Effects of Once-Daily Tadalafil on Treatment Satisfaction,Psychosocial Outcomes, Spontaneous Erections, and Measures ofEndothelial Function in Men With Erectile Dysfunction But Naiveto Phosphodiesterase Type 5 Inhibitors

HARTMUT PORST,* GERALD B. BROCK,{ KRZYSZTOF KULA,{ IGNACIO MONCADA,§ FRANCESCO

MONTORSI,5 BRUCE R. BASSON," KRAIG KINCHEN," AND ANTONIO AVERSA#

From the *Private Practice in Urology and Andrology, Hamburg, Germany; the �Division of Urology, Faculty of

Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; the `Division of Andrology,

Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; the

§Department of Urology, Hospital La Zarzuela, Madrid, Spain; the 5Department of Urology, Scientific Institute

Hospital, San Raffaele, Milan, Italy; the "Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana; and the

#Endocrinology Section, Department of Experimental Medicine, University of Rome, La Sapienza, Rome, Italy.

ABSTRACT: Previous studies established the efficacy of once-

daily tadalafil for men with erectile dysfunction. However, no trial has

focused on the effects of such treatment on men without previous

experience using oral phosphodiesterase type 5 inhibitors. Patients

were randomized (2:1) to once-daily tadalafil 5 mg (with possible

down-titration to 2.5 mg; n 5 146) or placebo (n 5 69) for 12 weeks.

Among 215 patients (mean age, 52 years), once-daily tadalafil

treatment resulted in 61.7% of study participants reporting their

ability to achieve and maintain erections as being much better or very

much better (vs 21.7% on placebo; P , .001). Tadalafil significantly

improved treatment satisfaction on the Erectile Dysfunction Inventory

of Treatment Satisfaction (P , .001 vs placebo at end point) and

psychosocial outcomes on the Self-Esteem and Relationship

(SEAR) questionnaire (least squares mean difference in SEAR total

score change from baseline, 11.8 [95% confidence interval, 5.4%–

18.2%; P , .001 vs placebo]). Patients receiving once-daily tadalafil

also experienced a higher proportion of daily self-reported sponta-

neous morning erections at end point (58.7%) compared with

placebo (42.2%; P , .001 for the between-treatment difference in

changes from baseline). However, no significant differences in

parameters of endothelial dysfunction (including biomarkers and

peripheral arterial tonometric measures) or nocturnal erections as

recorded by the nocturnal electrobioimpedance volumetric assess-

ment were observed between treatment groups. Tadalafil was well

tolerated; adverse events included back pain, headache, and

dyspepsia. These findings may contribute to a more comprehensive

understanding of once-daily tadalafil’s effects on phosphodiesterase

type 5 inhibitor–naive men.

Key words: Drug therapy, efficacy, endothelium, erection,

morning, nocturnal, phosphodiesterases, psychosocial assess-

ments, peripheral arterial tonometry, tolerability, treatment outcome.

J Androl 2012;33:1305–1322

The phosphodiesterase type 5 (PDE5) inhibitor

tadalafil can be administered on demand (5–20 mg)

or once daily (2.5–5 mg) to treat erectile dysfunction

(ED). Once-daily treatment largely obviates the need to

plan sexual activity within a narrow therapeutic window

after dosing. A number of recent studies using the

International Index of Erectile Function–Erectile Func-

tion (IIEF-EF) domain (Rosen et al, 1997) as well as the

Sexual Encounter Profile (SEP) questionnaire as out-

comes have supported the efficacy of once-daily tadalafil

(Porst et al, 2006; Rajfer et al, 2007; Donatucci et al, 2008;

Hatzichristou et al, 2008; Seftel et al, 2009, 2011).

Over time, in addition to the IIEF and SEP questions,

measures of the effectiveness of PDE5 inhibitors have

grown to include a number of other patient-reported

outcomes, such as 1) the Self-Esteem and Relationship

(SEAR) questionnaire, which measures male confidence

(subdivided into self-esteem and overall relationship

satisfaction) as well as sexual relationship satisfaction

(Althof et al, 2003; Cappelleri et al, 2004); 2) the Erectile

Dysfunction Inventory of Treatment Satisfaction (ED-

ITS), which assesses ED treatment satisfaction (Althof

et al, 1999); and 3) Global Assessment Questions

(GAQ1 and GAQ2). The wording of, and 7 response

options for, the GAQ questions (from ‘‘very much

Supported by Eli Lilly and Co (Indianapolis, IN), which had a role

in study design, data acquisition and interpretation, and the decision to

publish the findings.

Correspondence to: Dr Hartmut Porst, Private Practice of Urology

and Andrology, Neuer Jungfernstieg 6a, 20354 Hamburg, Germany

(e-mail: Porst20354@aol.com).

Received for publication August 24, 2011; accepted for publication

June 11, 2012.

DOI: 10.2164/jandrol.111.015289

Journal of Andrology, Vol. 33, No. 6, November/December 2012Copyright E American Society of Andrology

1305

better’’ to ‘‘very much worse’’) were in turn consistent

with the Patient Global Impression of Improvement

(PGI-I) questionnaire previously developed for psycho-pharmacologic research and applied most recently to

enable an overall appraisal of the severity of stress

urinary incontinence and its response to treatment (Guy,

1976; Yalcin and Bump, 2003). Studies across different

cultures have demonstrated that treatment with PDE5

inhibitors enhances erectile function and that these

improvements in turn correlate directly and significantly

with increments in treatment satisfaction and measuresof patient well-being and relationship satisfaction

(Althof et al, 2006a,b; Steidle et al, 2006; Ralph et al,

2007; Seftel et al, 2009). In a recent study, once-daily

tadalafil was associated with significantly (P , .001 vs

placebo) superior improvements in sexual satisfaction,

sexual relationships, confidence, and self-esteem (Seftel

et al, 2009).

Most men with ED enrolled in registration studies foronce-daily tadalafil had previous experience with PDE5

inhibitors, and initial European recommendations for

once-daily tadalafil treatment were for men who had

previously responded to on-demand PDE5 inhibitors. In

the primary manuscript from the current European

randomized, double-blind, placebo-controlled study

(Clinicaltrials.gov identifier NCT00836693), Montorsi

et al (2011) reported that once-daily tadalafil treatmentwas efficacious in, and well tolerated by, PDE5

inhibitor–naive men with ED. Efficacy was assessed

using least squares (LS) mean changes in the IIEF-EF

domain (7.3 for tadalafil 5 mg vs 3.4 for placebo, once

daily), percent of intercourse attempts in which the

patient was able to successfully insert his penis into the

vagina (change in SEP2 score, +23.8% vs +12.2%,

respectively), and percent of attempts lasting longenough for successful intercourse (change in SEP3 score,

+39.5% vs +21.5%, respectively; P , .001 for each

tadalafil-placebo comparison) as coprimary end points.

In the current study, we focus on additional end

points assessed in this study of PDE5-inhibitor–naive

men. Patient-reported outcome measures used in the

present study included the EDITS, SEAR, and GAQ1

and GAQ2 to assess perceived degrees of improvement.

In addition to evaluating these patient-reported out-come measures, this study also explored approaches

aimed at measuring objective end points that might

further inform the understanding of ED and its

treatment. Potential objective end points considered

relevant to ED treatment include assessments of

spontaneous nocturnal erections as well as indices of

endothelial dysfunction. Restoring spontaneous erec-

tions may have beneficial effects on penile hemodynam-ics and overall erectile function by enhancing intracor-

poreal perfusion and oxygenation, and hence combating

the development of hypoxia-induced tissue injury,

including downstream increases in growth factors within

the tunica albuginea (Montorsi et al, 1997, 2004).Devices developed to attempt to measure spontaneous

nocturnal erections include RigiScan (Timm Medical

Technologies Inc, Eden Prairie, Minnesota; Udelson

et al, 1999; Suzuki et al, 2001) and nocturnal electro-

bioimpedance volumetric assessment (NEVA; PJR Inc,

Minnetonka, Minnesota; Knoll and Abrams 1999a,b;

Mizuno et al, 2004).

Cavernous atherosclerotic endothelial dysfunction,with its imbalance of vasodilator (eg, nitric oxide

[NO]) and vasoconstrictor (eg, endothelin-1) factors,

can blunt the penile vascular response to sexual

stimulation necessary for normal erection (Foresta et

al, 2006; Aversa et al, 2007). Because of this intimate

‘‘endothelial-erectile dysfunction’’ connection (Costa

and Virag, 2009), ED is recognized as a sentinel

symptom of atherosclerosis in other vascular beds,including the coronary, cerebral (carotid-artery), and

peripheral (eg, femoral-artery) vasculature (Montorsi

et al, 2003; Gazzaruso et al, 2004, 2006; Caretta et al,

2005; Foresta et al, 2008; Tamler and Bar-Chama,

2008). Promising findings from trials involving partic-

ipants with ED (typically without atherosclerotic

plaque) receiving chronic rather than on-demand

PDE5 inhibitors suggested that therapy can help to‘‘recondition’’ dysfunctional cavernous endothelium,

resume spontaneous erections, and confer sustained

vasoprotective and erectile-rehabilitative effects, even

after treatment discontinuation, through increased NO

levels and/or structural changes in the penile vasculature

(McMahon, 2004; Caretta et al, 2005; Jackson, 2005).

Potential objective measures of cavernous endothelial

function include serum markers, cellular markers, andother physiologic assessments (Tamler and Bar-Chama,

2008). Putative serum markers of endothelial dysfunc-

tion include circulating levels of cellular adhesion

molecules (eg, soluble E-selectin), inflammatory cyto-

kines, the potent vasoconstrictor peptide endothelin-1,

and another inflammatory marker: high-sensitivity C-

reactive protein (hsCRP; Billups et al, 2003; Nawawi

et al, 2003; Giugliano et al, 2004; Bohm and Pernow,2007; Naya et al, 2007b; Ridker, 2007; Tamler and Bar-

Chama, 2008). Putative thromboembolic markers of

endothelial dysfunction include levels of plasminogen

activator inhibitor, tissue-type plasminogen activator

antigen, and von Willebrand factor (Bickel et al, 2002;

Naya et al, 2007a; Tamler and Bar-Chama, 2008).

