Urodynamic Effects of Once Daily Tadalafil in Men With Lower

Urinary Tract Symptoms Secondary to Clinical Benign Prostatic

Hyperplasia: A Randomized, Placebo Controlled 12-Week
Clinical Trial
Roger Dmochowski,*,† Claus Roehrborn,‡ Suzanne Klise,‡ Lei Xu,‡
Abbreviations
Jed Kaminetsky† and Stephen Kraus§
and Acronyms
From the Department of Urology, Vanderbilt University, Nashville, Tennessee (RD), the Department of Urology, UT
BOOI ⫽ bladder outlet obstruction Southwestern Medical School, Dallas (CR), Department of Urology, University of Texas Health Science Center at San
index Antonio, San Antonio (SK), Texas, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana (SK, LX),
BPH ⫽ benign prostatic and New York University, New York, New York (JK)

hyperplasia
BPH-LUTS ⫽ LUTS secondary to
clinical BPH
ED ⫽ erectile dysfunction
I-PSS ⫽ International Prostate
Symptom Score
LUTS ⫽ lower urinary tract
symptoms
PDE5 ⫽ phosphodiesterase type 5
pdetQmax ⫽ detrusor pressure at
maximum urinary flow rate
PFS ⫽ pressure flow studies
PSA ⫽ prostate specific antigen
PVR ⫽ post-void residual
PVRcath ⫽ PVR measured via
catheter
Qave ⫽ mean urinary flow rate
Qmax ⫽ maximum urinary flow rate
UDS ⫽ urodynamic studies
Vcomp ⫽ voided volume
Submitted for publication June 10, 2009.
Study received institutional review board ap-
proval.
* Correspondence: A1302 Medical Center North,
Nashville, Tennessee 37232 (telephone: 615-343-5602;
FAX: 615-322-8990; e-mail: roger.dmochowski@
Vanderbilt.Edu).
† Financial interest and/or other relationship
with Allergan, Astellas, Lilly, Novartis, Pfizer and
Watson.
‡ Financial interest and/or other relationship
with Eli Lilly.
§ Financial interest and/or other relationship
with Pfizer and Laborie Medical Technologies.
Purpose: We explored the impact of once daily tadalafil on urodynamic measures
in men with lower urinary tract symptoms secondary to clinical benign prostatic
hyperplasia via invasive and noninvasive urodynamic studies.
Materials and Methods: We conducted a multicenter, randomized, double blind,
placebo controlled clinical trial comparing once daily tadalafil 20 mg vs placebo
during 12 weeks in men with lower urinary tract symptoms secondary to clinical
benign prostatic hyperplasia with or without bladder outlet obstruction. Invasive
and noninvasive urodynamics, International Prostate Symptom Score and gen-
eral safety were assessed. The primary study end point was change in detrusor
pressure at maximum urinary flow rate.
Results: Urodynamic measures remained largely unchanged during the study
with no statistically significant or clinically adverse difference between tadalafil
and placebo in change in detrusor pressure at maximum urinary flow rate (mean
difference between treatments ⫺2.2 cm H2O, p ⫽ 0.33) or any other urodynamic
parameter assessed including maximum urinary flow rate, maximum detrusor
pressure, bladder outlet obstruction index or bladder capacity (all measures
p ⱖ0.13). Treatment with tadalafil resulted in significant improvements in In-
ternational Prostate Symptom Score (mean difference between treatments ⫺4.2,
p ⬍0.001). Tadalafil was generally well tolerated with the majority of adverse
events being mild to moderate in severity and few patients discontinuing due to
adverse events (tadalafil 2.0%, placebo 1.0%).
Conclusions: Treatment with tadalafil once daily for lower urinary tract symp-
toms secondary to clinical benign prostatic hyperplasia showed no negative
impact on bladder function as measured by detrusor pressure at maximum
urinary flow rate or on any other urodynamic parameter assessed. Nonetheless
men receiving tadalafil reported significant improvements in International Pros-
tate Symptom Score with an adverse events profile similar to other recent studies
of tadalafil for lower urinary tract symptoms secondary to clinical benign pros-
tatic hyperplasia.
Key Words: prostatic hyperplasia, phosphodiesterase inhibitors,
urodynamics, urinary bladder neck obstruction

