N = 167 N = 338 N = 374 N = 377 N = 751

Mean (SD) age, years 61.2 (8.7) 62.6 (8.3) 61.9 (8.5) 64.1 (8.7) 63.7 (8.3) 63.9 (8.5)
Mean (SD) BMI, kg/m2 28.3 (4.4) 27.5 (3.7) 27.9 (4.1) 28.4 (4.2) 27.8 (4.1) 28.1 (4.1)
Mean (SD) PSA, ng/mL 1.9 (1.6) 2.0 (1.6) 2.0 (1.6) 1.9 (1.6) 2.0 (1.7) 1.9 (1.6)
Mean (SD) total IPSS, before placebo run-in = screening 19.3 (5.2) 20.2 (5.2) 19.8 (5.2) 19.8 (5.3) 19.0 (4.9) 19.4 (5.1)
Sexually active*, n (%) 136 (79.5) 133 (79.6) 269 (79.6) 306 (81.8) 317 (84.1) 623 (83.0)
Baseline BPH severity, n (%)
Mild: IPSS <8 13 (7.6) 12 (7.2) 25 (7.4) 19 (5.1) 14 (3.7) 33 (4.4)
Moderate: IPSS ≥8 and <20 100 (58.5) 102 (61.1) 202 (59.8) 232 (62.0) 236 (62.6) 468 (62.3)
Severe: IPSS ≥20 58 (33.9) 53 (31.7) 111 (32.8) 123 (32.9) 127 (33.7) 250 (33.3)
Medical history, n (%)
Diabetes mellitus 10 (5.8) 13 (7.8) 23 (6.8) 55 (14.7) 60 (15.9) 115 (15.3)
Cardiovascular disease 71 (41.5) 68 (40.7) 139 (41.1) 187 (50.0) 186 (49.3) 373 (49.7)
Hypertension 59 (34.5) 60 (35.9) 119 (35.2) 163 (43.6) 163 (43.2) 326 (43.4)
Previous α-blocker therapy, n (%) 44 (25.7) 44 (26.3) 88 (26.0) 114 (30.5) 104 (27.6) 218 (29.0)
Previous PDE5-inhibitor therapy, n (%) 2 (1.2) 1 (0.6) 3 (0.69) 109 (29.1) 115 (30.5) 224 (29.8)

*Sexually active patients are those who were sexually active with an adult female partner and who expected to remain sexually active with the same female partner for the duration of
the study. n = number of patients with nonmissing data at baseline and at least one postbaseline visit; percentages are based on the number of patients with non-missing data in each
subgroup (with or without ED).

© 2013 The Authors

992 BJU International © 2013 BJU International
 Tadalafil treatment of BPH-LUTS in men without ED

AE profile in men without ED was consistent with that of men

<0.001

<0.001

<0.001

<0.001

<0.001
with ED treated with tadalafil. The results from this integrated
P

analysis of data from three global clinical trials provide further

evidence of tadalafil as an efficacious and safe treatment

(−3.2, −1.5)

(−2.1, −0.9)

(−1.2, −0.4)

(−1.0, −0.3)

(−0.5, −0.2)
95% CI

option, not only in men with coexisting ED and BPH-LUTS,

but also in men without ED.
Men with and without ED were well balanced in baseline BPH
LS Mean (SE)
Difference
Treatment

severity; ∼ 60% had moderate BPH severity in each group. Not

−2.3 (0.4)

−1.5 (0.3)

−0.8 (0.2)

−0.7 (0.2)

−0.4 (0.1)
surprisingly, men with ED more often had pre-existing
Patients with ED

diabetes mellitus and cardiovascular diseases, including

hypertension, than men without ED. In the present analysis,
there was no difference in reported TEAEs between the two
Mean (SD)
Tadalafil 5 mg

17.3 (5.4)
11.6 (7.0)
−5.7 (6.4)
9.9 (3.8)
6.4 (4.5)
−3.5 (4.3)
7.4 (2.8)
5.2 (3.2)
−2.2 (3.0)
4.9 (3.0)
3.3 (3.0)
−1.6 (3.0)
3.6 (1.2)
2.5 (1.5)
−1.1 (1.4)
patient samples. As currently available treatments for
BPH-LUTS may lead to AEs associated with hypotension and
sexual dysfunction [7,8,12,13] or potentially could negatively
impact underlying ED, tadalafil provides an alternative
373
373
373
373
373
373
373
373
373
369
369
369
373
373
373
n

risk-to-benefit profile in men with BPH-LUTS, with and

Mean (SD)

without ED, and would present the only single medication

17.1 (6.0)
13.8 (7.5)
−3.3 (6.2)
9.8 (4.1)
7.9 (4.8)
−1.9 (4.1)
7.3 (3.0)
6.0 (3.3)
−1.3 (2.8)
4.9 (3.2)
4.0 (3.0)
−0.9 (2.8)
3.5 (1.2)
2.8 (1.5)
−0.7 (1.3)

approved to treat men with both conditions.