A physiologic measure of global endothelial function

is the assessment of the reactive hyperemia index (RHI)

by noninvasive peripheral arterial tonometry (Endo-PAT; Itamar Medical Limited, Caesarea, Israel). This

finger plethysmographic device allows detection of

1306 Journal of Andrology N November �December 2012

minute fluxes in digital pulse volumes (pulsatile arterial

volume changes) secondary to microcirculatory endo-

thelial dysfunction (Bonetti et al, 2004; Rubinshtein et al,

2010; Aversa et al, 2011). The aim of the present study

was to investigate treatment satisfaction measures, as

well as other outcomes, such as nocturnal erections and

endothelial function, in patients participating in the

aforementioned clinical study (Montorsi et al, 2011),

whose main outcome comprised evaluations of the IIEF

(Rosen et al, 1997).

Materials and Methods

Study Design

The European multicenter, randomized, double-blind, paral-

lel-group trial was conducted across 22 sites in Germany,

Greece, Italy, Poland, and Spain. Tadalafil doses were based

on currently licensed regimens for once-daily administration in

Europe (European Medicines Agency, 2012). The study was

conducted in accordance with ethical tenets originating in the

Declaration of Helsinki. All study participants provided

written informed consent before participating in any assess-

ment or treatment, and the study protocol and consent

document underwent institutional ethics review.

Study participants entered a 4-week, treatment-free run-in

period, during which they were required to make $4 vaginal

intercourse attempts with the same female partners (Figure 1).

After this period, eligible participants with self-reported ED were

randomized in a 2:1 ratio to once-daily tadalafil 5 mg (with possible

down-titration to 2.5 mg according to individual tolerability) or

placebo, respectively, for 12 weeks (three 4-week visits).

Placebo tablets were matched to the tadalafil 2.5-mg and 5-

mg tablets, with all study drugs being identical in color, shape,

smell, and taste; drug supplies were labeled to further ensure

the study was blind. On computer-generated block (block size

5 3) randomization to treatment, participants were stratified

to balance enrollment (within country) by ED severity

according to baseline IIEF-EF domain scores (Rosen et al,

1997; Cappelleri et al, 1999). Eligibility for the study depended

on a self-reported history of ED, not a certain IIEF score. A

small number of men with IIEF-EF scores .25 entered the

study and were categorized as having mild ED for the purposes

of randomizing by ED severity.

Study Participants

Men aged 18 years or older who had a $3-month history of

ED and who agreed to remain sexually active with the same

heterosexual partner were eligible if they had not received

previous treatment with an oral PDE5 inhibitor. Some of the

key exclusion criteria included: 1) having received treatment

with doxazosin, nitrates, cancer chemotherapy, or antiandro-

gens (except finasteride or dutasteride); 2) having a history of

radical prostatectomy with subsequent failure to achieve

erections; or 3) having penile implants or deformities.

Outcome Measures

Efficacy—Data on primary efficacy measures have been

reported previously (Montorsi et al, 2011). As mentioned

Figure 1. Study design. V indicates visit.

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1307

earlier, these outcome variables included mean changes from

baseline to end point on the IIEF-EF, as well as in the per-

patient percentage of successful attempts at vaginal penetra-

tion (SEP2) and of successful attempts at sexual intercourse

(SEP3). Additional patient-reported outcome variables includ-

ed: 1) treatment satisfaction as measured by the EDITS

questionnaire (Althof et al, 1999); 2) psychosocial end points

as measured by the SEAR questionnaire (Althof et al, 2003;

Cappelleri et al, 2004); 3) the number (frequency) of self-

reported daily spontaneous morning erections; and 4) GAQ1

and GAQ2.

Each of the 11 questions on the EDITS was rated from 0

(extremely low) to 4 (extremely high) for treatment satisfaction

(Althof et al, 1999). A summary score ranging from 0 to 100

was obtained by summing the individual scores for all

questions, dividing by the number of questions answered,

and multiplying by 25. The validated SEAR questionnaire was

also completed by each study participant at baseline and the 3-

month final visit (or early discontinuation). This 14-item

questionnaire has two domains assessing sexual relationship

and confidence. Each item was scored from 1 to 5, and scores

were transformed (to 0–100), such that higher scores indicated

more favorable responses. The transformed score was equal to

100 times the actual raw score minus the lowest possible raw

score, divided by the possible range in raw scores.

Study participants also answered GAQ1 and GAQ2 at the

final 3-month visit (or early discontinuation): 1) ‘‘How do you

perceive your ability to achieve and maintain erections now,

compared to before you began taking the study medication?’’

(GAQ1); and 2) ‘‘How do you perceive your sexual life now,

compared to before you began taking the study medication?’’

(GAQ2). Responses were scored using a 7-point scale where a

response of 1 5 very much better, 2 5 much better, 3 5 a little

better, 4 5 no change, 5 5 a little worse, 6 5 much worse, and

7 5 very much worse. As mentioned earlier, questions and

response options were consistent with the validated PGI-I

questionnaire (Yalcin and Bump, 2003). Men completed a

daily diary to indicate whether they experienced morning

erections. For each man, the percent of mornings with waking

erections was calculated.

Nocturnal Electrobioimpedance Volumetric Assessment—

Spontaneous nocturnal erections were measured by nocturnal

electrobioimpedance volumetric assessment (NEVA). To use

NEVA, 2 electrodes are placed on a man’s penis, and 1

electrode is placed on the hip. The underlying operating

principles have been elaborated elsewhere (Levine and Caroll,

1994; Knoll and Abrams, 1999a,b; also see Supplemental Data

available online at http://www.andrologyjournal.org). In brief,

the property of electrobioimpedance changes with minute

variations in blood flow. Consequently, penile volumetric

changes can be calculated from changing measures of

impedance (Salama, 2004). Penile blood volume is computed

from NEVA data, including the cross-sectional area and length

of the penis. Recordings of nocturnal penile blood volume over

2 or 3 consecutive nights impart useful information for

individuals with abnormal erections.

By recording data on the number and duration of

spontaneous nocturnal erectile events and penile volume

changes (ie, erections not induced by sexual stimulation), the

NEVA device was developed to provide objective data on the

integrity of the erectile mechanism. Changes from baseline in

nocturnal penile tumescence (indicated by an increase in

volume, length, and/or area) were assessed by continuously (at

1-second intervals) measuring penile electrobioimpedance.

Consistent with manufacturer guidance, study participants

were instructed (by appropriately trained site personnel) to use

the NEVA device at home on 3 consecutive nights in each 1-

week period before baseline, end point, and 2 weeks after

treatment discontinuation. Studies suggest that 2 or 3 nights

of this type of monitoring are needed to characterize an

individual adequately (Levine and Carroll, 1994). During

this first ‘‘training’’ use of the device (ie, the first of 3 nights),

data on nocturnal tumescence parameters were not recorded

because this session was intended to allow each study par-

ticipant to become acquainted with and accustomed to using

the device.

NEVA data were collected for the 2 nights before the visit

and analyzed for nights on which the device was recorded as

having been worn for .4 hours and #20 hours. If a man had a

NEVA session recorded as .20 hours, the session was not

considered to be valid for analysis. An erectile event was

defined as a nocturnal peak penile volume that exceeded the

baseline value for $15 minutes. Study participants were

advised to avoid sexual activity immediately before testing.

They were also counseled to refrain from consuming coffee,

tea, cola, or alcoholic beverages, or taking sedatives, tranquil-

izers, muscle relaxants, or sleeping pills immediately before

testing. Other precautions included keeping the device away

from liquids (eg, shutting off the device before urinating).

Patients returned their devices to their sites after the period

of monitoring (ie, at randomization, end point, and after a 2-

week treatment-free washout), and the data were downloaded

and managed using the manufacturer’s software. Recorded

data for each erection included the date; start and stop times;

number of erectile events; the minimum and maximum cross-

sectional area, length, blood volume, and duration of each

erectile event; and the percent volume change from baseline.

Peripheral Arterial Tonometry—The EndoPAT2000 device

was used to measure reactive hyperemia (RH–peripheral

arterial tonometry [RH-PAT]) as well as arterial stiffness

(augmentation index [AI]) by PAT at baseline, week 4, end

point, and after a 2-week treatment-free interval. PAT is a

validated, noninvasive method of assessing systemic endothe-

lial function and arterial stiffness based on brachial-artery

occlusion and endothelial-mediated arterial responses at the

distal phalanx of the finger. The AI is a sensitive indicator of

arterial stiffness that: 1) captures the enhancing effects of a

reflected blood pressure pulse wave on central aortic pressure

(ie, augmentation); 2) is associated with target-organ damage;

3) predicts cardiovascular events across diverse populations;

and 4) can be used to discriminate between the vascular effects

of different vasoactive agents (Shimizu and Kario, 2008;

Boutouyrie et al, 2010).

EndoPAT assessments were scheduled to take place between

7 and 11 AM and, when possible, at the same time of day. Study

participants were counseled to fast and refrain from smoking

1308 Journal of Andrology N November �December 2012

from midnight until the time of the assessments. These

evaluations were performed before both blood sampling and

administration of study drug (or concomitant medications) if

possible. Study participants taking calcium channel blockers

were advised to take their previous doses approximately

24 hours before scheduled EndoPAT assessments.

Cellular and Biochemical Markers—Fasting blood samples

were obtained at baseline, end point, and after a 2-week

treatment-free interval to analyze circulating endothelial

progenitor cells (cEPC) and the other biomarkers, including

soluble E-selectin.

Safety—Adverse events were monitored throughout the

study. Treatment-emergent adverse events were defined as

occurring for the first time or worsening upon study treatment.

