EUROPEAN UROLOGY 65 (2014) 455–464

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Sexual Medicine

Editorial by Paolo Verze, Davide Arcaniolo, Roberto La Rocca and Vincenzo Mirone on pp. 465–466 of this issue

Tadalafil Once Daily in Men with Erectile Dysfunction: An

Integrated Analysis of Data Obtained from 1913 Patients from Six
Randomized, Double-blind, Placebo-controlled, Clinical Studies

Hartmut Porst a, Mauro Gacci b, Hartwig Büttner c, Carsten Henneges d, Frank Boess e,*
a b
Private Practice of Urology/Andrology, Hamburg, Germany; Department of Urology, University of Florence, Careggi Hospital, Florence, Italy; c Eli Lilly
d
Biomedicines BU – Men’s Health Therapeutic Area Europe, c/o Lilly Deutschland, GmbH, Bad Homburg, Germany; Global Statistical Sciences, Lilly
Deutschland GmbH, Bad Homburg, Germany; e Lilly Deutschland GmbH, Medical Department, Bad Homburg, Germany

Article info Abstract

Article history: Background: This analysis explores tadalafil once-daily treatment for 12 wk in clinical
Accepted September 20, 2013 subpopulations of men with erectile dysfunction (ED).
Published online ahead of Objective: Assess the efficacy and safety of once-daily tadalafil 2.5 mg and 5 mg in
patients with different ED characteristics and comorbidities.
print on October 2, 2013 Design, setting, and participants: This analysis integrated data from six randomized,
double-blind, placebo-controlled studies that assigned 1913 men with 3-mo history of
Keywords: ED either to once-daily placebo (n = 596), tadalafil 2.5 mg (n = 394), or tadalafil 5 mg
(n = 923). Clinical factors examined included: ethnicity, age, obesity, alcohol consump-
Comorbidities
tion, smoking, comorbidities, concomitant medication, and ED characteristics (etiology,
Diabetes duration, severity).
Erectile dysfunction Outcome measurements and statistical analysis: Descriptive statistics were reported for
Metabolic syndrome efficacy and safety, including International Index of Erectile Function Erectile Function
Once daily Domain (IIEF-EF) scores and Sexual Encounter Profile question 3 (SEP3) responses.
Clinical factors were included in analysis of covariance models using last observation
Phosphodiesterase type 5 carried forward for SEP3 and IIEF-EF scores.
inhibitors Results and limitations: Both tadalafil doses significantly improved SEP3 responses
Tadalafil (least-squares [LS] mean change: 17.8% and 23.6%, respectively) and IIEF-EF scores
(LS mean change: 4.2; 5.4) compared with placebo ( p < 0.01). Treatment with 2.5 mg and
5 mg tadalafil resulted in IIEF-EF LS mean improvements 4 (minimal clinically important
difference [MCID]) in patients with hypertension (4.3 [95% confidence interval (CI),
2.9–5.7]; 4.7 [95% CI, 3.5–5.8]), cardiac disorder (7.0 [95% CI, 4.7–9.3]; 6.3 [95% CI, 4.4–
8.2]), or hyperlipidemia (5.3 [95% CI, 3.4–7.1]; 5.8 [95% CI, 4.3–7.4]). Obese patients
(4.7 [95% CI, 3.4–6.0]), smokers (4.8 [95% CI, 3.0–6.7]), and psychogenic ED (7.3 [95% CI,
5.0–9.6]) reached MCID only after treatment with 5 mg tadalafil. Severity-specific MCID
(IIEF-EF change 7) was achieved by 44.5% of patients with severe baseline ED treated
with tadalafil 5 mg, compared with 11.6% of placebo-treated patients. No unexpected
safety findings were observed. These analyses were performed on integrated data and can
only provide descriptive results to guide further investigations.
Conclusions: Treatment with tadalafil 2.5 mg or 5 mg once daily was well tolerated
and resulted in clinically important improvements in patients with mild (54.3% and
74.8%, respectively), moderate (51.3% and 63.1%, respectively), or severe (33.7%
and 44.5%, respectively) ED.
# 2013 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Medical Department, Lilly Deutschland GmbH, Werner-Reimers-Strasse