Placebo

The impact of increasing doses was assessed post hoc in a

previous dose-finding study in men without ED and men with
372
372
372
372
372
372
372
372
372
367
367
367
372
372
372
n

ED. Tadalafil (2.5, 5, 10 and 20 mg) improved IPSS in both

Base, baseline; End, endpoint; Δ, change; n, number of subjects with non-missing data at baseline and at least one post-baseline visit.

groups of men and to similar magnitudes per insignificant

0.002

0.002

0.014

0.030

0.016
P

interaction analyses [20]. After 12 weeks of treatment with

Individual treatment group n values do not add up to subgroup N values because of missing IPSS data for several patients.

tadalafil 5 mg once daily, mean improvements in IPSS in men

(−3.3, −0.8)

(−2.1, −0.5)

(−1.3, −0.1)

(−1.1, −0.1)

(−0.6, −0.1)

without and with ED were −5.3 and −4.8, respectively. BII and
95% CI

IPSS-QoL scores also improved in both groups of men and by

similar magnitudes; however, a dose-dependent tendency was
not observed in the smaller samples of men without ED [20].
LS Mean (SE)
Difference
Table 2 IPSS change, BPH and quality of life from baseline to endpoint by ED status.

Treatment

As the study assessed dose-ranging data, sample sizes were

−2.1 (0.7)

−1.3 (0.4)

−0.7 (0.3)

−0.6 (0.3)

−0.3 (0.1)

small, ranging from 64 to 74 men without ED per treatment

Treatment-by-ED-status interaction: aP = 0.731; bP = 0.687; cP = 0.781; dP = 0.809; eP = 0.886.
Patients without ED

arm, thus providing insufficient statistical power to

demonstrate significant improvement from baseline. To
achieve appropriate statistical power for baseline-to-endpoint
Mean (SD)
Tadalafil 5 mg

17.1 (6.3)
11.7 (6.8)
−5.4 (5.9)
10.1 (4.3)
6.6 (4.4)
−3.5 (4.2)
7.0 (3.2)
5.1 (3.3)
−1.9 (2.7)
4.6 (2.8)
3.2 (2.9)
−1.4 (2.8)
3.6 (1.4)
2.6 (1.6)
−1.0 (1.3)

assessment, the present integrated analysis combined data

from three trials. Improvement in total IPSS in this analysis
was similar in men without ED compared with men with ED
(−5.4 vs −5.7, respectively).
163
163
163
163
163
163
163
163
163
163
163
163
163
163
163
n

Multiple studies have consistently shown improvement in

Mean (SD)

16.8 (6.4)
13.6 (7.7)
−3.3 (6.1)
9.6 (4.5)
7.6 (5.1)
−2.0 (4.1)
7.2 (3.3)
6.0 (3.4)
−1.3 (3.0)
4.9 (3.0)
3.9 (3.1)
−1.0 (2.6)
3.6 (1.4)
2.9 (1.6)
−0.7 (1.4)

BPH-LUTS and quality of life with tadalafil treatment, despite

Placebo

modest Qmax improvement [16–19,21]. Although a change in

Qmax with tadalafil treatment did not reach significance in
several studies, the consistency of tadalafil treatment in
167
167
167
167
167
167
167
167
167
166
166
166
167
167
167
n

improving BPH-LUTS severity in conjunction with small

improvements in Qmax was consistent with the updated BPH
Base

Base

Base

Base

Base
End

End

End

End

End

guideline that notes a poor correlation between BPH-LUTS

Δ

and Qmax [7,22].

(voiding) subscoreb

irritative subscorec
IPSS score type

While it is reasonable to consider that effective treatment of

IPSS obstructive

IPSS (storage)

either condition (BPH-LUTS or ED) improves the overall

Total IPSSa

IPSS-QoLe

quality of life, the degree of contribution and the relationship

of responses of the two conditions were beyond the scope of
BIId

a–e

this analysis; however, multiple tadalafil studies have reported

© 2013 The Authors

BJU International © 2013 BJU International 993
Brock et al.