0022-5347/10/1833-1092/0 Vol. 183, 1092-1097, March 2010

THE JOURNAL OF UROLOGY® Printed in U.S.A.
1092 www.jurology.com
© 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2009.11.014
 URODYNAMIC EFFECTS OF ONCE DAILY TADALAFIL
MEN with BPH may experience LUTS, which in-
clude increased urinary frequency, urgency, noc-
turia, intermittency, straining, incomplete empty-
ing and weak urinary stream, commonly classified
as irritative or obstructive symptoms. The inci-
dence of LUTS secondary to clinical BPH in-
creases with aging and is often a comorbid condi-
tion in men with ED. Medical therapies currently
available for the treatment of BPH-LUTS, such as
␣1-adrenergic blockers and/or 5␣-reductase inhib-
itors, have proven effective. However, side effects
associated with these therapies including dizzi-
ness, hypotension and sexual dysfunction may
prompt some men to avoid or discontinue treat-
ment.
Given the multiple pathways by which nitric
oxide influences and mediates male prostatic and
urinary function, and the frequent comorbid pre-
sentation of BPH and ED, there has been substan-
tial interest in the potential of PDE5 inhibitors as
treatments for LUTS. Prior studies of daily treat-
ment with tadalafil and other PDE5 inhibitors for
BPH-LUTS have demonstrated significant im-
provements in LUTS as assessed by I-PSS com-
pared to placebo.1– 4 However, in contrast to cur-
rently approved therapies for BPH-LUTS, those
improvements were not associated with statisti-
cally significant increases in Qmax. While the
mechanisms by which PDE5 inhibitors act to re-
duce LUTS in men with clinical BPH are still not
well understood, PDE5 inhibition has been shown
to cause the relaxation of human prostatic and
bladder smooth muscle in vitro,5 as well as relax-
ation of the bladder neck and decreased detrusor
muscle overactivity in animal6 and human stud-
ies.7 Taken with the improvements seen in I-PSS
without corresponding increases in flow rates, this
potential impact on detrusor activity raises the
theoretical possibility that improvements in LUTS
with daily PDE5 inhibitor treatment could be as-
sociated with impaired bladder function, which
might result in adverse long-term consequences.
Limited invasive urodynamic data exist for cur-
rent and investigational BPH therapies, with
most studies conducted in a relatively small num-
ber of men. We assessed the impact of tadalafil
treatment (20 mg once daily) compared to placebo
on pdetQmax, as well as on several other invasive
and noninvasive urodynamic parameters in a
large number of men with BPH-LUTS with or
without bladder outlet obstruction at baseline. In
particular this study was designed to provide ev-
idence to contradict the notion that improvements
in I-PSS following tadalafil treatment for BPH-
LUTS might be related to impaired bladder func-
tion.
1093
MATERIALS AND METHODS
Study Design and Participants
This study was a randomized, double blind, placebo con-
trolled clinical trial performed at 20 centers in the United
States and Canada. Men at least 40 years old with a
greater than 6-month history of BPH-LUTS (with or with-
out bladder outlet obstruction) and an I-PSS of 13 or more
at the screening visit were eligible for enrollment unless
PSA was greater than 10 ng/ml (men with PSA 4 to 10
ng/ml were eligible only with evidence of a prostate biopsy
negative for malignancy within 12 months or stable PSA
since the prior biopsy), or PVR was 350 ml or greater at
the screening visit. A 4-week washout period was required
for men reporting the use of other BPH or ED therapies.
Men were excluded from the study if they met any of
the criteria such as 5␣-reductase inhibitor use within the
previous 4 months; a history of penile or pelvic surgery or
radiotherapy; lower urinary tract malignancy, trauma or
recent instrumentation; urinary retention or bladder
stones; urethral obstruction due to stricture, valves, scle-
rosis or tumor; bladder calculi; atonic, decompensated or
hypocontractile bladder; detrusor-sphincter dyssynergia;
intravesical obstruction; urinary tract inflammation or
infection; or prostate cancer. Other exclusionary medical
conditions were clinically significant renal or hepatic in-
sufficiency; cardiovascular conditions such as significant
angina, recent myocardial infarction or poorly controlled
blood pressure; a recent history of stroke or spinal cord
injury; current treatment with nitrates, cancer chemo-
therapy, antiandrogens, or a potent cytochrome P450 3A4
inhibitor or inducer; or uncontrolled diabetes (glycosy-
lated hemoglobin greater than 9%).
All patients underwent baseline UDS approximately 1
week before randomization to placebo or 20 mg tadalafil
once daily for 12 weeks. End of study UDS were performed
on completion of the treatment period or early study dis-
continuation (fig. 1). The clinical trial was performed in
accordance with the Declaration of Helsinki and all appli-
cable local regulations. The institutional review boards for
each site approved the study and all men provided written
informed consent before undergoing any trial procedure or
intervention.
Screening/ Baseline Double-blind treatment period
washout
period
urodynamics
assessment
period
Placebo once daily
Tadalafil 20 mg once daily
Week -5 -1 0 6 12
Visit 1 2 3 4 5
Baseline Randomization End-of-study
urodynamics and study drug urodynamics
assessment dispensing assessment
Note: The duration of study periods may have varied depending on whether or not a
subject required a wash out period or a repeat urodynamics assessment.
Figure 1. Study design
1094 URODYNAMIC EFFECTS OF ONCE DAILY TADALAFIL