Statistical Analyses

Sample size was estimated based on an expected between-

treatment difference of 4.7 points (SD 5 8) in the IIEF-EF

domain score, which indicated a sample size of 174 partici-

pants (with a ratio of 2:1 tadalafil-placebo) to provide $95%

power to detect a significant effect between once-daily placebo

and tadalafil at a two-sided a 5 .05. Under the assumption of a

screening failure rate of 20%, 218 participants were needed to

result in the required sample size of 174.

Primary and secondary efficacy analyses were performed on

an intent-to-treat (ITT) basis. The ITT population included all

randomized participants who had $1 baseline and $1

postbaseline observation. Where missing values for the

treatment period were imputed, a last observation carried

forward approach within the treatment period was used.

The primary manuscript (Montorsi et al, 2011) addressed the

primary study hypothesis that once-daily tadalafil, compared

with placebo, would result in statistically significant improve-

ments in erectile function, as measured by the IIEF-EF domain,

SEP2, and SEP3. We also hypothesized that such differences

would be reflected in other measures, including the EDITS,

SEAR, and GAQ questionnaires. Assessments of endothelial

dysfunction were exploratory in nature and did not necessarily

support or contradict the primary analyses of parameters

supporting efficacy on ED as assessed via IIEF questionnaires

or SEP diaries. A priori, one would expect the following findings

in the event that tadalafil improved nocturnal erections and

endothelial function compared with placebo: 1) a decrease in the

PAT measure of arterial stiffness (AI); 2) an increase in the PAT

measure of microvascular endothelial function (RHI-PAT); 3)

reductions in inflammatory (eg, hsCRP, E-selectin) and

thrombotic/antifibrinolytic (t-PA, von Willebrand factor) bio-

markers; and 4) increases in cEPCs (Foresta et al, 2005a,b, 2006,

2009a,b, 2010a,b; Rosano et al, 2005).

Analysis of covariance models were used to evaluate changes

from baseline in the SEAR questionnaire. LS mean (x),

standard error (SE), 2-sided 95% confidence interval, and P

values for differences between placebo and tadalafil 5 mg

derived from an analysis of variance (ANOVA) including

terms for treatment group, country, baseline SEAR score, age

group, ED severity stratum, etiology, testosterone level, and

the RHI at baseline, as well as the baseline-by-treatment group

interaction if significant at P , .01.

The EDITS summary score was analyzed descriptively with

summary statistics, using an ANOVA model with treatment

and country as factors. Mean (6SD) end point EDITS total

scores were compared by baseline treatment assignment; in

those with moderate or severe (vs mild) ED at baseline; and in

those ages 50 to 59 years or $60 years (vs ,50 years) at

baseline. End point GAQ1 and GAQ2 data were analyzed

using the Wilcoxon rank sum test. Mean changes in the IIEF-

EF score, SEP2, and SEP3 were calculated according to levels

of responses to both GAQ1 and GAQ2. Correlations between

and among treatment efficacy, satisfaction, and psychosocial

outcomes were assessed using Spearman’s correlation coeffi-

cients in the ITT population, as were correlations between

numbers of spontaneous morning erections and spontaneous

nocturnal erections. The proportion of participants with IIEF-

EF domain scores ,26 at baseline and $26 (consistent with

‘‘no ED’’ [Cappelleri et al, 1999]) at end point were also

computed by treatment group and compared using Fisher’s

exact test.

NEVA data were analyzed in the ITT population using a

Kruskal-Wallis 1-way ANOVA, with P values generated for

differences in nocturnal erection parameters between the

placebo and tadalafil 5 mg treatment groups at end point.

Endothelial markers were analyzed using a prospectively

defined repeated-measures ANOVA, and correlations with

treatment and ED severity were assessed using Spearman’s

correlation coefficient. RH-PAT results were summarized by

treatment group with descriptive measures.

Post hoc analyses were conducted for 5 selected parameters

(RHI, AI, logarithm of hsCRP, soluble E-selectin, and

numbers of cEPCs) to determine the effects of tadalafil

treatment and other factors on measures of endothelial

function using a more tailored, backward-elimination, stepwise

modeling approach. For each measure, the initial model

included potentially predictive factors such as baseline level of

the measure, smoking, age, race, ED severity, and country.

Terms for treatment, time, and treatment-by-time interaction

were retained in all models, as were any factors with P , .10.

Subsequently, the effect of the number of cardiovascular risk

factors on endothelial function was examined by adding this

term to the model. These risk factors included body mass index

.30 kg/m2; current smoking; and/or a baseline diagnosis of (or

baseline concomitant medications for) hypertension, hyper-

cholesterolemia, diabetes, or coronary artery disease (CAD).

Treatment interactions with baseline response and number of

cardiovascular risk factors were examined where those factors

were found to significantly affect response (P , .10). Mixed-

effect model repeated-measures analyses with baseline mea-

sures as covariates were conducted to assess between-visit

changes in total cEPCs. Post hoc analyses were not adjusted

statistically for multiple comparisons.

Results

Participant Disposition and Baseline Demographics

Of 217 participants randomized, 200 (92.2%) completed

the 12-week double-blind treatment (Figure 2). Baseline

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1309

characteristics were well balanced across treatment

groups (Table 1).

Patient-Reported Outcomes

Efficacy: Treatment Satisfaction and Psychosocial Out-

comes—Responses to GAQ1 and GAQ2 were signifi-

cantly superior with once-daily tadalafil compared with

placebo (P , .0001; Figure 3). On GAQ1, a total of

61.7% of men in the tadalafil arm reported being ‘‘much

better’’ or ‘‘very much better’’ (vs 21.7% on placebo; P

, .001 for the comparison of responses between groups

by Wilcoxon rank sum test). Table 2 shows that, in

general, mean changes from baseline to end point in

IIEF-EF were greater in men who stated that they were

‘‘very much better’’ or ‘‘much better,’’ compared with

those who were ‘‘a little better’’ or who experienced no

perceived change on the GAQs.

At baseline, 1 study participant (1.5%) randomized to

placebo and 6 participants (4.1%) randomized to

tadalafil had IIEF-EF domain scores ($26) consistent

with ‘‘no ED.’’ Among 140 study participants with

IIEF-EF domain scores ,26 at baseline, 61 (43.6%)

randomized to tadalafil reached or exceeded this

threshold for normal erectile function at end point,

compared with 20 of 66 (30.3%) randomized to placebo

(P 5 .092).

At study end point, mean 6 SD EDITS total scores

were significantly higher among men receiving once-

daily tadalafil (72.8 6 20.7; out of best score 5 100)

compared with placebo (52.7 6 22.6; P , .001),

indicating greater satisfaction with tadalafil (Table 3).

Younger men and those with less severe ED tended to

have higher treatment satisfaction compared with their

older and more severely dysfunctional counterparts

(Table 3).

The LS mean difference in SEAR total score change

from baseline was 11.8 (95% confidence interval, 5.4–

18.2) in favor of once-daily tadalafil (P , .001 vs

placebo), indicating a significantly greater improvement

in psychosocial outcomes with tadalafil (Table 4).

Significant improvements from baseline to end point

with once-daily tadalafil (vs placebo) were also observed

across the sexual relationship (P , .001), confidence (P

5 .004), and self-esteem (P 5 .002; Table 4) subdomains

but not the overall relationship subdomain (P 5 .067).

Treatment satisfaction and psychosocial outcomes

were significantly and positively correlated (P , .001)

with efficacy (at end point in all participants) across

Figure 2. Participant disposition. Of 217 participants randomized, 215 (n 5 146 tadalafil; n 5 69 placebo) comprised the intent-to-treat (primaryefficacy) population by having data at baseline and at least 1 postrandomization visit. On the other hand, the safety population was composedof the total number of participants randomized (n 5 217; n 5 147 tadalafil and n 5 70 placebo). aReasons for discontinuation in placebo group:adverse event (1 participant), sponsor decision (1 participant), and participant decision (4 participants). bReasons for discontinuation in tadalafilgroup: adverse event (4 participants), physician decision (2 participants), participant decision (9 participants), protocol violation (1 participant),lost to follow-up (1 participant).

1310 Journal of Andrology N November �December 2012

most questionnaires and domains. For each association

between the EDITS or SEAR total score and each

domain of the IIEF (except the SEAR with the

orgasmic-function domain; r 5 0.12; P 5 .090), Pearson

r values ranged from 0.26 to 0.54 and were P , .001 for

correlations (Table 5). Positive correlations between

EDITS and SEAR total scores and SEP questions 3,

4, and 5 were also statistically significant (each P , .001;

Table 5).

Spontaneous Morning Erections—Men receiving once-

daily tadalafil experienced a significantly higher proportion

of self-reported daily spontaneous morning erections at

study end point compared with placebo (58.7% vs 42.2%; P

, .001). The LS mean change in spontaneous morning

erections from baseline to end point in the tadalafil group

was 27.6% (adjusted for treatment group, age, and baseline

score), compared with 11.5% in the placebo group

(adjusted for the mentioned factors; P , .001 between

groups).