Fig. 1 IPSS total and subgroup changes from

Baseline
Endpoint Change baseline to endpoint by ED status. Mean
baseline, endpoint and change-from-baseline
IPSS total scores and IPSS voiding and storage
IPSS Total Score IPSS Voiding Subscore IPSS Storage Subscore
subscores in men without ED (no ED) and men
†
with ED (ED) treated with placebo or tadalafil.
**
Treatment difference (placebo and tadalafil)
*
18 18 18 between men with and without ED: †P = 0.73,
16 16 †† 16 ††
P = 0.69, †††P = 0.78. ED: †P = 0.73, ††P = 0.69,
14 −3.3 −3.3 14 ** 14 ††† †††
P = 0.78. Treatment difference between
12 −5.4 −5.7 12 * 12 ** placebo and tadalafil: *P < 0.05, **P < 0.001.
10 10 10 *
−1.9
8 8 −2.0 −3.5 −3.5 8
6 6 6 −1.3 −1.3 −1.9 −2.2
4 4 4
2 2 2
0 0 0
No ED ED No ED ED No ED ED No ED ED No ED ED No ED ED
Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil

Fig. 2 IPSS-QoL subscore and BII changes from

Baseline
Change baseline to endpoint by ED status. Mean
Endpoint
baseline, endpoint, and change-from-baseline
IPSS-QoL subscore and BII in men without ED
IPSS QoL Subscore BII Score (no ED) and men with ED (ED) treated with
†† placebo or tadalafil. Treatment difference
† (placebo and tadalafil) between men with
**
** and without ED: † P = 0.89, ††P = 0.81. Treatment
*
4 * 5 difference between placebo and tadalafil:
*P < 0.05, **P < 0.001.
−1.0 −0.9
−0.7 4
3 −0.7
−1.0 −1.4 −1.6
−1.1
3
2
2

1
1

0 0
No ED ED No ED ED No ED ED No ED ED
Placebo Tadalafil Placebo Tadalafil

significant improvement in quality of life based on specific
questionnaires assessing changes in urinary symptoms
[16–19].
As tadalafil is an erectogenic drug, concerns about
unintentional unblinding have been raised. Such concerns are
not unusual among efficacious agents with easily identifiable
efficacy outcomes or those with significant or easily
identifiable adverse reactions. In the present analysis, a similar
reduction in BPH-LUTS and associated improvement in
quality of life was observed both in men without ED and in
men with ED, suggesting that unintentional unblinding did
not play a significant role.
Regular intercourse may have a role in preserving erectile
function among elderly men [23]; however, whether an
improvement in erection leads to increased sexual activity is
not clear and could not be confirmed in a post hoc analysis
based on a large dose-finding tadalafil study in men with
BPH-LUTS, which showed that increasing tadalafil doses from
2.5 to 20 mg increasingly improved ED [24]. In that study,
frequency of sexual intercourse attempts was similar across
doses, including placebo, suggesting no association between
erection improvement and number of intercourse attempts.
It has been proposed that increased frequency of ejaculation
may indirectly improve LUTS, but in an assessment of LUTS
severity in a cross-sectional analysis of 2115 white male
subjects between the ages of 40 and 79 from the Olmsted
study population, Jacobsen et al. [25] could not confirm an
association between frequency of ejaculation and LUTS, peak
urinary flow rates or prostate volume after accounting for the
confounding effects of age.

© 2013 The Authors

994 BJU International © 2013 BJU International
 Tadalafil treatment of BPH-LUTS in men without ED

Table 3 Safety and tolerability of tadalafil 5 mg once daily, by ED status.

Patients without ED Patients with ED

Placebo, Tadalafil 5 mg, Total, Placebo, Tadalafil 5 mg, Total,

N = 171 N = 167 N = 338 N = 374 N = 377 N = 751

n (%) n (%) n (%) n (%) n (%) n (%)