2-4, 61352 Bad Homburg, Germany. Tel. +49 6172 2732284; Fax: +49 6172 2732531.
E-mail address: boess_frank@lilly.com (F. Boess).
0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
http://dx.doi.org/10.1016/j.eururo.2013.09.037
456 EUROPEAN UROLOGY 65 (2014) 455–464
1. Introduction
Phosphodiesterase type 5 inhibitors (PDE5-Is), such as
tadalafil, sildenafil, and vardenafil, are recommended as
first-line therapy for men with erectile dysfunction (ED)
[1,2]. The guidelines of the International Society for Sexual
Medicine (ISSM) Standards Committee for Sexual Medicine
suggest that treatment with PDE5-Is can be effective in the
majority of ED etiologies except after severe damage of
the parasympathetic cavernous nerves [3]. The relatively
long half life of tadalafil (17.5 h) allowed the successful
clinical development and subsequent regulatory approval
of tadalafil 2.5 mg or 5 mg once daily, providing continuous
PDE5 inhibition levels sufficient for ED treatment in the
majority of patients [4,5]. Data from long-term studies of up
to 2 yr suggest tadalafil once daily provided efficacy for the
duration of therapy [6].
Several factors can either cause or worsen ED, including
aging, obesity, smoking, diabetes, cardiovascular diseases
(CVDs), or use of certain medications [7–11]. Factors
associated with ED in the European Male Aging Study were
CVD, diabetes, obesity, lower urinary tract symptoms, and
depression [12]. Men with ED and one of these character-
istics may respond differently to tadalafil once-daily
therapy.
This analysis pooled data from six double-blind, placebo-
controlled, randomized trials to assess the efficacy and
safety of tadalafil 2.5 mg and 5 mg once daily for the
treatment of ED in relevant clinical subpopulations.
2. Patients and methods
2.1. Study design and setting
Data were collected and pooled from six clinical studies (Table 1)
[4,5,13–16].
2.2. Patient population
Men aged 18 yr with a history of ED for 3 mo and a stable relationship
were enrolled. Detailed inclusion/exclusion criteria have been published
[4,5,13–16]. Patients were randomly assigned to placebo (n = 596)
or tadalafil at fixed doses of 2.5 mg (n = 394) or 5 mg (n = 923).
Patients took the study drug once daily, preferably at the same time
Table 1 – Description of multicenter, randomized, double-blind, placebo-controlled studies of tadalafil once daily in men with erectile
dysfunction (2001–2010)
Study name* Lead-in phase
H6D-MC-LVCV [4] Treatment free
H6D-MC-LVFP [5] Treatment free
H6D-MC-LVFZ [14] Treatment free
H6D-MC-LVGH [15] Treatment free
H6D-MC-LVHR [13] Placebo lead-in
H6D-MC-LVHX [16] Treatment free
ED = erectile dysfunction; T2DM = type 2 diabetes mellitus; BPH = benign prostatic hyperplasia; LUTS = lower urinary tract symptoms; PDE5-I = phosphodiesterase
5 inhibitor.
*
European Union Clinical Trial Registry.
every day without regard to food intake or timing of sexual activity after
dosing.
2.3. Clinical evaluation
Patients completed the Sexual Encounter Profile (SEP) [17,18] after each
sexual intercourse attempt and the International Index of Erectile
Function (IIEF) [19] at baseline and at 4-wk intervals during the
treatment period (postbaseline). Patient scores for the erectile function
domain of the IIEF (IIEF-EF; defined as the sum of responses to IIEF
questions 1–5 and 15) at the end of the lead-in period were used to
determine baseline severity scores: mild (IIEF-EF: 17–25), moderate
(IIEF-EF: 11–16), or severe ED (IIEF-EF: 10) [20].
The efficacy variables evaluated in this post hoc analysis of the
integrated data set included (1) the least-squares (LS) mean changes
from baseline to end point in the per-patient percentage of Yes responses
to SEP question 3 (SEP3; ‘‘Did your erection last long enough for you to
have successful intercourse?’’), (2) the LS mean changes from baseline to
end point in IIEF-EF scores, and (3) the odds ratio (OR) between men
attaining a normal IIEF-EF score (26) at end point (IIEF-EF normaliza-
tion) compared with those who did not normalize. The clinical relevance
of IIEF-EF changes were interpreted using the minimal clinically
important differences (MCIDs) defined by Rosen et al. [21]: improve-
ment in IIEF-EF scores of 2 points (mild ED), 5 points (moderate ED),
7 points (severe ED), or improvement of 4 points for the overall
population regardless of baseline ED severity. LS mean improvements
4 were considered to reach MCID and superior to MCID if the lower 95%
CI was also 4. Incidences and percentages of reported treatment-
emergent adverse events (TEAEs) were pooled from all six studies.
2.4. Clinical subpopulations under investigation
Subpopulations were stratified by baseline factors, including: ethnicity,
age, body mass index (BMI), alcohol consumption, smoking, presence of
comorbidities (eg, diabetes, CVDs, cardiac disorders, and hyperlipid-
emia), use of concomitant medications (eg, antihypertensives and/or
statins), and ED characteristics (eg, duration, etiology, severity, and
previous use of PDE5-Is) (Table 2).
2.5. Statistical analyses
All analyses were conducted on an intent-to-treat basis. Efficacy
analyses included all patients with a baseline measurement and at
least one postbaseline measurement. Mean end-point values and mean
baseline-to-end point changes for both IIEF-EF scores and the percentage
of Yes responses to SEP3 were analyzed by using last observation carried
forward (LOCF). Patient demographics were similar across the six studies
and all studies assessed the 12-wk efficacy end point for IIEF-EF and SEP;
Clinical trial no. Patients, no. Patient presentation
Lilly Registry #4972 163 ED
NCT00381732 287 ED
NCT00547183 298 ED plus T2DM
NCT00422734 342 ED
NCT00855582 606 ED plus BPH/LUTS
NCT00836693 217 ED (PDE5-I naı̈ve)
 EUROPEAN UROLOGY 65 (2014) 455–464 457

Table 2 – Baseline characteristics of clinical subpopulations by category and predictive factor: data pooled from six studies of tadalafil
once-daily dosing in men with erectile dysfunction

Category Predictive factor Placebo Tadalafil 2.5 mg Tadalafil 5 mg

(n = 596) (n = 394) (n = 923)

Demographics Ethnicity, no. (%)

White 527 (88.4) 341 (86.5) 792 85.8)
Nonwhite 69 (11.6) 53 (13.5) 131 (14.2)
Age, yr, mean (SD) 58.4 (10.3) 60.2 (9.1) 56.9 (10.7)
Age yr, range 20.7–83.2 26.3–82.2 24.1–82.0
Age 65 yr, no. (%) 158 (26.5) 123 (31.2) 211 (22.9)
BMI, no. (%)
30 179 (30.0) 110 (27.9) 260 (28.2)
<30 417 (70.0) 284 (72.1) 663 (71.8)
Lifestyle behaviors Alcohol consumption, no. (%)
Yes 318 (53.4) 234 (59.4) 406 (44.0)
No 200 (33.6) 160 (40.6) 253 (27.4)
Missing 78 (13.1) 0 (0.0) 264 (28.6)
Smokers, no. (%)
Yes 93 (15.6) 69 (17.5) 128 (13.9)
No 402 (67.4) 325 (82.5) 472 (51.1)
Missing 101 (16.9) 0 (0.0) 323 (35.0)
Comorbidities/concomitant medications Comorbidities, no. (%)
Diabetes mellitus 175 (29.4) 147 (37.3) 221 (23.9)
Cardiovascular disorder 283 (47.5) 200 (50.8) 410 (44.4)
Hypertension 231 (38.8) 167 (42.4) 335 (36.3)
Cardiac disorder 86 (14.4) 55 (14.0) 125 (13.5)
Hyperlipidemia 133 (22.3) 93 (23.6) 182 (19.7)
Concomitant medications, no. (%)
No antihypertensive medication 318 (53.4) 201 (51.0) 500 (54.2)
One antihypertensive medication 159 (26.7) 92 (23.4) 219 (23.7)
Two or more antihypertensive medications 119 (19.9) 101 (25.6) 204 (22.1)
Statin(s) 139 (23.3) 100 (25.4) 176 (19.1)
ED characteristics ED 1 yr, no. (%) 534 (89.6) 364 (92.4) 820 (88.8)
ED etiology, no. (%)
Mixed 193 (32.4) 119 (30.2) 344 (37.3)
Organic 300 (50.3) 212 (53.8) 384 (41.6)
Psychogenic 50 (8.4) 19 (4.8) 103 (11.2)
Unknown 53 (8.9) 44 (11.2) 92 (10.0)
ED severity, no. (%)a
Mild (IIEF-EF 17–25) 89 (14.9) 70 (17.8) 131 (14.2)
Moderate (IIEF-EF 11–16) 361 (60.6) 226 (57.4) 583 (63.2)
Severe (IIEF-EF 10) 146 (24.5) 98 (24.9) 209 (22.6)
Previous PDE5-I therapy, no. (%)
Yes 276 (46.3) 205 (52.0) 426 (46.2)
No 240 (40.3) 149 (37.8) 404 (43.8)
Missing 80 (13.4) 40 (10.2) 93 (10.1)