Urodynamic Studies and Other Measures and were evaluated at the 0.05 level of significance. The
UDS were performed based on the International Conti- analysis of general safety included all randomly assigned
nence Society testing guidelines and were performed by subjects who received study treatment.
certified testers with the resulting traces interpreted by a
blinded central reader.8 For initial noninvasive uroflow
subjects voided in their normal position (standing or sit- RESULTS
ting) and this position was retained for all UDS through- Patient demographics and baseline characteristics
out the study. PFS were performed using a 7Fr dual were similar across treatment groups at baseline
lumen urethral catheter and standard closed system rec- (table 1). The study population was mostly white
tal balloon catheter with externally based fluid filled with a mean age of 58.6 ⫾ 9.3 years. Of the popula-
transducers. The standard infusion rate was 50 ml per
tion 64% (128 of 200) had severe LUTS and 59% (118
minute. Additional information on the UDS methods used
of 200) reported a history of erectile dysfunction at
in this study were recently reported by Kraus et al.9
UDS assessed pdetQmax, Qmax, Qave, Vcomp, maximum baseline. More than 90% (181 of 200) of randomized
detrusor pressure during voiding, bladder contractility patients completed the study, including similar pro-
index (calculated as pdetQmax ⫹ 5Qmax), BOOI (calculated portions from the placebo and tadalafil treatment
as pdetQmax – 2Qmax), PVRcath, bladder capacity (calcu- groups (fig. 2). Baseline and end point PFS were
lated as Vcomp ⫹ PVRcath), bladder voiding efficiency available for 175 patients. However, after study un-
([Vcomp/bladder capacity] ⫻ 100) and detrusor overactivity blinding PFS traces for 2 patients in the placebo
(assessed as incidence and volume at first involuntary group and 1 in the tadalafil group were designated
contraction). The effect of treatment on LUTS was as- as invalid (per the urodynamic procedure manual)
sessed as change from baseline to end of study in total due to apparent detrusor overactivity simultaneous
I-PSS and subscores. General safety assessments included with the initiation of voiding. Thus, the analysis
patient reported treatment emergent adverse events, se-
population for this report consisted of 172 patients
rious adverse events, and changes in vital signs and clin-
with valid baseline and end point PFS.
ical laboratory values.
The primary outcome measure of this clinical
Statistical Analysis trial, pdetQmax, showed little change between base-
The primary end point of this study was change in pdetQmax line and end point for patients treated with tadalafil
from baseline to week 12 and the study was specifically (change from baseline to end point -2.1 ⫾ 13.8 cm
powered to detect changes in pdetQmax rather than second- H2O) or placebo (0.1 ⫾ 15.5 cm H2O) with no signif-
ary urodynamic or efficacy measures. Based on a previous
icant difference observed between the treatment
study of tolterodine a clinically relevant value for change
groups (p ⫽ 0.33, table 2). Similarly no significant
in pdetQmax of 15 cm H2O was adopted and sample size
calculated to provide an 80% probability that a 2-sided
differences were observed between tadalafil and pla-
95% CI would exclude a difference of greater than 15 cm cebo treatment for change from baseline in any of
H2O in pdetQmax when the true difference was 0.10 Based
on an estimated standard error of the change from base-
Table 1. Patient demographics and baseline characteristics
line to week 12 in pdetQmax of 30 cm H2O, a total sample
size of approximately 190 subjects was determined to yield Placebo Tadalafil
approximately 128 subjects with baseline and end of study
No. randomized pts 101 99
urodynamic results (allowing for up to 30% of subjects to
Mean ⫾ SD age 59.0 ⫾ 9.7 58.2 ⫾ 8.8
have baseline but not end of study UDS). % Race:
The evaluable population presented in this report in- White 77.2 75.8
cluded all men who were randomized, started study med- Black 11.9 13.1
ication, had a valid baseline and end of study PFS, and Hispanic 7.9 8.1
had at least 37 days between randomization and end point Other 3.0 3.0
PFS. Intent to treat analysis was not performed because Mean ⫾ SD kg/m2 body mass index 29.4 ⫾ 4.5 29.5 ⫾ 4.9
inclusion of patients lacking a reasonable period of drug % Yes previous ␣-blocker use 21.8 21.2
dosing would tend, on average, to reduce the potential for % Yes ED 59.4 58.6
Mean ⫾ SD ng/ml PSA 1.6 ⫾ 1.1 1.5 ⫾ 1.1
measuring an impact of study drug on urodynamic safety
Mean ⫾ SD ml PVR 59.3 ⫾ 60.9 45.7 ⫾ 49.6
end points. ANOVA models were used to compare treat- Mean ⫾ SD ml/sec noninvasive 13.3 ⫾ 7.4 15.4 ⫾ 11.1
ment groups for change from baseline to end point. The uroflow Qmax*
model included therapy, randomization stratum, and the % LUTS category:
interaction of therapy and randomization stratum as fac- Moderate 33.7 35.4
tors. Randomization strata included baseline BOOI cate- Severe 65.4 62.6
gory (unobstructed—BOOI less than 20, equivocal—BOOI Mean ⫾ SD I-PSS 22.0 ⫾ 5.7 21.5 ⫾ 5.6
20 to 40, obstructed—BOOI greater than 40) and baseline % BOOI category:
LUTS severity (severe—I-PSS 20 or greater, moderate— Obstructed 32.7 34.3
Equivocal 34.7 34.3
I-PSS less than 20). Data are presented as mean ⫾ SD for
Unobstructed 32.7 31.3
baseline characteristics and mean ⫾ SE for 12-week
change from baseline data. All statistical tests were 2-sided * Qmax at baseline not significantly different between arms, p ⬎0.05.
 URODYNAMIC EFFECTS OF ONCE DAILY TADALAFIL 1095