Patients with ≥1 TEAE 38 (22.2) 53 (31.7) 91 (26.9) 78 (20.9) 96 (25.5) 174 (23.2)
Headache 2 (1.2) 7 (4.2) 9 (2.7) 7 (1.9) 10 (2.7) 17 (2.3)
Dyspepsia 0 6 (3.6) 6 (1.8) 1 (0.3) 9 (2.4) 10 (1.3)
Back pain 3 (1.8) 5 (3.0) 8 (2.4) 3 (0.8) 7 (1.9) 10 (1.3)
Nasopharyngitis 4 (2.3) 6 (3.6) 10 (3.0) 9 (2.4) 6 (1.6) 15 (2.0)
Pain in extremity 0 2 (1.2) 2 (0.6) 0 8 (2.1) 8 (1.1)
Diarrhoea 2 (1.2) 5 (3.0) 7 (2.1) 5 (1.3) 4 (1.1) 9 (1.2)
Hypertension 2 (1.2) 0 2 (0.6) 2 (0.5) 9 (2.4) 11 (1.5)
Dizziness 2 (1.2) 1 (0.6) 3 (0.9) 2 (0.5) 7 (1.9) 9 (1.2)
Gastroesophageal reflux disease 0 1 (0.6) 1 (0.3) 0 6 (1.6) 6 (0.8)
Myalgia 1 (0.6) 5 (3.0) 6 (1.8) 1 (0.3) 2 (0.5) 3 (0.4)

n, number of patients with non-missing data at baseline and at least one post-baseline visit. Note: TEAEs ≥1% in either 5-mg tadalafil group. MedDRA Version 13.1.

Several key mechanisms through which tadalafil or other
PDE5 inhibitors may affect BPH-LUTS or ED independently
have been identified [26,27]. PDE5-isoenzymes are known to
suppress nitric oxide/cGMP) signalling, thereby impairing the
normal micturition cycle and leading to LUTS [26,27]. The
effect of PDE5 inhibition leading to increased NO/cGMP
concentration in the corpus cavernosum and pulmonary
arteries has been observed in the smooth muscle of the
prostate and bladder and their vascular supply. Vascular
relaxation results in increased blood perfusion and may
reduce BPH symptoms [28,29]. Relaxation of stromal smooth
muscle of the prostate and bladder may complement these
vascular effects [26,27,30]. Recently, a novel L-cysteine/
hydrogen sulphide pathway in the human bladder, modulated
through a mostly NO-independent mechanism and activated
by PDE5 inhibition, has been identified [31]. Animal studies
have suggested that PDE5-inhibition may also modulate the
afferent-nerve activity from the lower urinary tract, decreasing
the perception of bladder fullness and feeling of urgency
[27,32]. Whether or not similar mechanisms as reported in the
bladder are also represented in the penile cavernous tissue is
unclear, but these findings may support independence of the
ED and BPH-LUTS response.
The present analysis includes an integrated population of
subjects both with and without ED in an ANCOVA model to
allow interaction assessment; however, the efficacy evaluation
within subjects without ED was the primary objective. A
strength of the analysis is its sufficient statistical power that is
based on a larger sample size of integrated data to assess
tadalafil’s effect on BPH-LUTS in men without ED, which was
not achievable in any of the single studies. A limitation of this
analysis may be the methodology in determining the ED
population. For the purposes of this analysis, ED reflected the
clinical diagnosis of ED based on a physical examination and
functional inquiry. Additional assessment of ED was made by
collecting data from the erectile function (EF) domain of the
International Index of Erectile Function (IIEF). By definition,
an IIEF-EF domain score <26 [33] would substantiate the
clinical diagnosis of ED. In this dataset, the IIEF questionnaire
was only administered to those patients who were sexually
active with a female partner, with the intent of evaluating
response to therapy. While representing ∼80% of the
population deemed to meet the clinical diagnosis of ED, other
populations were unable to benefit from this assessment.
Furthermore, when sexually active men with BPH-LUTS but
no history of ED were treated with tadalafil in blinded
placebo-controlled studies, the IIEF-EF change was only 0.8
point, suggesting that the methodology for determining ED
history is reasonably reliable [34]. Nevertheless, neither clinical
determination of ED nor the IIEF tool alone can fully rule out
ED in this population recruited for BPH-LUTS.
In this integrated analysis of 1089 men with BPH-LUTS, of
whom 338 did not have ED, tadalafil was well tolerated and
significantly improved BPH-LUTS and quality of life. These
results suggest that PDE5 inhibitors may provide an effective
therapeutic alternative for the treatment of BPH-LUTS in men
both with and without coexisting ED.
Acknowledgments
This study was supported by Eli Lilly and Co. Nicole Johnston
and Joseph Giaconia of INC Research (Raleigh, NC) provided
writing assistance.
Conflict of Interest
Lei Xu, David Wong and Lars Viktrup are employees and
stockholders of Eli Lilly and Company (Lilly). Gerald Brock
and Claus Roehrborn are paid consultants to Lilly.
Gregory Broderick has no conflicts to declare.