SD = standard deviation; BMI = body mass index; ED = erectile dysfunction; IIEF-EF = International Index of Erectile Function–Erectile Function domain; PDE5-I =
phosphodiesterase type 5 inhibitor.
a
Based on predefined ranges for scores to the IIEF-EF, which is the sum of the responses to IIEF questions 1–5 and 15.

therefore, 12-wk efficacy and safety data were integrated. Descriptive
statistics (mean, standard deviation) for IIEF-EF and SEP3 were pooled by
treatment group. A chi-squared test determined differences in the
incidences of TEAEs between all treatment groups where at least one
group showed an incidence >2%.
For overall efficacy assessment, IIEF-EF scores and SEP3 response
percentages were analyzed using analysis of covariance (ANCOVA)
models. The LS mean change from baseline SEP3 and IIEF-EF scores using
ANCOVA models included terms for baseline response, study, and
treatment. To assess the subgroup effect of the different predictive
factors, each of those overall models was then extended per predictive
factor with both the predictor and treatment-by-predictor interaction
term. A supportive univariate logistic regression was used to analyze
IIEF-EF normalization in patients with baseline IIEF-EF scores <26. An
analysis was considered to be statistically significant if the p value was
<0.05 (two-sided test). All p values, produced post hoc, are considered
descriptive. Statistical Analysis Software v.9.2 (SAS Institute Inc., Cary,
NC, USA) was used.
3. Results
3.1. Baseline characteristics
Demographics and baseline characteristics for the integrat-
ed patient populations, stratified by treatment groups, are
presented in Table 2. The mean age was 58 yr (range: 20.7–
83.2 yr); 25.7% of the patients were aged 65 yr. A third of
the patients were obese (BMI 30), >50% consumed
alcohol, and >15% smoked. Nearly half of the total number
of patients suffered from CVD, 28% had comorbid diabetes,
and approximately 38% of all patients had hypertension.
 458
Table 3 – Summary and analysis of changes in International Index of Erectile Function–Erectile Function domain score from baseline to end point (last observation carried forward at 12 wk)

Placebo Tadalafil 2.5 mg Tadalafil 5 mg

Subgroup No. Baseline End LS mean No. Baseline End PBO-adjusted (95% CI) No. Baseline End PBO-adjusted (95% CI)
point change point LS mean change point LS mean change

Overally 574 14.8 16.3 1.7 380 15.0 20.1 4.2** (3.3, 5.1) 893 15.0 22.2 5.4** (4.7, 6.1)
Ethnicity
White 509 14.6 16.1 1.5 331 14.9 20.1 4.4** (3.4, 5.4) 767 14.9 22.1 5.5** (4.8, 6.3)
Nonwhite 65 16.4 18.6 3.1 49 15.7 20.1 2.5 (0.0, 5.0) 126 15.5 23.0 4.4** (2.4, 6.5)
Age group
<65 yr 419 15.4 17.1 1.9 262 16.2 21.2 4.2** (3.1, 5.3) 690 15.4 22.9 5.5** (4.7, 6.4)
65 yr 155 13.0 14.4 0.8 118 12.3 17.7 4.1** (2.4, 5.7) 203 13.7 20.0 5.0** (3.6, 6.4)
BMI
30 166 14.7 16.7 2.2 105 14.7 18.4 2.3* (0.6, 3.9) 254 14.5 21.6 4.7** (3.4, 6.0)

EUROPEAN UROLOGY 65 (2014) 455–464

<30 408 14.8 16.2 1.5 275 15.1 20.8 4.9** (3.9, 6.0) 639 15.2 22.5 5.7** (4.8, 6.5)
Alcohol consumption at baseline
Yes 312 14.7 16.4 1.8 226 15.1 19.8 3.6** (2.5, 4.8) 398 14.6 21.4 4.8** (3.8, 5.9)
No 190 14.7 16.5 2.0 154 14.9 20.6 4.5** (3.0, 5.9) 251 14.9 22.1 5.2** (3.9, 6.5)
Smoker at baseline
Yes 91 15.2 17.6 2.7 66 15.0 19.0 2.1 (0.1, 4.2) 126 15.3 22.9 4.8** (3.0, 6.7)
No 388 14.6 16.0 1.6 314 15.0 20.4 4.4** (3.4, 5.5) 465 14.5 21.3 5.2** (4.2, 6.1)
Diabetes mellitus
Yes 168 13.2 14.6 1.4 143 13.4 18.4 4.0** (2.5, 5.5) 215 13.1 18.5 3.6** (2.3, 5.0)
No 406 15.4 17.1 1.8 237 15.9 21.2 4.2** (3.1, 5.3) 678 15.6 23.4 6.0** (5.2, 6.9)
Cardiovascular disorder
Yes 273 13.5 14.9 1.2 194 13.8 19.5 4.8** (3.6, 6.1) 397 14.2 20.8 5.1** (4.1, 6.1)
No 301 15.9 17.6 2.1 186 16.2 20.8 3.5** (2.2, 4.7) 496 15.6 23.4 5.7** (4.7, 6.6)
Hypertension
Yes 223 13.2 14.9 1.3 162 13.9 19.1 4.3** (2.9, 5.7) 323 14.2 20.4 4.7** (3.5, 5.8)
No 351 15.7 17.3 1.9 218 15.8 20.9 4.1** (2.9, 5.2) 570 15.5 23.3 5.8** (4.9, 6.7)
Cardiac disorder
Yes 83 12.7 13.3 0.2 54 12.7 19.9 7.0** (4.7, 9.3) 119 13.4 20.5 6.3** (4.4, 8.2)
No 491 15.1 16.9 1.9 326 15.4 20.2 3.7** (2.7, 4.7) 774 15.2 22.5 5.2** (4.5, 6.0)
Hyperlipidemia
Yes 130 13.2 13.9 0.5 90 13.9 19.2 5.3** (3.4, 7.1) 174 13.8 20.5 5.8** (4.3, 7.4)
No 444 15.2 17.1 2.0 290 15.3 20.4 3.9** (2.8, 4.9) 719 15.3 22.6 5.2** (4.4, 6.0)
Antihypertensive use
None at baseline 306 15.8 17.4 1.9 192 16.1 21.2 4.1** (2.8, 5.3) 485 15.7 23.4 5.8** (4.8, 6.8)
One at baseline 153 14.3 16.1 1.8 88 14.3 19.7 4.0** (2.2, 5.8) 212 14.5 21.4 4.9** (3.5, 6.3)
Two or more at baseline 115 12.7 13.9 0.8 100 13.4 18.6 4.6** (2.8, 6.4) 196 13.8 20.2 5.3** (3.7, 6.8)
Statin use
Yes 137 13.3 13.7 0.3 97 13.0 17.3 4.1** (2.4, 5.9) 168 13.5 19.5 5.3** (3.8, 6.8)
No 437 15.2 17.2 2.1 283 15.7 21.1 4.2** (3.1, 5.2) 725 15.4 22.9 5.3** (4.5, 6.2)
ED duration
<1 yr 59 17.0 19.5 3.1 30 17.0 23.1 4.6* (1.6, 7.6) 101 16.9 24.0 4.3** (2.2, 6.5)
1 yr 515 14.5 16.0 1.5 350 14.8 19.9 4.2** (3.2, 5.1) 792 14.8 22.0 5.5** (4.8, 6.3)
 EUROPEAN UROLOGY 65 (2014) 455–464 459