Screened Patients emergent adverse events was higher in the tadalafil

N = 345
treatment group (55, 55.6%) than in the placebo
group (28, 27.7%). The frequency of the most com-
Randomized Patients
N = 200 monly reported adverse events was dyspepsia—
tadalafil 8.1% (8) vs placebo 0%, headache—tadalafil
7.1% (7) vs placebo 3.0% (3), back pain—tadalafil
Placebo Tadalafil 20 mg
n = 101 n = 99 5.1% (5) vs placebo 3.0% (3) and gastroesophageal
reflux disease—tadalafil 3.0% (3) vs placebo 0%. No
Discontinued, N = 9 Discontinued, N = 10 patients in the tadalafil or placebo group reported
Adverse Event 1 Adverse Event 2 urinary retention. Most adverse events were mild or
Lost to follow up 1 Lost to follow up 1
Protocol violation 1 Protocol entry criteria not met 2 moderate in severity. Serious adverse events were
Subject decision 5 Subject decision 4
Sponsor decision 1 Sponsor decision 1 reported in 3 patients (tadalafil—1 pleurisy/pneu-
monia; placebo—1 hypoesthesia, 1 myocardial in-
Completed, N = 92 Completed, N = 89
farction resulting in death). Tadalafil treatment was
Non-evaluable* 3 Non-evaluable* 6
not associated with any clinically adverse changes in
laboratory values or vital signs.
Analyzed, N = 89 Analyzed, N = 83
* Non-evaluable due to missing baseline or end-of-study PFS; less than 37 days
between randomization and endpoint PFS; or invalid PFS results DISCUSSION
In this study once daily treatment with tadalafil for
Figure 2. Disposition of patients 12 weeks was not associated with a negative impact
on detrusor function because the change on treat-
ment in pdetQmax, the primary study end point, was
the UDS measures assessed. There were no clini- below the predefined clinical cut point of ⫾ 15 cm
cally relevant changes or trends in the incidence of H2O, and was not significantly different between the
involuntary detrusor overactivity or the volume at tadalafil and placebo treatment arms. Neither was
first contraction (data not shown). Men treated with there any suggestion of a clinically adverse impact