Spontaneous Nocturnal Erections—Among 217 men in

the NEVA ITT population, only 138 (63.6%) had

available data at both baseline and end point: 91

Table 1. Baseline patient characteristicsa

Characteristic Placebo (n 5 69) Tadalafil 5 mg (n 5 146)

Age, y, x 6 SD 51.9 6 10.4 52.2 6 10.9

Body mass index, kg/m2, x 6 SD 27.7 6 3.4 27.9 6 4.7

Race, No. (%)

White 69 (100.0) 144 (98.6)

Asian 0 (0) 2 (1.4)

ED etiology, No. (%)b

Psychogenic 9 (13.0) 22 (15.1)

Organic 23 (33.3) 40 (27.4)

Mixed 27 (39.1) 61 (41.8)

Unknown 10 (14.5) 23 (15.8)

ED duration, No. (%)b

3 to ,6 mo 6 (8.7) 10 (6.8)

6 to ,12 mo 14 (20.3) 33 (22.6)

$12 mo 49 (71.0) 103 (70.5)

IIEF-EF domain score, x 6 SD 15.9 6 6.2 15.5 6 6.0

ED severity (categories of IIEF-EF domain scores), No. (%)

Mild (17–30) 31 (44.9) 64 (43.8)

Moderate (11–16) 22 (31.9) 47 (32.2)

Severe (1–10) 16 (23.2) 35 (24.0)

Comorbid cardiovascular risk factors, No. (%)

Hypertension 20 (29.0) 46 (31.5)

Hypercholesterolemia 6 (8.7) 17 (11.6)

Diabetes mellitus 6 (8.7) 19 (13.0)

Coronary artery disease 1 (1.4) 1 (0.7)

Endothelial-function parameters, x 6 SDc

RHI, AU 2.0 6 0.5 1.9 6 0.6

AI, % 8.2 6 14.4 9.3 6 15.7

hsCRP, mg/L 1.8 6 2.3 2.3 6 3.9

No. of cEPCs, cells per milliliter 183.1 6 100.7 169.7 6 124.5

Soluble E-selectin, ng/mL 29.7 6 14.1 27.4 6 13.3

RHI, No. (%) with values AUc,d

,1.67 26 (38.8) 63 (43.8)

1.67–2.07 18 (26.9) 50 (34.7)

.2.07 23 (34.3) 31 (21.5)

Abbreviations: AI, augmentation index; AU, arbitrary units; cEPCs, circulating endothelial progenitor cells; ED, erectile dysfunction; hsCRP,

high-sensitivity C-reactive protein; IIEF-EF, International Index of Erectile Function–Erectile Function domain; RHI, reactive hyperemia index.a Intent-to-treat population (n 5 215): placebo (n 5 69) and tadalafil (n 5 146); 2 participants without follow-up data were excluded from all

outcome analyses except adverse events.b Some percent values do not sum to 100 because of rounding.c The intent-to-treat population with available data for endothelial function parameters included 59–67 participants in the placebo group and

134–145 in the tadalafil group.d One patient (in the tadalafil group) did not have data on this parameter.

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1311

tadalafil-treated patients and 47 placebo recipients. A

total of 100 study participants (68 tadalafil-treated

patients [46.3%] and 32 placebo recipients [45.7%])

wore the device for 2 nights at both baseline and end

point, and also wore it for the appropriate length of time

(.4 but #20 hours) on at least 1 night at both baseline

and end point or early discontinuation. A total of 76

participants (54 tadalafil-treated individuals [36.7%] and

22 placebo recipients [31.4%]) wore the NEVA device

for the appropriate duration (see earlier text) on each of

the 2 nights at both baseline and end point or early

discontinuation. The mean 6 SD time that participants

wore the NEVA device was 6.3 6 1.8 hours at baseline

and 6.2 6 1.8 hours at end point.

No significant differences in NEVA-measured fre-

quency or duration of spontaneous nocturnal erections,

or percent change in penile volume, were observed

between once-daily tadalafil and placebo (Table 6).

There was also no significant correlation between mean

numbers of self-reported spontaneous morning erections

and spontaneous nocturnal erections (by NEVA) among

all study participants in the ITT population (Figure 4).

Endothelial Function—Prospectively defined analyses

of RHI and AI, as well as of key cellular and serum

biomarkers, did not indicate that once-daily tadalafil

treatment was associated with significant changes

compared with placebo. LS mean differences in param-

eters of endothelial function at end point are presented

in Table 7. Except for soluble E-selectin (Spearman

coefficient 5 20.14; P 5 .050), there was no significant

association between changes in ED severity and changes

in any endothelial marker. The RHI also did not

correlate significantly with spontaneous nocturnal erec-

tion parameters on NEVA.

Further, post hoc analyses that included cardiovas-

cular risk factors did not show significant effects of

treatment (tadalafil vs placebo) on most endothelial

function parameters. The 66 participants (31%) who had

Figure 3. Responses to the global assessment questionnaire (GAQ) by treatment group in the intent-to-treat population. P , .0001 for tadalafilvs placebo for GAQ1 and GAQ2. *Worse 5 ‘‘a little worse,’’ ‘‘much worse,’’ and ‘‘very much worse.’’

Table 2. General Assessment Question (GAQ; x 6 SD) 1 and 2 by changes from baseline to end point in efficacy scoresamong all patients in the intent-to-treat population (n 5 215)

GAQ1 GAQ2

Response IIEF-EF IIEF-EF

Very much better (n 5 56; n 5 45a) 9.7 (6.0) 10.0 (5.6)

Much better (n 5 49; n 5 60a) 7.7 (4.2) 7.7 (4.8)

A little better (n 5 48; n 5 45a) 5.5 (5.6) 6.1 (5.6)

No change (n 5 38; n 5 44a) 0.4 (4.9) 0.2 (4.5)

Worseb (n 5 18; n 5 15a) 3.7 (7.1) 4.4 (7.6)

Abbreviation: IIEF-EF, International Index of Erectile Function–Erectile Function domain.a The n values are for GAQ1 and GAQ2 responses, respectively. Numbers do not add to 215 because of missing data for some responses; 5

patients did not have available data for GAQ1 or GAQ2.b Worse 5 ‘‘a little worse,’’ ‘‘much worse,’’ and ‘‘very much worse.’’

1312 Journal of Andrology N November �December 2012

at least 2 cardiovascular risk factors also had a

significantly lower mean RHI (ie, greater degree of

endothelial dysfunction) compared with their counter-

parts having fewer risk factors; however, only the

baseline mean RHI value (not tadalafil vs placebo

treatment) was significantly predictive of lower RHI

values (P , .001) on treatment. In models including

cardiovascular risk factors, the baseline AI (P , .001),

age (P , .001), and country (P 5 .043) were

significantly associated with AI values during the study;

a treatment effect of tadalafil (vs placebo) did not reach

statistical significance. Similarly, only the baseline

logarithm of hsCRP was unequivocally significantly

associated with on-treatment levels, and tadalafil did not

exert a significant beneficial effect (vs placebo).

Participants randomized to tadalafil experienced

larger decreases from baseline to end point in raw

numbers of total cEPCs compared with placebo (mean

6 SD changes from baseline, 220.7 6 133.7 cells per

milliliter in the tadalafil group and 212.3 6 115.2 cells

per milliliter in the placebo group). In a post hoc

subgroup analysis, the effects of once-daily tadalafil

on levels of cEPCs were found to depend on each

participant’s number of baseline cardiovascular risk

factors (significant interaction; P 5 .015). In participants

with 2 or more risk factors, tadalafil treatment was

associated with a significant LS mean 6 SE reduction

from baseline to end point of 32.5 6 12.4 cEPCs per

milliliter compared with an increase of 42.6 6 20.3 cEPCs

per milliliter with placebo (P 5 .002). In study partici-

pants with fewer than 2 cardiovascular risk factors, the

between-treatment difference was not significant. Partic-

ipants with hypertension did not have significantly

different changes in cEPCs compared with those without

hypertension, and the presence or absence of hypertension

did not significantly influence the overall treatment effect.

Treatment significantly influenced changes in mean

soluble E-selectin levels, depending on baseline concen-

trations of the marker (significant treatment interaction;

P , .001). Among participants with higher baseline

soluble E-selectin levels (ie, third quartile or .36 ng/

mL), those randomized to tadalafil experienced signif-

icantly greater reductions in soluble E-selectin (23.71 ng/

mL) compared with changes with placebo (+0.06 ng/mL;

P 5 .013). Among study participants with lower

baseline soluble E-selectin levels (ie, first quartile or

,21 ng/mL), however, between-treatment differences

were not statistically significant (P 5 .408).

Safety—Tadalafil was well tolerated in this study. As

previously reported, the leading treatment-emergent

adverse events (each occurring in .2% of tadalafil-

treated participants) included back pain (3.4%) as well as

nasopharyngitis, dyspepsia, headache, and myalgia (each

2.7%; Montorsi et al, 2011). These findings are similar to

previously reported data in other once-daily tadalafil

trials (Porst et al, 2006; Rajfer et al, 2007; Hatzichristou

et al, 2008; Rubio-Aurioles et al, 2009). Less than 3% of

participants in each group discontinued treatment pre-

maturely because of adverse events (Montorsi et al, 2011).

Discussion

In this study of men previously naive to PDE5 inhibitor

therapy, significantly higher proportions of participants

Table 4. Changes in scores on the Self-Esteem and Relationship (SEAR) questionnaire by treatment groupa

SEAR Domain/Subdomain

Change From Baseline, x 6 SELS Mean Treatment Difference (95%

CI) in Change From Baseline PPlacebo (n 5 66) Tadalafil (n 5 141)

Total score 8.3 6 21.1 20.4 6 23.9 11.8 (5.4, 18.2) ,.001

Sexual relationship domain 9.7 6 22.4 23.4 6 25.9 13.1 (6.3, 20.0) ,.001

Confidence domain 6.5 6 24.6 16.5 6 25.6 9.9 (3.3, 16.5) .004

Self-esteem subdomain 9.3 6 30.1 19.2 6 27.9 11.2 (4.2, 18.3) .002

Overall relationship subdomain 0.9 6 30.2 11.0 6 32.5 7.4 (20.5, 15.3) .067

Abbreviations: CI, confidence interval; LS, least squares.a Intent-to-treat population (n 5 215) with data at baseline and end point.

Table 3. End point total scores on the Erectile DysfunctionInventory of Treatment Satisfaction (EDITS) by treatmentgroup, overall and in different groups, by baselinecharacteristicsa

Parameter No. (x 6 SD) P

EDITS

Placebo 67 (52.7 6 22.6) . . .