Overall: Analysis of covariance (ANCOVA) model with study, treatment, country, and baseline terms; all other rows present ANCOVA models with study, treatment, country, baseline, predictor, and treatment-by-predictor
Nearly 90% had suffered from ED for at least 1 yr; most had
(4.8, 7.2)
(3.8, 5.9)

(2.7, 6.3)
(4.6, 6.4)
(4.4, 7.2)

(5.2, 7.3)
(3.9, 6.1)
(5.0, 9.6) moderate (n = 1170; 61.2%) or severe (n = 453; 23.7%) ED,
and nearly half of the patients had received previous PDE5-I
treatment (Table 2).

3.2. Efficacy analyses in overall population

4.8**
7.3**

4.5**
5.5**
5.8**

6.2**
6.0**

5.0** Treatment with tadalafil 2.5 mg and 5 mg once daily for

12 wk significantly improved erectile function (Table 3,
Supplemental Table 1-2, Fig. 1a–1c), as measured by
placebo-adjusted IIEF-EF (4.2 [95% CI, 3.3–5.1] and 5.4
23.5

26.1
22.9
17.9

21.6
22.3
20.6
25.0

[95% CI, 4.7–6.1], respectively) and SEP3 LS mean improve-

ments (17.8 [95% CI, 13.6–22.0] and 23.6 [95% CI, 20.2–
26.9], respectively) as well as IIEF-EF normalization (OR:
15.7
14.2
15.8

19.6
15.2
11.5

14.2
15.3

2.76 [95% CI, 1.97–3.85] and 3.80 [95% CI, 2.91–4.97],

respectively) (treatment effect p < 0.001). A dose effect was
observed for all three efficacy variables, as the improve-
333
375

128
564

393
97

201

409

LS = least-squares; PBO = placebo; CI = confidence interval; BMI = body mass index; ED = erectile dysfunction; PDE5-I = phosphodiesterase type 5 inhibitor.

ments observed with tadalafil 5 mg once daily were

significantly greater compared with 2.5 mg for SEP3
(0.4, 6.7)

( p = 0.007), IIEF-EF score ( p = 0.008), and IIEF-EF normali-

(3.3, 5.6)
(2.9, 6.4)

(3.5, 6.1)
(2.4, 5.3)
(3.0, 5.4)

(0.1, 4.4)
(2.8, 6.0)

zation ( p = 0.036). In the overall population, the IIEF-EF LS

mean improvement of placebo-treated patients (1.7) did
not reach the overall MCID criterion of 4 points, while
MCID was reached after treatment with 2.5 mg (4.2 [95% CI,
3.3–5.1]) and the treatment effect of 5 mg tadalafil (5.4 [95%
4.4**
4.2**

4.4**
4.6**

4.8**
3.9**

CI, 4.7–6.1]) was superior to MCID.

2.3*
3.2

3.3. Efficacy analyses in subpopulations

Changes in percentages of Yes responses to SEP3 are

19.5

23.2
21.3
15.2

18.9
20.4

20.8

20.7

presented in Supplemental Table 1; changes in IIEF-EF

scores and logistic regression analysis of IIEF-EF normali-
zation are shown in Table 3 and Supplemental Table 2,
14.5
16.6

19.7
15.5

13.7
15.5
10.4
14.0

respectively. Baseline and end point SEP3 values for each

subpopulation are depicted in Figure 2a–2d.
Significant interaction terms ( p < 0.05) for IIEF-EF were
116

143
203
19

66
221
93

200

BMI, cardiac disorder, and diabetes; for SEP3, diabetes. For

the logistic regression analysis, significant interaction terms
were CVD and diabetes.
1.9
1.4
1.7

3.7
2.1

2.1
0.7

1.0

Based on a limited number of nonwhite participants

(253 patients [13.2%]), the treatment effect of tadalafil was
not influenced by ethnicity (white versus nonwhite).
The placebo-adjusted IIEF-EF LS mean improvements in
16.9
15.3
18.7

21.2
17.2
11.3

14.3
17.4

patients aged 65 yr reached MCID (4) with tadalafil

2.5 mg (4.1 [95% CI, 2.4–5.7]) and 5 mg (5.0 [95% CI, 3.6–
6.4]). IIEF-EF LS mean improvements reached MCID in obese
15.2
13.8
17.8

19.2
15.3

13.2
15.7
10.7

patients treated with tadalafil 5 mg (4.7 [95% CI, 3.4–6.0])

but not 2.5 mg (2.3 [95% CI, 0.6–3.9]).
IIEF-EF LS mean improvements reached MCID in patients
187
288

266
233
49

87
347
140

consuming alcohol who were treated with 5 mg tadalafil

(4.8 [95% CI, 3.8–5.9]) but not 2.5 mg (3.6 [95% CI, 2.5–4.8]).
In patients who consumed alcohol, tadalafil 5 mg resulted
in a significant improvement in IIEF-EF scores compared
Previous PDE5-I use

with tadalafil 2.5 mg (a dose effect of +1.2 in favor of

tadalafil 5 mg, p = 0.039). Smokers treated with tadalafil
Psychogenic

p  0.001.