tadalafil reported significantly greater improvement on bladder function based on analysis of other uro-
in total I-PSS and in the irritative and obstructive dynamic measures since differences between treat-
subscores than did those receiving placebo (table 3). ment groups for all parameters were small and none
The incidence of discontinuations due to adverse was statistically significant. Nonetheless patients
events was low in each treatment group (tadalafil administered tadalafil in the current study had sig-
2.0%, placebo 1.0%). The incidence of treatment nificant improvements in I-PSS and, thus, our find-

Table 2. Change in pressure flow and free flow urodynamic parameters from baseline to end point

Mean ⫾ SD Mean ⫾ SD Mean ⫾ SD Mean ⫾ SD Mean ⫾ SE

Placebo Placebo Tadalafil Tadalafil Difference of Change
Baseline (89) Change (89) Baseline (83) Change (83) (tadalafil ⫺ placebo) p Value

Pressure flow parameters:

pdetQmax (cm H2O) 54.9 ⫾ 27.6 0.1 ⫾ 15.5 56.2 ⫾ 29.2 ⫺2.1 ⫾ 13.8 ⫺2.2 ⫾ 2.2 0.33
Qmax (ml/sec) 9.5 ⫾ 4.9 0.5 ⫾ 2.9 10.3 ⫾ 4.5 0.4 ⫾ 2.9 ⫺0.1 ⫾ 0.5 0.79
Qave (ml/sec)* 4.6 ⫾ 2.4 0.5 ⫾ 1.6 5.5 ⫾ 2.7 0.6 ⫾ 1.9 0.1 ⫾ 0.3 0.68
Vcomp (ml) 294.5 ⫾ 148.1 4.1 ⫾ 141.9 297.9 ⫾ 143.7 13.6 ⫾ 100.2 15.1 ⫾ 18.9 0.43
Max detrusor pressure (cm H2O)* 67.3 ⫾ 31.9 ⫺3.4 ⫾ 20.6 71.6 ⫾ 38.6 ⫺3.2 ⫾ 22.0 0.6 ⫾ 3.4 0.87
Bladder contractility index 102.2 ⫾ 33.0 2.8 ⫾ 17.8 107.7 ⫾ 31.8 ⫺0.2 ⫾ 19.0 ⫺2.8 ⫾ 2.9 0.33
BOOI 36.0 ⫾ 31.2 ⫺0.9 ⫾ 18.2 35.6 ⫾ 32.7 ⫺2.8 ⫾ 15.6 ⫺1.9 ⫾ 2.5 0.45
Noninvasive uroflow parameters:
Qmax (ml/sec)†,‡ 13.3 ⫾ 7.5 0.5 ⫾ 8.0 15.5 ⫾ 11.1 ⫺0.1 ⫾ 9.3 ⫺0.6 ⫾ 1.5 0.67
Qave (ml/sec)‡ 7.1 ⫾ 4.5 ⫺0.1 ⫾ 4.1 7.4 ⫾ 4.3 0.9 ⫾ 3.0 1.0 ⫾ 0.7 0.13
Vcomp (ml)‡ 262.6 ⫾ 138.0 ⫺15.6 ⫾ 147.4 270.8 ⫾ 154.8 ⫺1.4 ⫾ 153.6 7.9 ⫾ 24.6 0.75
PVRcath (ml)‡ 62.1 ⫾ 68.0 ⫺1.8 ⫾ 86.6 52.6 ⫾ 68.9 ⫺10.4 ⫾ 78.1 ⫺13.0 ⫾ 14.7 0.38
Bladder capacity (ml)‡ 333.1 ⫾ 169.0 ⫺29.0 ⫾ 180.7 323.1 ⫾ 195.1 ⫺12.3 ⫾ 196.4 3.5 ⫾ 32.0 0.91
Voiding efficiency (%)‡ 83.5 ⫾ 14.8 ⫺0.6 ⫾ 17.2 85.1 ⫾ 13.7 1.9 ⫾ 17.6 2.7 ⫾ 3.2 0.39