Tadalafil 142 (72.8 6 20.7) ,.001 vs placebo

ED severity

Mild 94 (71.4 6 21.9) Referent

Moderate 65 (66.2 6 22.9) .106 vs mild

Severe 50 (57.0 6 23.7) ,.001 vs mild

Age, y

,50 87 (72.7 6 20.3) Referent

50–59 60 (62.8 6 23.9) .021 vs ,50 y

$60 62 (60.8 6 24.6) .008 vs ,50 y

Abbreviation: ED, erectile dysfunction.a Intent-to-treat population (n 5 215) with data at end point.

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1313

receiving once-daily tadalafil (vs placebo) reported

improved erections (GAQ1) and sex lives (GAQ2).

Once-daily tadalafil treatment also resulted in: 1)

significantly higher treatment satisfaction on the

EDITS at end point and 2) significantly improved

psychosocial outcomes, as indicated by increases in the

total score of the SEAR and 3 of the 4 SEAR

subdomains compared with placebo. Previous positive

findings for psychosocial outcomes (eg, sexual self-

confidence) and treatment satisfaction on the EDITS

have also been reported in studies of on-demand

tadalafil (Skoumal et al, 2004; Carson et al, 2005;

Martin-Morales et al, 2007).

The present findings also confirm previously reported

data showing that once-daily tadalafil significantly

improved the IIEF-EF domain, SEP, and GAQ

outcomes (Rajfer et al, 2007; Hatzichristou et al, 2008;

Rubio-Aurioles et al, 2009; Porst et al, 2010) and further

support the previously reported coprimary outcomes

(IIEF-EF, SEP2, SEP3) of the current study (Montorsi

et al, 2011). For the first time, to our knowledge, we also

report that treatment with tadalafil significantly im-

proved (vs placebo) the proportion of participants with

morning erections at end point, as well as the change

(increase) from baseline to end point in this parameter.

Although formal questionnaires such as the IIEF may

be important in research and clinical settings to assess

the impact of treatment, many practitioners will not

use formal questionnaires in everyday clinical practice.

Rather, clinicians may rely more on global assessments to

evaluate treatment responses. It may be argued that

GAQ1 and GAQ2 mirror clinicians’ global assessments

by asking patients how much better or worse they find

themselves since starting ED treatment. In contrast to

previous studies, in which GAQ1 and GAQ2 had only a

yes/no response, this is the first tadalafil study in which 7-

point scale responses (‘‘very much better’’ to ‘‘very much

worse’’) were used. The results showing mean changes in

the IIEF-EF domain, SEP2, and SEP3 with different

levels of response on the GAQ1 and GAQ2 may help

Table 6. x 6 SD changes from baseline in spontaneous nocturnal erection parameters as evaluated by nocturnal peniletumescence testing using nocturnal electrobioimpedance volumetric assessment a

Parameter Placebo Patients, No. Placebo, x 6 SD Tadalafil Patients, No. Tadalafil, x 6 SD P

No. of spontaneous nocturnal erections per night

Baseline 60 2.5 6 2.0 120 2.8 6 2.3

End point 51 2.4 6 2.4 108 2.7 6 2.3 .433

Duration of erectile events, min

Baseline 54 26.2 6 11.9 103 28.6 6 14.5

End point 41 28.0 6 10.6 92 29.0 6 15.1 .819

Penile volume, %

Baseline 54 222 6 123 103 201 6 74

End point 41 198 6 70 92 207 6 93 .347

a Intent-to-treat population. x 6 SD of nontransformed data are presented along with P values from log-transformed data.

Table 5. Correlations among total end point scores on the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS)and Self-Esteem and Relationship (SEAR) questionnaire with measures of treatment efficacya

Efficacy Measure

EDITS Total Score SEAR Total Score

Coefficient P Coefficient P

IIEF-EF 0.54 ,.001 0.47 ,.001

IIEF-IS 0.46 ,.001 0.41 ,.001

IIEF-OF 0.26 ,.001 0.12 .090

IIEF-SD 0.40 ,.001 0.41 ,.001

IIEF-OS 0.51 ,.001 0.45 ,.001

SEP1 20.05 .482 20.13 .066

SEP2 0.12 .072 0.06 .406

SEP3 0.43 ,.001 0.38 ,.001

SEP4 0.64 ,.001 0.58 ,.001

SEP5 0.64 ,.001 0.59 ,.001

Abbreviations: EF, erectile function; IIEF, International Index of Erectile Function; IS, intercourse satisfaction; OF, orgasmic function; OS,

overall satisfaction; SD, sexual desire; SEP, Sexual Encounter Profile.a Spearman correlation coefficients in the intent-to-treat population (n 5 215).

1314 Journal of Andrology N November �December 2012

clinicians gain a better understanding of the meaning of

the patient’s responses to global assessments.

The present study and previous clinical trials also

demonstrated significant correlations between treatment

satisfaction on the EDITS (and psychosocial variables

on the SEAR) and other self-reported efficacy data (eg,

IIEF, SEP; Cappelleri et al, 2005; Althof et al, 2006b;

O’Leary et al, 2006; Steidle et al, 2006). Prior clinical

trials also demonstrated that effective ED management

with PDE5 inhibitors and more invasive therapies (ie,

intracavernosal injection therapy) led to resumption of

spontaneous waking (and nocturnal) erections, even after

treatment had been discontinued (Montorsi et al, 1997;

Brock et al, 2001; Mulhall et al, 2005; Aversa et al, 2007).

The requirement in the present study that partici-

pants be PDE5 inhibitor naive may have resulted in a

relatively healthy population, with nearly half of the

patients suffering from only mild ED according to the

Figure 4. Correlations of the number of morning erections during 4 weeks with mean number of nocturnal erectile events per night by nocturnalpenile tumescence testing via nocturnal electrobioimpedance assessment in the intent-to-treat population.

Table 7. Associations of treatments with markers/indices of endothelial functiona

Endothelial Function Marker/Indicator

Least Squares Mean Difference (95% CI)

Between Treatments at End Point P

Circulating endothelial progenitor cells, total cells per milliliter 220.2 (250.1, 9.7) .184

t-PA antigen, ng/mL 20.6 (21.7, 0.4) .234

von Willebrand factor antigen, ng/mL 0.0 (20.2, 0.1) .634

Soluble E-selectin, ng/mL 23.2 (27.3, 0.9) .125

Log hsCRP, mg/L 0.2 (20.2, 0.5) .292

EndoPAT2000–derived indices

Reactive hyperemia index, AU 0.0 (20.2, 0.1) .732

Augmentation index, % 22.1 (26.9, 2.7) .393

Abbreviations: AU, arbitrary units; CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; PAT, peripheral arterial tonometry; t-PA,

tissue-type plasminogen activator.a P values are for differences between treatment groups (tadalafil x 2 placebo x) at end point.

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1315

baseline IIEF-EF. Only 23.7% had severe ED, com-

pared with a range of approximately 24% to 40% in

previous once-daily trials (Porst et al, 2006; Rajfer et al,2007; Rubio-Aurioles et al, 2009). In addition, the mean

age of the present population (52 years) was lower in the

current study compared with previous once-daily

tadalafil trials: approximately 54 years (Rubio-Aurioles

et al, 2009), 56 years (Porst et al, 2006), and 60 years

(Rajfer et al, 2007). Proportions of participants with

vascular risk factors were also near the lower limits of

ranges established in previous studies of once-dailytadalafil that enrolled patients with previous exposure to

PDE5 inhibitors, including hypertension (30.7% vs a range

of 29%–43%), diabetes (11.6% vs a range of 14%–15%),

and hyperlipidemia/hypercholesterolemia (10.7% vs a

range of 10%–22%). Under such conditions, once-daily

tadalafil might not be expected to substantially improve

endothelial function that was not profoundly abnormal

in most patients. The impact of daily tadalafil onendothelial dysfunction might be assessed more appro-

priately in a study specifically focused on men with

defined endothelial dysfunction and documented arter-

iogenic ED.

Once-daily tadalafil did not significantly improve

objective measures of spontaneous nocturnal erections

compared with placebo. However, with regard to the

NEVA data, there was substantial patient attrition,which was largely attributed to operator difficulties (eg,

problems wearing the device throughout the night,

difficulties with batteries). Only 138 of 217 patients

(63.6%) had available data on at least 1 night at baseline

and end point to compute changes in the number of

spontaneous nocturnal erections. Relatively few study

participants successfully wore the device for .4 hours

nightly on consecutive nights, at baseline and end point,as planned. These patient-attrition issues may have

served to minimize any treatment effect with tadalafil

(vs placebo) because of type II (b) statistical error.

The observations of the essentially neutral effects of

tadalafil (vs placebo) on objective measures of endothe-

lial function in the current study are somewhat at odds

with data from previous clinical studies involving

treatment with tadalafil. For example, Rosano et al(2005) studied alternate-day tadalafil (vs placebo) in

men with increased cardiovascular risk and found

improved endothelial function, as measured by flow-

mediated dilatation (FMD) and endothelin-1 levels, in

the tadalafil treatment group.

In another study, treatment with tadalafil 20 mg 3

times per week was associated with improved brachial

artery FMD and increased progenitor cells in men with

ED (Foresta et al, 2006). In general, PDE5 inhibitors arenot effective in improving endothelial function in

healthy individuals (Dishy et al, 2001). This observation

is supported by a study conducted by Bocchio and

colleagues (2008), in which changes in circulating

angiogenic cells and improved brachial artery FMD inmen receiving tadalafil 20 mg every other day (vs

placebo) were associated with the presence of baseline

endothelial dysfunction.