5 mg once daily exhibited significant dose effects in both

Moderate
ED etiology

ED severity

p < 0.05.
Organic

Severe
Mixed

the SEP3 variable (+10.9% in favor of tadalafil 5 mg;

Mild

terms.
Yes
No

p = 0.022) and for changes in the IIEF-EF score (+2.7 in

**

favor of tadalafil 5 mg; p = 0.009).

y

*
460 EUROPEAN UROLOGY 65 (2014) 455–464
[(Fig._1)TD$IG]
(a) Baseline * p < 0.05 vs placebo
(b) Baseline * p < 0.05 vs placebo
100 50
End point † p < 0.05 vs tadalafil 2.5 mg End point † p < 0.05 vs tadalafil 2.5 mg
m

90

Mean LIEF-EF domain score

Mean per-patient % of "yes"

80 40
* †
responses to SEP3

70
65.6
*
60 55.9
30

50 *†
* 22.2
40.1 20.1
40 20
16.3
30.2 14.8 15.0 15.0
30 27.9 27.5

20 10

10

0 0
Patients, no. 592 569 394 373 919 893 Patients, no. 595 574 394 380 916 893
Placebo Tadalafil 2.5 mg Tadalafil 5.0 mg Placebo Tadalafil 2.5 mg Tadalafil 5.0 mg

Placebo * p < 0.05 vs placebo

Tadalafil 2.5 mg † p < 0.05 vs tadalafil 2.5 mg
(c)
Tadalafil 5.0 mg
50 *†
46.0
Patients who achieved IIEF-EF

40
*
32.6
normalization, %

30

20 17.1

10

0
Patients, no. 539 347 840
Placebo Tadalafil 2.5 mg Tadalafil 5.0 mg

Fig. 1 – Baseline and end point values for efficacy parameters for all patients treated with placebo, tadalafil 2.5 mg, and tadalafil 5 mg once daily for 12 wk
in the six studies pooled for these analyses. (a) Mean per-patient percentages of successful sexual intercourse attempts (yes responses to SEP3) within
each treatment group: overall population. (b) Mean IIEF-EF scores within each treatment group: overall population. (c) Percentages of patients within
each treatment group who achieved IIEF-EF normalization (IIEF-EF score I26): overall population.
IIEF = International Index of Erectile Function–Erectile Function domain; SEP3 = Sexual Encounter Profile question 3.

Placebo-adjusted IIEF-EF LS mean improvements reached with mild, moderate, or severe ED at baseline, and those
MCID in patients treated with 2.5 mg tadalafil once daily who had suffered from ED for <1 yr versus 1 yr,
regardless of CVD (4.8 [95% CI, 3.6–6.1]), diabetes (4.0 [95% CI, significant treatment effects were observed in all three
2.5–5.5]), hypertension (4.3 [95% CI, 2.9–5.7]), cardiac efficacy parameters for both doses. The overall MCID
disorders (7.0 [95% CI, 4.7–9.3]), or hyperlipidemia (5.3 criterion of 4 (independent of ED severity) was met by
[95% CI, 3.4–7.1]). Placebo-adjusted IIEF-EF improvements 33.7% (placebo), 41.4% (tadalafil 2.5 mg), and 67.2%
were superior to MCID in patients with CVD (5.1 [95% CI, (tadalafil 5 mg) of men with mild ED at baseline
4.1–6.1]), cardiac disorders (6.3 [95% CI, 4.4–8.2]), or (n = 290) and the severity-specific MCID threshold (2)
hyperlipidemia (5.8 [95% CI, 4.3–7.4]) treated with tadalafil was achieved by 50.6% (placebo), 54.3% (tadalafil 2.5 mg),
5 mg. Statistically significant treatment effects were ob- and 74.8% (tadalafil 5 mg). In the population with mild
served with tadalafil 2.5 mg and 5 mg once daily, regardless ED, placebo-adjusted IIEF-EF LS mean improvement after
of treatment with concomitant antihypertensive medica- treatment with tadalafil 5 mg (4.5 [95% CI, 2.7–6.3]) was
tions or statins. superior to MCID and reached MCID for 2.5 mg (2.3 [95%
In patients with previous PDE5-I treatment, placebo- CI, 0.1–4.4]).
adjusted IIEF-EF LS mean improvements reached MCID after In patients with moderate ED, the severity-specific MCID
treatment with 2.5 mg tadalafil (4.8 [95% CI, 3.5–6.1]) and (5) was achieved by 31.3% (placebo), 51.3% (tadalafil
the treatment effect was superior to MCID after treatment 2.5 mg), and 63.1% (tadalafil 5 mg), while in men with
with 5 mg tadalafil once daily (6.2 [95% CI, 5.2–7.3]). In men severe ED, severity-specific MCID (7) was reached by
 EUROPEAN UROLOGY 65 (2014) 455–464 461
[(Fig._2)TD$IG]
Placebo * p < 0.05 vs placebo Placebo * p < 0.05 vs Placebo
(a) Tadalafil 2.5 mg † p < 0.05 vs tadalafil 2.5 mg
(b) † p < 0.05 vs Tadalafil 2.5 mg
Tadalafil 2.5 mg
100 Tadalafil 5.0 mg Baseline Tadalafil 5.0 mg Baseline
100
90 90

Mean per-patient % of "yes"

80
Mean per-patient % of "yes"

80
* *† *† *†
*† * *† *† *†

responses to SEP3
68.6 * 71.3 70.8 70.0
70 *
responses to SEP3

65.8 * 67.0 * 70 67.0

63.2 65.0 65.4 66.7
62.1 61.6 * * * * *
*† * * * 61.1 * * *
60 57.6 * 57.6 59.0 60.5 60.2
58.3 * 59.5 58.7
55.3 * 54.7 54.2 56.3 60 57.7
* 56.4
51.4 * * * 53.1
51.6 *
50 47.3 * 47.7 50.1
50 47.3 45.7 47.1
42.9 * 44.4 43.9 42.9
40.4 39.6 40.3 40.3 41.0 42.3
40 38.5
40
32.5 33.9 34.2
29.5 30.1
30 30 27.1

20 20

10 10

0 0
Patients, no. Patients, no.
< 65 yr ≥ 65 yr Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Age group BMI at Alcohol use Smoking Diabetes Cardiovascular Hypertension Cardiac Hyperlipidemia
baseline ≥30 at baseline at baseline disorder disorder

* p < 0.05 vs placebo Placebo

(c) Placebo
† p < 0.05 vs tadalafil 2.5 mg
(d) Tadalafil 2.5 mg
* p <0.05 vs placebo
Tadalafil 2.5 mg † p <0.05 vs tadalafil 2.5 mg
Baseline Tadalafil 5.0 mg
Tadalafil 5.0 mg Baseline
100 100

90 90 *
82.9
* *
Mean per-patient % of "yes"

Mean per-patient % of "yes"

80 80 77.2 75.8
*† *† * *† *
71.8 *† 72.1 71.1
72.6 *†
69.1
responses to SEP3
responses to SEP3

70 67.7 70 *† 66.3
68.1
* * * 64.1
61.3 * * 60.8 * * 62.1 *
*† 59.9 * 58.4 59.8 59.0
60 *
58.3 58.0 56.1 56.3 60 *
* 55.8 54.5 56.0 *
52.7 * 52.9
50.2 *
50 48.4 50 47.5
44.5 * 43.6 43.6
41.5 43.5 43.0
40 38.6 40 38.3 *
36.2
30.5 32.2
30.4 28.7
30 30