© 2013 The Authors

BJU International © 2013 BJU International 995
Brock et al.
References
1 Jacobsen SJ, Girman CJ, Guess HA et al. Natural history of prostatism:
factors associated with discordance between frequency and bother of
urinary symptoms. Urology 1993; 42: 663–71
2 Norman RW, Nickel JC, Fish D, Pickett SN. ‘Prostate-related symptoms’
in Canadian men 50 years of age or older: prevalence and relationships
among symptoms. Br J Urol 1994; 74: 542–50
3 Sagnier PP, MacFarlane G, Teillac P, Botto H, Richard F, Boyle P.
Impact of symptoms of prostatism on level of bother and quality of life of
men in the French community. J Urol 1995; 153 (3 Pt 1): 669–73
4 McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care
2006; 12 (5 Suppl.): S122–8
5 Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and
male sexual dysfunction: the multinational survey of the aging male
(MSAM-7). Eur Urol 2003; 44: 637–49
6 Casabe AR, Roehrborn C, Da Pozza LF et al. Combination therapy with
finasteride and tadalafil once daily for 6 months: a randomized,
placebo-controlled study in men with lower urinary tract symptoms
secondary to benign prostatic hyperplasia. Eur Urol 2013; 12 (Suppl):
e1096
7 Kaplan SA. Update on the American Urological Association guidelines for
the treatment of benign prostatic hyperplasia. Rev Urol 2006; 8 (Suppl. 4):
S10–7
8 Schulman CC. Lower urinary tract symptoms/benign prostatic
hyperplasia: minimizing morbidity caused by treatment. Urology 2003; 62
(3 Suppl. 1): 24–33
9 Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin
versus alfuzosin on ejaculatory function in normal volunteers. J Urol
2006; 176 (4 Pt 1): 1529–33
10 Flomax® (Tamsulosin) [Package Insert]. Ridgefield, CT: Boehringer
Ingelheim Pharmaceuticals, Inc, 2009. Available at: http://dailymed.nlm
.nih.gov/dailymed/lookup.cfm?setid=6db9cdec-0833-4391-8764
-079ce6f7e4d1. Accessed July 2013
11 Rapaflo® (Silodosin) [Package Insert]. Corona, CA: Watson
Pharmaceuticals, Inc, 2011. Available at: http://dailymed.nlm.nih.gov/
dailymed/lookup.cfm?setid=96425d91-cfe1-477d-a130-b58c330ca8a3.
Accessed July 2013
12 McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect
of doxazosin, finasteride, and combination therapy on the clinical
progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:
2387–98
13 AUA Practice Guidelines Committee. AUA guideline on the
management of benign prostatic hyperplasia, chapter 1: diagnosis and
treatment recommendations. Available at: http://www.auanet.org/
common/pdf/education/Arc-BPH-Chapter1.pdf. Revised 2003. Accessed
July 2013
14 US Food and Drug Administration, US Department of Health and
Human Services. Questions and Answers: Finasteride Label Changes.
Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrug
Class/ucm299754.htm. Revised April 2012. Accessed July 2013
15 Proscar® (Finasteride) [Package Insert]. Whitehouse Station, NJ: Merck &
Co, Inc, 2012. Available at: http://dailymed.nlm.nih.gov/dailymed/
lookup.cfm?setid=7c01f541-1c88-400c-41a9-7cbb9dee50c0. Accessed July
2013
16 Egerdie RB, Auerbach S, Roehrborn CG et al. Tadalafil 2.5 or 5 mg
administered once daily for 12 weeks in men with both erectile
dysfunction and signs and symptoms of benign prostatic hyperplasia:
results of a randomized, placebo-controlled, double-blind study. J Sex
Med 2012; 9: 271–81
17 Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil
administered once daily for lower urinary tract symptoms secondary to
benign prostatic hyperplasia: a dose finding study. J Urol 2008; 180:
1228–34
© 2013 The Authors
996 BJU International © 2013 BJU International
18 Porst H, Kim ED, Casabé AR et al. Efficacy and safety of tadalafil once
daily in the treatment of men with lower urinary tract symptoms
suggestive of benign prostatic hyperplasia: results of an international
randomized, double-blind, placebo-controlled trial. Eur Urol 2011; 60:
1105–13
19 Oelke M, Giuliano F, Mirone V, Cox D, Viktrup L. Monotherapy with
tadalafil or tamsulosin similarly improved lower urinary tract symptoms