In the current study, we chose a range of putative

cellular markers as exploratory end points in an effort

to better understand the potential impact of tadalafil

once daily on endothelial function. However, there is

no consensus concerning which of these markers shouldbe evaluated in such an analysis. In addition, we do

not yet have reliable population data on normative

values for each of these markers, the sensitivities and

specificities of abnormal levels in detecting endothelial

dysfunction, and the levels of changes in these

parameters that might be clinically meaningful. In a

recent article, for example, Costa and Virag (2009)

observed that, ‘‘To date, many circulating biomarkershave been proposed for the evaluation of endothelial

function; however, none have been considered the ideal

or more specific, and most are unavailable for current

practice.’’ Despite these limitations, we felt that it was

important to contribute our results to this growing area

of scientific investigation.

Given that eligible participants could not have had

previous exposure to PDE5 inhibitors, a ‘‘ceiling’’ effectmay have limited the degree to which once-daily

tadalafil for 12 weeks could further improve objective

measures of endothelial function compared with place-

bo. The fact that our study population involved men

with ED naive to PDE5 inhibitors (and hence with

mainly mild ED) helps to explain why tadalafil did not

result in higher proportions of men with normal IIEF-

EF domain scores at end point: 43.6% compared with30.3% with placebo. In this context, Rosen and

colleagues (2011) demonstrated that minimum clinically

important differences in the IIEF-EF domain are

directly related to baseline ED severity, with patients

having mild ED exhibiting a minimum clinically

important difference of 2; moderate ED, 5; and severe

ED, 7. Hence, given the large proportion of our patient

population with mild ED, it is not entirely surprisingthat tadalafil-associated improvements in normalization

of erectile function according to the IIEF-EF domain

would be modest.

Evidence that patients analyzed in the present study

had mild overall vascular disease and experienced a

ceiling effect with tadalafil included the fact that 122

participants (57.5%) in the ITT population had RHI

data that were considered a priori to be either

inconclusive for endothelial dysfunction (RHI-PATindex $1.67 and #2.07) or normal (.2.07), where a

value of #1.67 has been associated with endothelial

1316 Journal of Andrology N November �December 2012

dysfunction in a population at risk for ischemic heart

disease (Yinon et al, 2006). Although the proportion of

participants with hypertension (30.7%) was not dissim-ilar in our study and previous trials, a smaller

proportion of our patient sample had diabetes: approx-

imately 12% in the total population compared with 14%

to 21% in previous studies of tadalafil once daily and as

needed (Carson et al, 2004; Porst et al, 2006; Rajfer et al,

2007; Donatucci et al, 2008). Corresponding data for

CAD were 0.9% of participants in the present study

compared with 5% to 14% of those in previous tadalafiltrials.

Other baseline data in the current study support the

explanation of a ceiling effect as having limited potential

improvements in endothelial dysfunction with tadalafil

(vs placebo). The mean participant age was 52 years,

approximately 75% of study participants had mild

(44.2% of the total ITT population) or moderate

(32.1%) ED, and 29.3% of the entire study populationhad organic ED.

Most other parameters of endothelial dysfunction

were also not profoundly elevated at baseline. The

baseline RHI-PAT index value in the total ITT

population of the present study was higher than the

previously reported cutoff of #1.67 for endothelial

dysfunction (mean 6 SD, 1.89 6 0.57 in all participants)

and consistent with an inconclusive finding aboutendothelial dysfunction.

On the other hand, it is also possible that the daily

dose of tadalafil evaluated in the present study (5 mg)

was too low to expect consistent beneficial effects on

biomarkers of endothelial dysfunction in a low-risk

population when compared with previous studies

(Foresta et al, 2006, 2009; Aversa et al 2007). In the

future, it might be of interest to compare PAT findings

with results from other forms of testing, including FMDand other, penile hemodynamic and anatomic measures,

such as cavernous artery intima-media thickness (Car-

etta et al, 2009). FMD remains the first-choice

noninvasive method to measure endothelial function

and has the most data relating to CAD risk (Tamler and

Bar-Chama, 2008). Considering that endothelial dys-

function of penile arteries is a different entity from

systemic endothelial dysfunction as detected by othermodalities (ie, veno-occlusive plethysmography and

FMD), the utility of evaluating penile arterial dysfunc-

tion as an early marker of atherosclerotic disease seems

to be more promising than fingertip PAT, especially in

men with ED (Aversa, 2012).

Similarly, the baseline mean 6 SD hsCRP level of

2.12 6 3.44 mg/L (and median of 1.19 mg/L) in the

present study is not consistent with elevated cardiovas-cular risk (Ridker et al, 2008; Genest et al, 2009). In a

randomized, open-label crossover study of 20 individuals

with ED in whom alternate-day tadalafil 20 mg treatment

significantly reduced hsCRP, the baseline value was

considerably higher (x 6 SD, 3.1 6 0.4 mg/L; Aversa etal, 2007).

A 12-week randomized, double-blind, placebo-con-

trolled study of 298 men with comorbid ED and

diabetes showed that once-daily tadalafil 2.5- to 5-mg

treatment did not significantly reduce hsCRP, intercel-

lular adhesion molecule (ICAM-1), or vascular cell

adhesion molecule (VCAM-1), but the baseline values

were within normal limits (Hatzichristou et al, 2008).Two studies involving alternate-day treatment with

tadalafil 20 mg for 4 weeks showed significant reduc-

tions in endothelin-1 on active therapy in study

participants with baseline mean values of 3.3 ng/L in

both studies (Rosano et al, 2005; Aversa et al, 2007).

Our post hoc analyses demonstrated that changes in

levels of the cellular adhesion molecule soluble E-

selectin correlated inversely with ED severity on theIIEF. To our knowledge, this is the first reported

observation of such a relationship. The origins of

circulating adhesion molecules are not entirely clear,

but these cells may derive from shedding or proteolytic

cleavage from endothelial cells, and thus reflect

increased expression of membrane-bound adhesion

molecules (an initiating event in atherogenesis). Men

with ED have increased levels of adhesion molecules,including soluble P-selectin (Bocchio et al, 2004), which

recruits leukocytes to the site of arterial injury, and

hence is intimately involved in the inflammatory

pathway. In the present study, tadalafil treatment

significantly reduced soluble E-selectin levels only in

participants with baseline soluble E-selectin values in the

upper tertile (or above the median; data not shown).

This finding suggests that in such study participants,soluble E-selectin may represent an early marker of

endothelial repair during progression of the atherogenic

process.

The number of EPCs is considered to be an indicator

of the presence of vascular injury as well as an

expression of reparative mechanisms and vascular

protection, including angiogenesis and vasculogenesis

(Rauscher et al, 2003; Foresta et al, 2010a). In previous

studies by Foresta et al (2005a,b, 2006, 2007, 2009a,b,2010a,b), patients with increasing degrees of endothelial

dysfunction exhibited progressive decreases in numbers

of cEPCs. However, age-specific normative values for

cEPCs have yet to be established, and larger studies are

needed to determine the clinical significance of cEPC

numbers in the general population. In a previous study

involving an Asian population, most of whom did not

have cardiovascular risk factors, there was no significantcorrelation between numbers of cEPCs (and surface

marker expression) and blood pressure, cholesterol or

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1317

glucose levels, or a history of smoking (Chen et al,

2010). It is also important to note that not all studies of

EPCs have focused on the same cell types, including

progenitors expressing CD34, CD133, KDR, and/or

VEGFR2. Taken together, these factors may have

contributed to uncertainty in the evaluation of our

results. In this context, Esposito et al (2009) stated that

‘‘. . .there is no clear consensus on which antigenic

profile best identifies progenitor cells with the potential

to repair the endothelium.’’ They concluded that

‘‘literature data evaluating the putative causative role

of EPCs in ED are scanty and discordant.’’

In the current study, there were no statistically

significant differences between tadalafil and placebo

in terms of mean changes in levels of cEPCs. However,

a post hoc analysis showed a reduction in cEPCs with

tadalafil compared with placebo in men with 2 or more

cardiac risk factors. The results of cEPC analyses in the

current study must be interpreted with great caution

given the mentioned discussion on the limitations

introduced by the relatively mild ED population in

this study, the current understanding of how cEPCs

should best be studied in endothelial function, and the

relatively small number of participants in the subgroup

analysis involving those with 2 or more risk factors. It

is possible, for example, that decreases in cEPCs

observed in our study may represent reductions in

ligand-mediated activation of cEPCs, with stabilization

of the cEPC pool and potential long-term beneficial

outcomes, especially in study participants at high

cardiovascular risk. Further, it is plausible that PDE5

inhibitors do not increase cEPCs and other salutary

biomarkers to the same extent as other medications for

vascular diseases; in one small study of patients with

angiographically documented stable CAD, daily treat-

ment with an HMG-CoA reductase inhibitor (statin)

for 4 weeks increased numbers of cEPCs by a factor of

1.5 to 3 (Vasa et al, 2001). Work in one of our

institutions (Aversa, 2012), which included both PAT

and cEPC measures, demonstrated that low-dose once-

daily tadalafil did not affect endothelial function in

men with mild ED.

Potential Study Limitations

As mentioned earlier, the requirement in this study that

eligible participants could have no previous experience

using PDE5 inhibitors may have resulted in our

enrolling a greater proportion of men with less severe

ED and less advanced cavernous endothelial dysfunc-

tion. To reduce the probability of a potential ceiling

effect with tadalafil (vs placebo) because of mild

pathology at baseline, our study could be repeated in

larger and more heterogeneous patient populations

without regard to previous use of or degree of responses

to PDE5 inhibitors; in study participants with more

severe ED and/or more frequent vascular comorbidities

(eg, diabetes); and possibly using more sensitive or

effective objective measures (eg, FMD).

The NEVA device was suboptimally tolerated, and a

relatively small number of participants had data

recorded on consecutive nights at baseline and end

point per the study protocol. At times, patients reported

considerable difficulties in operating the NEVA device.

Taken together, these difficulties likely contributed to

important limitations in the analysis of the NEVA data.

Our choice of NEVA was dictated largely by the fact

that this technology was Conformite Europeenne

(European Conformity) marked, ensuring its overall

safety according to requirements of the European

Union.