* Number of patients with data for placebo and tadalafil was different from total number of randomized patients, with Qave placebo 85, tadalafil 80; maximum detrusor
pressure placebo 81, tadalafil 77.
† Qmax at baseline not significantly different between arms, p ⬎0.05.
‡ Number of patients with baseline and change data, respectively, for Qmax placebo 82 and 76, tadalafil 72 and 67; Qave placebo 67 and 67, tadalafil 55 and 55;
Vcomp placebo 81 and 75, tadalafil 72 and 67; PVRcath placebo 73 and 68, tadalafil 69 and 64; and for bladder capacity and voiding efficiency placebo 72 and 67,
tadalafil 68 and 63.
1096 URODYNAMIC EFFECTS OF ONCE DAILY TADALAFIL
Table 3. Change from baseline to end point in I-PSS scores
Mean ⫾ SD (No. pts) I-PSS Total
Placebo baseline (89) 22.0 ⫾ 5.8
Placebo change (89) ⫺5.1 ⫾ 7.0
Tadalafil baseline (82) 21.3 ⫾ 5.5
Tadalafil change (82) ⫺9.2 ⫾ 6.9
Difference of change (tadalafil-placebo) ⫺4.2 ⫾ 1.1
p Value ⬍0.001
ings contradict the theoretical notion that impaired
detrusor function might be responsible for the im-
provements in LUTS previously reported during
studies of daily tadalafil therapy.
The significant improvements in I-PSS compared
to those of men receiving placebo despite a lack of
effect on urodynamic parameters including Qmax
are consistent with previous studies of PDE5 inhib-
itor therapy for BPH-LUTS.1– 4 In contrast, cur-
rently approved medical treatments for BPH-LUTS
(including ␣-adrenergic blockers, 5␣-reductase in-
hibitors and combination therapies) have generally
demonstrated significant improvements in I-PSS (1
to 2.5 points over placebo for monotherapies and 3 to
4 points for combination therapy) and in Qmax (ap-
proximately 1 to 2 ml per second for monotherapies
and 1 to 3 ml per second for combination thera-
pies),11 a finding qualitatively similar to but sub-
stantially lower in magnitude than improvements
seen with surgical interventions.12 Notably studies
of medical therapies and surgical interventions for
BPH-LUTS have generally enrolled only men with
evidence of bladder outlet obstruction, resulting in a
lower mean baseline Qmax than the present study,
which makes direct comparison of results problem-
atic.
While the exact mechanism through which PDE5
inhibitors alleviate BPH-LUTS remains unclear,
several possibilities have been suggested by earlier
studies. In addition to the potential for a direct effect
on LUTS through relaxation of the prostatic stroma
and capsule, another mechanism is suggested by the
observation that pelvic arterial insufficiency and
ischemia are common in men with BPH-LUTS,13
and may represent a major link between atheroscle-
rosis and BPH.14,15 Indeed in an animal model hyp-
oxia was shown to induce prostatic contraction as
well as proliferation in the prostatic stroma and
capsule, which were reversed by PDE5 inhibitor
treatment.16 In support of this animal study alter-
nate-day tadalafil dosing in men with ED has been
shown to decrease levels of several markers of endo-
thelial dysfunction, suggesting that tadalafil could
well act to improve perfusion of PDE5 expressing
tissues in the urogenital tract.17 A contribution
through alterations in afferent signaling from the
bladder, urethra and prostate has also been pro-
Obstructive Subscore Irritative Subscore
11.9 ⫾ 4.0 10.1 ⫾ 2.7
⫺2.8 ⫾ 4.5 ⫺2.3 ⫾ 3.2
11.6 ⫾ 4.2 9.7 ⫾ 2.9
⫺5.6 ⫾ 4.6 ⫺3.6 ⫾ 3.2
⫺2.8 ⫾ 0.7 ⫺1.4 ⫾ 0.5
⬍0.001 0.006
posed.18,19 This mechanism seems particularly con-
sistent with the improvements in I-PSS seen with
tadalafil despite limited changes in flow rate. How-
ever, additional studies will clearly be needed to
further understand the mechanisms by which PDE5
inhibitors impact LUTS in men.
This study had several limitations that should be
considered when interpreting the data. As previ-
ously mentioned a relatively high proportion of men
without bladder outlet obstruction were enrolled in
the study which may have limited our ability to
detect improvements in some secondary UDS mea-
sures such as bladder outlet obstruction or Qmax. In
addition, this was primarily a urinary safety study
and, as such, it used a relatively high tadalafil dose,
did not have a placebo run-in period and did not
evaluate a strict intent to treat population. Thus,
the improvements in I-PSS obtained under these
conditions are not directly comparable to results
obtained in typical efficacy studies. Furthermore,
after this study’s inception Roehrborn et al pub-
lished a report suggesting that a 5 mg daily dose
may show a more favorable risk/benefit profile than
20 mg daily.2 Thus, caution should also be exercised
in extrapolating the magnitude of improvements ob-
served in this study to future clinical use. Despite
these limitations our results were consistent with pre-
vious reports of tadalafil treatment for BPH-LUTS
and, thus, support and extend those findings to a rel-
atively broad population of men with and without sig-
nificant bladder outlet obstruction. Given that the ini-
tial medical management of LUTS often occurs in a
primary care setting without the benefit of urody-
namic testing, results based on the population studied
here may be of particular interest in evaluating the
potential for the treatment of BPH-LUTS with
tadalafil by primary care physicians in the future.10
CONCLUSIONS
No significant difference between tadalafil and pla-
cebo treatment was seen for mean change in any
urodynamic parameter assessed in this study. Thus,
there was no suggestion of a negative impact on
bladder function. Nonetheless tadalafil treatment
was associated with improvements in I-PSS that
 URODYNAMIC EFFECTS OF ONCE DAILY TADALAFIL 1097