20 19.3
20

10 10

0 0
Patients, no. Patients, no.
0 1 ≥2 Yes No Yes No <1 Yr ≥ 1 Yr Mixed Organic Psychogenic Mild Moderate Severe

Number of antihypertensive Statin Use Previous PDE5 ED duration ED etiology ED severity

medications inhibitor use

Fig. 2 – Mean per-patient baseline and end point percentages of successful sexual intercourse attempts ( yes responses to SEP3) for clinical
subpopulations treated with placebo, tadalafil 2.5 mg, and tadalafil 5 mg once daily for 12 wk in the six studies pooled for these analyses:
(a) Clinical subpopulations sorted by the demographic characteristics age group (<65 yr vs I65 yr) and BMI I30 (yes vs no), as well as the lifestyle
behaviors alcohol use at baseline (yes vs no) and smoking at baseline (yes vs no). (b) Clinical subpopulations sorted by the presence or absence of
the comorbidities diabetes mellitus, cardiovascular disorder(s), hypertension, cardiac disorder(s), and hyperlipidemia. (c) Clinical subpopulations
sorted by number of antihypertensive medications used (0, 1, or I2), statin use (yes vs no), and previous PDE5-I use (yes vs no). (d) Clinical
subpopulations sorted by the ED characteristics duration (<1 yr vs I1 yr), etiology (mixed, organic, or psychogenic), and severity (mild,
moderate, or severe). BMI = body mass index; ED = erectile dysfunction; PDE5-I = phosphodiesterase type 5 inhibitor; SEP3 = Sexual Encounter
Profile question 3.

11.6% (placebo), 33.7% (tadalafil 2.5 mg), and 44.5% tadalafil in patients with psychogenic etiology (7.3 [95% CI,
(tadalafil 5 mg), respectively. 5.0–9.6]).
Treatment with tadalafil 5 mg resulted in IIEF-EF
normalization for 66.1% of patients with mild, 48.0% with 3.4. Safety
moderate, and 29.3% with severe ED at baseline, respec-
tively, compared with 29.0%, 18.4%, and 7.9% after TEAEs reported by 2% of patients within any of the three
treatment with placebo (Supplemental Table 2). treatment groups in this integrated dataset are presented in
Placebo-adjusted IIEF-EF LS mean improvements reached Table 4. The most frequently reported TEAEs include
MCID in patients with mixed or organic ED etiology treated headache, nasopharyngitis, back pain/myalgia, dyspepsia,
with either 2.5 mg (4.4 [95% CI, 2.8–6.0] or 4.2 [95% CI, 3.0– and influenza. These findings are consistent with the well
5.4]) or 5 mg (6.0 [95% CI, 4.8–7.2] or 4.8 [95% CI, 3.8–5.9]) known safety profile for tadalafil [22], and no unexpected
tadalafil once daily, but only after treatment with 5 mg safety findings were identified.
462 EUROPEAN UROLOGY 65 (2014) 455–464

Table 4 – Treatment-emergent adverse events (TEAEs) reported by I2% of patients taking placebo, tadalafil 2.5 mg, or tadalafil 5 mg once
daily: data pooled from all six studies

TEAE (MedDRA preferred term) Placebo (n = 596) Tadalafil 2.5 mg (n = 394) Tadalafil 5 mg (n = 923) p valuea

Headache 27 (4.5) 10 (2.5) 64 (6.9) 0.003

Nasopharyngitis 20 (3.4) 18 (4.6) 28 (3.0) 0.372
Back pain 15 (2.5) 11 (2.8) 33 (3.6) 0.473
Dyspepsia 9 (1.5) 9 (2.3) 37 (4.0) 0.013
Influenza 15 (2.5) 16 (4.1) 15 (1.6) 0.030
Myalgia 7 (1.2) 6 (1.5) 19 (2.1) 0.409
Upper respiratory tract infection 4 (0.7) 9 (2.3) 15 (1.6) 0.100
Sinusitis 10 (1.7) 10 (2.5) 4 (0.4) 0.004
Bronchitis 7 (1.2) 14 (3.6) 0 (0.0) <0.001
Cough 5 (0.8) 8 (2.0) 7 (0.8) 0.097

MedDRA = Medical Dictionary for Regulatory Activities.

a
Chi-square test.