suggestive of benign prostatic hyperplasia in an international,
randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012; 61:
917–25
20 Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A,
Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary
to benign prostatic hyperplasia in men with or without erectile
dysfunction. Urology 2010; 75: 1452–8
21 McVary KT, Roehrborn CG, Kaminetsky JC et al. Tadalafil relieves lower
urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol
2007; 177: 1401–7
22 AUA Practice Guidelines Committee. American Urological Association
guideline: on the management of benign prostatic hyperplasia (BPH).
Available at: http://www.auanet.org/education/guidelines/benign
-prostatic-hyperplasia.cfm. Revised 2010. Accessed July 2013
23 Koskimäki J, Shiri R, Tammela T, Häkkinen J, Hakama M, Auvinen A.
Regular intercourse protects against erectile dysfunction: Tampere Aging
Male Urologic Study. Am J Med 2008; 121: 592–6
24 Porst H, McVary KT, Montorsi F et al. Effects of once-daily tadalafil on
erectile function in men with erectile dysfunction and signs and
symptoms of benign prostatic hyperplasia. Eur Urol 2009; 56:
727–35
25 Jacobsen SJ, Jacobson DJ, Rohe DE, Girman CJ, Roberts RO, Lieber
MM. Frequency of sexual activity and prostatic health: fact or fairy tale?
Urology 2003; 61: 348–53
26 Andersson KE, de Groat WC, McVary KT et al. Tadalafil for the
treatment of lower urinary tract symptoms secondary to benign prostatic
hyperplasia: pathophysiology and mechanism(s) of action. Neurourol
Urodyn 2011; 30: 292–301
27 Giuliano F, Uckert S, Maggi M, Birder L, Kissel J, Viktrup L. The
mechanism of action of phosphodiesterase type 5 inhibitors in the
treatment of Lower Urinary Tract Symptoms Related to Benign Prostatic
Hyperplasia. Eur Urol 2012; 63: 506–16
28 Morelli A, Filippi S, Comeglio P et al. Acute vardenafil administration
improves bladder oxygenation in spontaneously hypertensive rats. J Sex
Med 2010; 7 (1 Pt 1): 107–20
29 Morelli A, Sarchielli E, Comeglio P et al. Phosphodiesterase type 5
expression in human and rat lower urinary tract tissues and the effect of
tadalafil on prostate gland oxygenation in spontaneously hypertensive
rats. J Sex Med 2011; 8: 2746–60
30 Cialis® (Tadalafil) [Package Insert]. Indianapolis, IN: Lilly USA, LLC, 2011.
Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid
=bcd8f8ab-81a2-4891-83db-24a0b0e25895. Accessed July 2013
31 Fusco F, di Villa Bianca Rd, Mitidieri E, Cirino G, Sorrentino R,
Mirone V. Sildenafil effect on the human bladder involves the
L-cysteine/hydrogen sulfide pathway: a novel mechanism of
action of phosphodiesterase type 5 inhibitors. Eur Urol 2012; 62:
1174–80
32 Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ. Inhibitory effects of
phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder
afferent nerve activities of the rat, and on acrolein-induced hyperactivity
of these nerves. BJU Int 2012; 110 (6 Pt B): E259–66
33 Rosen RC, Cappelleri JC, Gendrano N 3rd. The International Index of
Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res
2002; 14: 226–44
34 Giuliano F, Viktrup L. Reply from Authors re: Steven A. Kaplan. Tadalafil
for the Treatment of Benign Prostatic Hyperplasia: when the Moment

Does Not Add Up. Eur Urol 2013; 63: 517–8: Tadalafil in the Treatment of
Men with Lower Urinary Tract Symptoms and/or Erectile Dysfunction
Symptoms. Eur Urol 2013; 63: 519–20
Correspondence: Gerald Brock, St Joseph’s Health Care
London, University of Western Ontario, London, Canada.
e-mail: gebrock@sympatico.ca
Tadalafil treatment of BPH-LUTS in men without ED
Abbreviations: ED, erectile dysfunction; BPH-LUTS, LUTS
suggestive of clinical BPH; BII, BPH Impact Index; IPSS-QoL,
IPSS quality of life; PDE5, phosphodiesterase type 5; 5-ARI,
5α-reductase inhibitor; α-blocker, α1-adrenergic blocker; AE,
adverse event; Qmax, maximum urinary flow rate; TEAE,
treatment-emergent adverse event; LS, least-squares; IIEF,
International Index of Erectile Function; EF, erectile function.
© 2013 The Authors
BJU International © 2013 BJU International 997