were clinically meaningful and significantly greater
than those seen with placebo. Overall tadalafil was
well tolerated with a profile of adverse events com-
parable to that observed in clinical experience in
men with ED and in previous studies of tadalafil for
the treatment of BPH-LUTS.
ACKNOWLEDGMENTS
Dr. Lars Viktrup (Eli Lilly and Company) provided
assistance with study design and implementation,
and with data interpretation. Thomas Melby (i3
Statprobe) and Dr. Rita Gonneau (Eli Lilly and
Company) also provided assistance.
APPENDIX
Trial Investigators
A. Te, New York, NY; B. Hertzman, Cincinnati, OH; C. Hudnall, San Antonio, TX; C.
Steidle, Fort Wayne, IN; D. Jablonski, Orlando, FL; E. Dula, Tarzana, CA; G.
Steinhoff, Victoria, British Columbia; J. Kaminetsky, New York, NY; K. McVary,
Chicago, IL; L. Kaufman, Lake Worth, FL; M. Albo, San Diego, CA; M. Efros, Garden
City, NY; M. L. Moy, Philadelphia, PA; N. Baum, New Orleans, LA; R. Egerdie,
Kitchener, Ontario; R. Feldman, Middlebury, CT; R. Rames, Charleston, SC; S.
Auerbach, Newport Beach, CA; S. Kraus, San Antonio, TX; S. MacDiarmid,
Greensboro, NC.

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