4. Discussion the current integrated analysis, smokers showed larger

This analysis of data from 1913 men with ED demonstrated
that tadalafil 2.5 mg and 5 mg once daily were effective in a
variety of relevant patient subpopulations. In patients
treated with placebo, IIEF-EF LS mean improvements did
not reach the overall MCID threshold (4) in any of the
subpopulations, in contrast to patients treated with tadalafil
2.5 mg or 5 mg once daily who experienced improvements
reaching or superior to MCID in most clinical subpopulations
examined, except for patients with BMI 30, smokers,
alcohol consumption at baseline, psychogenic ED, and
nonwhites treated with 2.5 mg.
Tadalafil 5 mg significantly improved erectile function
in both white and nonwhite patients (LS mean changes
IIEF-EF: 5.5 [95% CI, 4.8–6.3] and 4.4 [95% CI, 2.4–6.5]; SEP3:
23.3 [95% CI, 19.8–26.8] and 25.3 [95% CI, 16.1–34.5],
respectively). Given the low number of nonwhite patients
(13.2% of the total population), further analyses based on
stratification by ethnicity were not performed. Previous
analyses of tadalafil on-demand demonstrated efficacy
among different racial/ethnic groups [23].
Placebo-adjusted IIEF-EF LS mean improvements reached
MCID in obese patients treated with tadalafil 5 mg
(4.7 [95% CI, 3.4–6.0]) but not with 2.5 mg (2.3 [95% CI,
0.6–3.9]). This dose-dependent response may be due to
drug concentration (lower milligrams per weight in obese
men) or to metabolic syndrome-associated inflammation,
which, in animal models, led to hypoxygenation and
fibrosis of erectile tissues, with a consequent reduction
of response to PDE5-Is [24]. High BMI is associated with a
higher risk for ED [25], while weight loss and increased
physical activity can improve ED in obese men [26]. A
systematic review and meta-analysis concluded that
lifestyle modifications (exercise, Mediterranean diet,
weight loss) were associated with significant improvement
in sexual function [27]. Our data suggest that certain
lifestyle factors may also affect treatment response.
Smoking is a significant risk factor for worsening ED in
patients with comorbidities, due to its association with
CVD, atherosclerosis, neuropathy, and endothelial dysfunc-
tion [10,28,29] A recent meta-analysis of prospective cohort
studies found that current smokers had an OR for ED of
1.51 (95% CI, 1.34–1.71) compared with nonsmokers [30]. In
improvements with tadalafil 5 mg. However, these obser-
vations should be interpreted with caution, as the
information on current smoking status was not available
in 22% of patients (Table 2). Regular alcohol consumption
had no apparent effect on the efficacy of tadalafil; these data
complement previous observations indicating that systemic
exposure to tadalafil is not influenced by acute alcohol
consumption [31].
While in most subpopulations analyzed (including
patients with CVD), a consistent trend in the direction of
an increased response with tadalafil 5 mg compared with
2.5 mg or a significant dose effect was present (smokers,
obese patients, patients without CVD, patients without
diabetes), this was not observed for patients with comorbid
diabetes. This intriguing observation may be due to an
imbalance in duration or severity of diabetes and other
comorbidities between the 2.5-mg and 5-mg dose groups.
The majority of patients treated with tadalafil 2.5 mg were
enrolled in European Union clinical trials register studies
H6D-MC-LVFZ (ED plus comorbid diabetes [14]) or H6D-
MC-LVHR (benign prostatic hyperplasia [BPH] plus comor-
bid ED [13]). To address potential effects due to the presence
of multiple comorbidities in these patients, we conducted
sensitivity analyses (excluding either data from study H6D-
MC-LVFZ or H6D-MC-LVHR), which were consistent with
the overall analysis. In patients with diabetes, placebo-
adjusted IIEF-EF LS mean change after treatment with
2.5 mg tadalafil (4.0 [95% CI, 2.5–5.5]) reached MCID.
Previous studies have demonstrated that various CVDs
can be associated with ED [9,10]. Cardiovascular patients
frequently present with ED of greater severity; moreover,
these patients may use thiazide diuretics that can induce ED
in CVD patients [9,10,28]. The current analyses demon-
strated tadalafil 2.5 mg and 5 mg once daily improved all
efficacy variables regardless of whether or not patients
were taking antihypertensive medications.
Patients with psychogenic ED treated with tadalafil
2.5 mg did not show significant treatment effects. These
results could be due to the low number of patients (n = 172).
An alternative explanation may be a reduced responsiveness
to pharmacologic intervention in patients with increased
adrenaline/noradrenaline levels, as suggested in a study
measuring responses to intracorporeal injections of
 EUROPEAN UROLOGY 65 (2014) 455–464
papaverine in men with psychogenic ED [32]. However,
increased catecholamine levels have not been shown to
impair erections induced by intracavernosal prostaglandin
E1 in patients with psychogenic ED [33]. Whether these
observations can be extrapolated to PDE5-Is is currently
unknown.
Patients with different baseline ED severity showed
significant improvements of SEP3 and IIEF scores that were
numerically higher in patients with moderate to severe
compared with mild ED. Patients with mild ED exhibited
placebo-adjusted IIEF-EF LS mean improvements of +2.3
and +4.5 with tadalafil 2.5 mg and 5 mg, respectively
(Table 3). Rosen and colleagues determined that an
improvement of 2 points, 5 points, and 7 points in
the IIEF-EF score can be considered clinically meaningful for
patients with mild, moderate, and severe ED, respectively
[19,21]. Of patients with mild, moderate, or severe ED at
baseline, 74.8%, 63.1%, or 44.5%, respectively, reached these
criteria for MCID following treatment with tadalafil 5 mg,
compared with 50.6%, 31.3%, and 11.6%, respectively, after
placebo. It is of interest that although patients with mild ED
showed a strong placebo response, the placebo-adjusted
treatment effect of tadalafil 5 mg was superior to MCID in
this subpopulation. High placebo-responder rates have
been reported in previous studies examining the efficacy of
PDE5-Is in mild ED patients [34]. Notably, 66.1%, 48.0%, and
29.3% of tadalafil-treated (5 mg) patients with mild,
moderate, and severe ED at baseline reached normalization
of erectile function (IIEF-EF 26).
These retrospective analyses of the outcome of prospec-
tive randomized, double-blind, and placebo-controlled
studies were performed on integrated data and can only
provide descriptive results to guide further investigations.
The conclusions regarding efficacy across relevant clinical
subpopulations should be interpreted with caution, consid-
ering that the number of patients available for several
subcategories (nonwhite, smokers, cardiac disorder, psy-
chogenic etiology) is limited.
5. Conclusions
Tadalafil 2.5 mg and 5 mg once daily were effective in
improving erectile function. Of patients with mild, moder-
ate, or severe ED at baseline, 74.8%, 63.1%, or 44.5%,
respectively, reached severity-specific criteria for MCID and
66.1%, 48.0%, and 29.3%, respectively, reached IIEF-EF
normalization following treatment with tadalafil 5 mg.
Headache, nasopharyngitis, back pain, and dyspepsia were
the most common side effects.
Author contributions: Hartmut Porst had full access to all the data in the
study and takes responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Boess, Büttner, Henneges, Porst.
Acquisition of data: Henneges.
Analysis and interpretation of data: Boess, Büttner, Gacci, Henneges, Porst.
Drafting of the manuscript: Boess, Büttner, Gacci, Henneges, Porst.
Critical revision of the manuscript for important intellectual content: Boess,
Büttner, Gacci, Henneges, Porst.