The post hoc subgroup analyses were of a mainly

exploratory, hypothesis-generating nature, were subject

to potential biases, and were not adjusted for multiple

comparisons. The present study did not assess potential

diurnal fluctuations in endothelial function (eg, in RHI

[Ohno et al, 2010]) or treatment satisfaction from the

sexual partner’s perspective.

Conclusion

European men with ED who had not previously used

PDE5 inhibitors experienced superior self-reported

treatment satisfaction and improvements in psychoso-

cial function (vs placebo) after receiving once-daily

tadalafil. Data from GAQs (scored for the first time

using a 7-point scale response set in tadalafil studies)

further supported the efficacy of tadalafil in this patient

population. Enhanced treatment satisfaction and psy-

chosocial function were significantly correlated with

improvements in efficacy. Once-daily tadalafil treat-

ment also significantly increased the frequency of self-

reported spontaneous morning erections. No signifi-

cant effects of active treatment on spontaneous

nocturnal erections by NEVA were observed, but a

relatively low proportion of study participants were

able to provide data per protocol. Other objective

measures of endothelial function were not improved by

once-daily tadalafil (vs placebo) in this multicenter

study.

Summary

Once-daily tadalafil significantly improved erectile func-

tion, satisfaction, psychosocial factors, and frequencies of

morning erections, but it did not significantly enhance

objectively measured spontaneous nocturnal erections or

endothelial dysfunction.

1318 Journal of Andrology N November �December 2012

AcknowledgmentsResearch on circulating endothelial progenitor cells was conducted by

Sunil Kadam, PhD, Eli Lilly and Company (Indianapolis, Indiana),

who also reviewed and commented on the manuscript and assisted the

authors in interpreting the findings. Assistance in manuscript

preparation was provided by Stephen W. Gutkin, Rete Biomedical

Communications Corp (Wyckoff, New Jersey), with support from Eli

Lilly. Initial statistical support was provided by Clare Barker, MSc

(current affiliation: PRA International Inc). At the time of early

statistical analysis, Ms Barker was an employee of, and minor

shareholder in, Eli Lilly.

Selected findings were presented at the 13th Congress of the European

Society for Sexual Medicine, Palacio de Ferias y Congresos, Malaga,

Spain, November 14–17, 2010.

Study identifiers: Clinicaltrials.gov registration number NCT00836693;

Internal Study Identifier H6D-MC-LVHX.

Financial Disclosure

Dr Porst: study sponsor, Bayer, Pfizer, Janssen-Cilag, Auxilium; Dr

Aversa: study sponsor, Bayer, Pfizer, Pierre Fabre; Dr Brock: study

sponsor, Pfizer, Bayer, Coloplast, American Medical Systems, Johnson

& Johnson, GlaxoSmithKline; Dr Kula: study sponsor; Dr Moncada:

study sponsor, Bayer, GSK, Janssen-Cilag; Dr Montorsi: study

sponsor, AMS, Bayer, GlaxoSmithKline (GSK), Pfizer, Pierre Fabre;

Dr Kinchen and Mr Basson: employees of, and minor shareholders in,

the study sponsor. Mr Basson is now affiliated with Quintiles

(Indianapolis, Indiana).

Author Contributions

Category 1: a) Conception and Design: Drs Porst, Brock, Kula,

Moncada, Montorsi, and Aversa, and Ms Barker. b) Acquisition of

Data: Drs Porst, Aversa, Kula, Moncada, and Montorsi, along with

other clinical investigators. c) Analysis and Interpretation of Data: Mr

Basson and Ms Barker conducted statistical analyses, and all authors

interpreted data.

Category 2: a) Drafting the Article: Dr Porst with assistance from Mr

Gutkin. b) Revising the Article for Intellectual Content: All authors.

Category 3: Final Approval of the Completed Article: All authors.

Study Guarantor

Dr Porst had access to all study data and takes responsibility for the

study and this report.

ReferencesAlthof SE, Cappelleri JC, Shpilsky A, Stecher V, Diuguid C, Sweeney

M, Duttagupta S. Treatment responsiveness of the Self-Esteem

And Relationship questionnaire in erectile dysfunction. Urology.

2003;61:888–892.

Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K,

Stecher V, Seftel AD. EDITS: development of questionnaires for

evaluating satisfaction with treatments for erectile dysfunction.

Urology. 1999;53:793–799.

Althof SE, O’Leary MP, Cappelleri JC, Glina S, King R, Tseng LJ,

Bowler JL. Self-esteem, confidence, and relationships in men

treated with sildenafil citrate for erectile dysfunction: results of two

double-blind, placebo-controlled trials. J Gen Intern Med. 2006a;

21:1069–1074.

Althof SE, O’Leary MP, Cappelleri JC, Hyidsten K, Stecher VJ, Glina

S, King R, Siegel RL; International SEAR Study Group. Sildenafil

citrate improves self-esteem, confidence, and relationships in men

with erectile dysfunction: results from an international, multi-

center, double-blind, placebo-controlled trial. J Sex Med. 2006b;

3:521–529.

Aversa A. Sexual dysfunction: a new tool for early identification of

penile endothelial dysfunction. Nat Rev Urol. 2012;9(4):182–183.

Aversa A, Francomano D, Bruzziches R, Pili M, Natali M, Spera G,

Lenzi A. The application of digital pulse amplitude tonometry to

the diagnostic investigation of endothelial dysfunction in men with

erectile dysfunction. Andrologia. 2011;43:9–15.

Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G.

Relationship between chronic tadalafil administration and im-

provement of endothelial function in men with erectile dysfunction:

a pilot study. Int J Impot Res. 2007;19:200–207.

Bickel C, Rupprecht HJ, Blankenberg S, Espiniola-Klein C, Schlitt A,

Rippin G, Hafner G, Treude R, Othman H, Hofmann KP, Meyer

J; AtheroGene Investigators. Relation of markers of inflammation

(C-reactive protein, fibrinogen, von Willebrand factor, and

leukocyte count) and statin therapy to long-term mortality in

patients with angiographically proven coronary artery disease.

Am J Cardiol. 2002;89:901–908.

Billups KL, Kaiser DR, Kelly AS, Wetterling RA, Tsai MY, Hanson

N, Bank AJ. Relation of C-reactive protein and other cardiovas-

cular risk factors to penile vascular disease in men with erectile

dysfunction. Int J Impot Res. 2003;15:231–236.

Bocchio M, Desideri G, Scarpelli P, Necozione S, Properzi G, Spartera

C, Francavilla F, Ferri C, Francavilla S. Endothelial cell activation

in men with erectile dysfunction without cardiovascular risk factors

and overt vascular damage. J Urol. 2004;171:1601–1604.

Bocchio M, Pelliccione F, Passaquale G, Mihalca R, Necozione S,

Desideri G, Francavilla F, Ferri C, Francavilla S. Inhibition of

phosphodiesterase type 5 with tadalafil is associated to an

improved activity of circulating angiogenic cells in men with

cardiovascular risk factors and erectile dysfunction. Atherosclero-

sis. 2008;196:313–319.

Bohm F, Pernow J. The importance of endothelin-1 for vascular

dysfunction in cardiovascular disease. Cardiovasc Res. 2007;

76:8–18.

Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT,

Lerman A. Noninvasive identification of patients with early

coronary atherosclerosis by assessment of digital reactive hyper-

emia. J Am Coll Cardiol. 2004;44:2137–2141.

Boutouyrie P, Achouba A, Trunet P, Laurent S; EXPLOR Trialist

Group. Amlodipine-valsartan combination decreases central systolic

blood pressure more effectively than the amlodipine-atenolol

combination: the EXPLOR study. Hypertension. 2010;55:1314–

1322.

Brock G, Tu LM, Linet OI. Return of spontaneous erection during

long-term intracavernosal alprostadil (Caverject) treatment. Urol-

ogy. 2001;57:536–541.

Cappelleri JC, Althof SE, Siegel RL, Shpilsky A, Bell SS, Duttagupta

S. Development and validation of the Self-Esteem and Relation-

ship (SEAR) questionnaire in erectile dysfunction. Int J Impot Res.

2004;16:30–38.

Cappelleri JC, Althof SE, Siegel RL, Stecher VJ, Tseng LJ,

Duttagupta S. Association between the Erectile Dysfunction

Inventory of Treatment Satisfaction and the Self-Esteem and

Relationship Questionnaire following treatment with sildenafil

citrate for men with erectile dysfunction. Value Health. 2005;

8(suppl 1):S54–S60.

Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH.

Diagnostic evaluation of the erectile function domain of the

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1319

International Index of Erectile Function. Urology. 1999;54:

346–351.

Caretta N, Palego P, Ferlin A, Garolla A, Bettella A, Selice R, Foresta

C. Resumption of spontaneous erections in selected patients

affected by erectile dysfunction and various degrees of carotid

wall alteration: role of tadalafil. Eur Urol. 2005;48:326–331.

Caretta N, Palego P, Schipilliti M, Ferlin A, Di Mamro A, Foresta C.

Cavernous artery intima-media thickness: a new parameter in the

diagnosis of vascular erectile dysfunction. J Sex Med. 2009;

6:1117–1126.

Carson C, Shabsigh R, Segal S, Murphy A, Fredlund P, Kuepfer C.

Efficacy, safety, and treatment satisfaction of tadalafil versus

placebo in patients with erectile dysfunction evaluated at tertiary-

care academic centers. Urology. 2005;65:353–359.

Carson CC, Rajfer J, Eardley I, Carrier S, Denne JS, Walker DJ, Shen

W, Cordell W. The efficacy and safety of tadalafil: an update.

Br J Urol Int. 2004;93:1276–1281.

Chen CH, Cheng BC, Leu S, Chen CH, Tsai TH, Leu S, Chang HW,

Chung SY, Chua S, Yeh KH, Chen YL, Yip HK. Circulating level

of endothelial progenitor cells in healthy Taiwanese. Acta Cardiol

Sing. 2010;26:94–100.