463
Statistical analysis: Henneges.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Porst.
Other (specify): None.
Financial disclosures: Hartmut Porst certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Hartmut Porst is an investigator,
speaker, and consultant for Eli Lilly and Company, Bayer Healthcare, and
Pfizer. Mauro Gacci is a speaker and consultant for Eli Lilly and Company.
Frank Boess, Hartwig Büttner, and Carsten Henneges are employees and
stockholders of Eli Lilly and Company.
Funding/Support and role of the sponsor: Eli Lilly and Company designed,
conducted, and supported the analyses described in this manuscript.
Data collection, data management, and all statistical analyses were
performed and retained by the sponsor. The lead/corresponding author,
Hartmut Porst, together with the Lilly study team and other coauthors,
interpreted the data and participated in the preparation, review, and
approval of the manuscript.
Acknowledgment statement: The authors certify that this manuscript
represents valid work and that neither this manuscript nor one with
substantially similar content has been published or is being considered
for publication elsewhere. We would like to thank Sabine Weitckus, PhD
(Lilly-Austria), for her guidance in managing the preparation and
submission of this manuscript. We would also like to thank Scott J. Burke
and Gina Coviello (inVentiv Health Clinical) for their technical and
scientific expertise in preparing and modifying this manuscript; Vinay
Pagadala (PharmaNet/i3) for his assistance in the preparation of tables
and graphics in this manuscript; Alexey Maximovich (PSI CRO Ltd) for
the programming of SAS analyses; and Cindi Wood (inVentiv Health
Clinical) for her editorial assistance. We are grateful to Patrick R. Burns,
Pharm.D. and Xiao Ni, Ph.D. (Lilly Research Laboratories, Indianapolis)
for scientific and statistical advice.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.eururo.2013.09.037.
References
[1] Eardley I, Donatucci C, Corbin J, et al. Pharmacotherapy for erectile
dysfunction. J Sex Med 2010;7:524–40.
[2] Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male
sexual dysfunction: erectile dysfunction and premature ejacula-
tion. Eur Urol 2010;57:804–14.
[3] Porst H, Burnett A, Brock G, et al. SOP conservative (medical and
mechanical) treatment of erectile dysfunction. J Sex Med 2013;10:
130–71.
[4] Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy and
safety of once-a-day dosing of tadalafil 5 mg and 10 mg in the
treatment of erectile dysfunction: results of a multicenter, random-
ized, double-blind, placebo-controlled trial. Eur Urol 2006;50:
351–9.
[5] Rajfer J, Aliotta PJ, Steidle CP, Fitch III WP, Zhao Y, Yu A. Tadalafil
dosed once a day in men with erectile dysfunction: a randomized,
double-blind, placebo-controlled study in the US. Int J Impot Res
2007;19:95–103.
464 EUROPEAN UROLOGY 65 (2014) 455–464
[6] Porst H, Rajfer J, Casabé A, et al. Long-term safety and efficacy of
tadalafil 5 mg dosed once daily in men with erectile dysfunction.
J Sex Med 2008;5:2160–9.
[7] Kubin M, Wagner G, Fugl-Meyer AR. Epidemiology of erectile
dysfunction. Int J Impot Res 2003;15:63–71.
[8] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB.
Impotence and its medical and psychosocial correlates: results of
the Massachusetts Male Aging Study. J Urol 1994;151:54–61.
[9] Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hy-
perlipidemia, diabetes mellitus, and depression in men with erec-
tile dysfunction. J Urol 2004;171:2341–5.
[10] Sullivan ME, Keoghane SR, Miller MAW. Vascular risk factors and
erectile dysfunction. BJU Int 2001;87:838–45.
[11] Ricci E, Parazzini F, Mirone V, et al. Current drug use as risk factor
for erectile dysfunction: results from an Italian epidemiological
study. Int J Impot Res 2003;15:221–4.
[12] Corona G, Lee DM, Forti G, et al. Age-related changes in general
and sexual health in middle-aged and older men: results from the
European Male Ageing Study (EMAS). J Sex Med 2010;7:1362–80.
[13] 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 hyperpla-
sia: results of a randomized, placebo-controlled, double-blind
study. J Sex Med 2012;9:271–81.
[14] Hatzichristou D, Gambla M, Rubio-Aurioles E, et al. Efficacy of
tadalafil once daily in men with diabetes mellitus and erectile
dysfunction. Diab Med 2008;25:138–46.
[15] Rubio-Aurioles E, Kim ED, Rosen RC, et al. Impact on erectile
function and sexual quality of life of couples: a double-blind,
randomized, placebo-controlled trial of tadalafil taken once daily.
J Sex Med 2009;6:1314–23.
[16] Montorsi F, Aversa A, Moncada I, et al. A randomized, double-blind,
placebo-controlled, parallel study to assess the efficacy and safety
of once-a-day tadalafil in men with erectile dysfunction who are
naive to PDE5 inhibitors. J Sex Med 2011;8:2617–24.
[17] Rosen RC. Sexual function assessment in the male: physiological
and self-report measures. Int J Impot Res 1998;10(Suppl 2):
S59–63.
[18] Rosen RC. Measurement of male and female sexual dysfunction.
Curr Psychiatry Rep 2001;3:182–7.
[19] Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A.
The International Index of Erectile Function (IIEF): a multidimen-
sional scale for assessment of erectile dysfunction. Urology 1997;49:
822–30.
[20] Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnos-
tic evaluation of the erectile function domain of the International
Index of Erectile Function. Urology 1999;54:346–51.
[21] Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important
differences in the erectile function domain of the International
Index of Erectile Function scale. Eur Urol 2011;60:1010–6.
[22] Cialis (tadalafil) [package insert]. Indianapolis, IN; Eli Lilly and
Company; 2012.
[23] Lewis RW, Sadovsky R, Eardley I, et al. The efficacy of tadalafil in
clinical populations. J Sex Med 2005;2:517–31.
[24] Morelli A, Comeglio P, Filippi S, et al. Mechanism of action of
phosphodiesterase type 5 inhibition in metabolic syndrome-
associated prostate alterations: an experimental study in the rab-
bit. Prostate 2013;73:428–41.
[25] Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men
older than 50 years of age: results from the Health Professionals
Follow-up Study. Ann Intern Med 2003;139:161–8.
[26] Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on
erectile dysfunction in obese men: a randomized controlled trial.
JAMA 2004;292:2978–84.
[27] Gupta BP, Murad H, Clifton MM, et al. The effect of lifestyle
modification and cardiovascular risk factor reduction on erectile
dysfunction. Arch Intern Med 2011;171:1797–803.
[28] Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and
coronary risk factors: prospective results from the Massachusetts
Male Aging Study. Prevent Med 2000;30:328–38.
[29] Andersson K-E. Erectile physiological and patho-physiological path-
ways involved in erectile dysfunction. J Urology 2003;170:S6–14.
[30] Cao S, Yin X, Wang Y, et al. Smoking and risk of erectile dysfunction:
systematic review of observational studies with meta-analysis.
PLoS One 2013;8:1–6.
[31] Traconiz IF, Tillmann C, Staab A, Rapado J, Forgue ST. Tadalafil
population pharmacokinetics in patients with erectile dysfunction.
Eur J Clin Pharmacol 2007;63:583–90.
[32] Kim SC, Oh MM. Norepinephrine involvement in response to in-
tracorporeal injection of papaverine in psychogenic impotence.
J Urology 1992;147:1530–2.
[33] Pagani E, Glina S, Puech-Leão P, Strunz CM, Chao S, Timo-Laria C.
Anxiety and high plasma catecholamines do not impair pharmaco-
induced erection of psychogenic erectile dysfunctional patients. Int
J Impot Res 2003;15:282–6.
[34] Bénard F, Carrier S, Lee JC, Talwar V, Defoy I. Men with mild erectile
dysfunction benefit from sildenafil treatment. J Sex Med 2010;7:
3725–35.