Costa C, Virag R. The endothelial-erectile dysfunction connection: an

essential update. J Sex Med. 2009;6:2390–2404.

Dishy V, Sofowora G, Harris PA, Kandcer M, Zhan F, Wood AJ, Stein

CM. The effect of sildenafil on nitric oxide-mediated vasodilation in

healthy men. Clin Pharmacol Ther. 2001;70:270–279.

Donatucci CF, Wong DG, Giuliano F, Glina S, Dowsett SA, Watts S,

Sorsaburu S. Efficacy and safety of tadalafil once daily:

considerations for the practical application of a daily dosing

option. Curr Med Res Opin. 2008;24:3383–3392.

Esposito K, Ciotola M, Maiorino MI, Giugliano F, Autorino R, De Sio

M, Jannini E, Lenzi A, Giugliano D. Circulating CD34+ KDR+endothelial progenitor cells correlate with erectile function and

endothelial function in overweight men. J Sex Med. 2009;6:107–114.

European Medicines Agency. Cialis summary of product characteristics

2012. Available at http://www.ema.europa.eu/docs/en_GB/document_

library/EPAR_-_Product_Information/human/000436/WC500026318.

pdf. Accessed September 28, 2012.

Foresta C, Caretta N, Lana A, Cabrelle A, Palu G, Ferlin A.

Circulating endothelial progenitor cells in patients with erectile

dysfunction. Int J Impot Res. 2005a;17:288–290.

Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Vinanzi C,

Ferlin A. Relationship between vascular damage degrees and

endothelial progenitor cells in patients with erectile dysfunction:

effect of vardenafil administration and PDE5 expression in the

bone marrow. Eur Urol. 2007;51:1411–1417.

Foresta C, De Toni L, Biagioli A, Ganz F. Magagna S, Caretta N.

Increased levels of osteocalcin-positive endothelial progenitor cells

in patients affected by erectile dysfunction and cavernous

atherosclerosis. J Sex Med. 2010a;7:751–757.

Foresta C, De Toni L, Garolla A, Ferlin A, Zuccarello D. The PDE5

inhibitor sildenafil increases circulating endothelial progenitor cells

and CXCR4 expression. J Sex Med. 2009a;6:369–372.

Foresta C, De Toni L, Magagna S, Galan A, Garolla A. Phospho-

diesterase-5 inhibitor tadalafil acts on endothelial progenitor cells

by CXCR4 signalling. Curr Drug Deliv. 2010b;7:274–282.

Foresta C, Di Mambro A, Caretta N, De Toni L, Zuccarello D, Ferlin

A. Effect of vardenafil on endothelial progenitor cells in

hypogonadotrophic hypogonadal patients: role of testosterone

treatment. Clin Endocrinol (Oxf). 2009b;71:412–416.

Foresta C, Ferlin A, De Toni L, Lana A, Vinanzi C, Galan A, Caretta

N. Circulating endothelial progenitor cells and endothelial function

after chronic tadalafil treatment in subjects with erectile dysfunc-

tion. Int J Impot Res. 2006;18:484–488.

Foresta C, Lana A, Cabrelle A, Ferigo M, Caretta N, Garolla A, Palu

G, Ferlin A. PDE-5 inhibitor, Vardenafil, increases circulating

progenitor cells in humans. Int J Impot Res. 2005b;17:377–380.

Foresta C, Palego P, Schipilliti M, Selice R, Ferlin A, Caretta N.

Asymmetric development of peripheral atherosclerosis in patients

with erectile dysfunction: an ultrasonographic study. Atherosclero-

sis. 2008;197:889–895.

Gazzaruso C, Giordanetti S, De Amici E, Bertone G, Falcone C,

Geroldi D, Fratino P, Solerte SB, Garzaniti A. Relationship

between erectile dysfunction and silent myocardial ischemia in

apparently uncomplicated type 2 diabetic patients. Circulation.

2004;110:22–26.

Gazzaruso C, Pujia A, Solerte SB, Amici ED, Emanuele E, Falcone C,

Geroldi D, Giustina A, Garzaniti A. Erectile dysfunction and

angiographic extent of coronary artery disease in type II diabetic

patients. Int J Impot Res. 2006;18:311–315.

Genest J, McPherson R, Frohlich J, Anderson T, Campbell N,

Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover

S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E,

Mancini GB, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E.

2009 Canadian Cardiovascular Society/Canadian guidelines for

the diagnosis and treatment of dyslipidemia and prevention of

cardiovascular disease in the adult - 2009 recommendations.

Can J Cardiol. 2009;25:567–579.

Giugliano F, Esposito K, Di Palo C, Ciotola M, Giugliano G,

Marfella R, D’Armiento M, Giugliano D. Erectile dysfunction

associates with endothelial dysfunction and raised proinflamma-

tory cytokine levels in obese men. J Endocrinol Invest. 2004;

27:665–669.

Guy W. ECDEU Assessment Manual for Psychopharmacology–

Revised. DHEW Publication No. ADM 76-338. Rockville, MD:

National Institute of Mental Health; 1976:218–222.

Hatzichristou D, Gambla M, Rubio-Aurioles E, Buvat J, Brock GB,

Spera G, Rose L, Lording D, Liang S. Efficacy of tadalafil once

daily in men with diabetes mellitus and erectile dysfunction. Diabet

Med. 2008;25:138–146.

Jackson G. Editorial comment on Caretta N et al. Resumption of

spontaneous erections in selected patients affected by erectile

dysfunction and various degrees of carotid wall alteration: role of

tadalafil. Eur Urol. 2005;332.

Knoll LD, Abrams JH. Application of nocturnal electrobioimpedance

volumetric assessment: a feasibility study in men without erectile

dysfunction. J Urol. 1999a;161:1137–1140.

Knoll LD, Abrams JH. Nocturnal electrobioimpedance volumetric

assessment of patients with erectile dysfunction. Urology. 1999b;

53:1200–1204.

Levine LA, Carroll RA. Nocturnal penile tumescence and rigidity in

men without complaints of erectile dysfunction using a new

quantitative analysis software. J Urol. 1994;152:1103–1107.

Martin-Morales A, Haro JM, Beardsworth A, Bertsch J, Kontodimas

S. Therapeutic effectiveness and patient satisfaction after 6 months

of treatment with tadalafil, sildenafil, and vardenafil: results from

the erectile dysfunction observational study (EDOS). Eur Urol.

2007;51:541–550.

McMahon C. Efficacy and safety of daily tadalafil in men with erectile

dysfunction previously unresponsive to on-demand tadalafil. J Sex

Med. 2004;1:292–300.

Mizuno I, Fuse H, Fujiuchi Y, Nakagawa O, Akashi T. Comparative

study between audiovisual sexual stimulation test and nocturnal

penile tumescence test using RigiScan Plus in the evaluation of

erectile dysfunction. Urol Int. 2004;72:221–224.

Montorsi F, Aversa A, Moncada I, Perimenis P, Porst H, Barker C, Shane

MA, Sorsaburu S. A randomized, double-blind, placebo-controlled,

parallel study to assess the efficacy and safety of once-a-day tadalafil in

1320 Journal of Andrology N November �December 2012

men with erectile dysfunction who are naıve to PDE5 inhibitors. J Sex

Med. 2011;8:2617–2624.

Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. Current and

future strategies for preventing and managing erectile dysfunction

following radical prostatectomy. Eur Urol. 2004;45:123–133.

Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi

A, Galli S, Ravagnani PM, Montorsi P. Erectile dysfunction

prevalence, time of onset and association with risk factors in 300

consecutive patients with acute chest pain and angiographically

documented coronary artery disease. Eur Urol. 2003;44:360–364.

Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri

L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile

function after nerve-sparing radical retropubic prostatectomy

with and without early intracavernous injections of alprostadil:

results of a prospective, randomized trial. J Urol. 1997;158:1408–

1410.

Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. The use of an

erectogenic pharmacotherapy regimen following radical prostatec-

tomy improves recovery of spontaneous erectile function. J Sex

Med. 2005;2:532–540.

Nawawi H, Osman NS, Annuar R, Khalid BA, Yusoff K. Soluble

intercellular adhesion molecule-1 and interleukin-6 levels reflect

endothelial dysfunction in patients with primary hypercholesterol-

aemia treated with atorvastatin. Atherosclerosis. 2003;169:283–291.

Naya M, Tsukamoto T, Inubushi M, Morita K, Katoh C, Furumoto T,

Fujii S, Tsutsui H, Tamaki N. Elevated plasma plasminogen activator

inhibitor type-1 is an independent predictor of coronary microvas-

cular dysfunction in hypertension. Circulation J. 2007a;71:348–

353.

Naya M, Tsukamoto T, Morita K, Katoh C, Furumoto T, Fujii S,

Tamaki N, Tsutsui H. Plasma interleukin-6 and tumor necrosis

factor-alpha can predict coronary endothelial dysfunction in

hypertensive patients. Hypertens Res. 2007b;30:541–548.

Ohno Y, Hashiguchi T, Maenosono R, Yamashita H, Taira Y,

Minowa K, Yamashita Y, Kato Y, Kawahara KI, Maruyama I.

The diagnostic value of endothelial function as a potential sensor of

fatigue in health. Vasc Health Risk Manag. 2010;6:135–144.

O’Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N,

Duttagupta S; United States Self-Esteem and Relationship Question-

naire Study Group. Self-esteem, confidence and relationship satisfac-

tion of men with erectile dysfunction treated with sildenafil citrate: a

multicenter, randomized, parallel group, double-blind, placebo con-

trolled study in the United States. J Urol. 2006;175:1058–1062.

Porst H, Giuliano F, Glina S, Ralph D, Casabe AR, Elion-Mboussa

A, Shen W, Whitaker JS. Evaluation of the efficacy and safety of

once-a-day dosing of tadalafil 5mg and 10mg in the treatment of

erectile dysfunction: results of a multicenter, randomized, double-

blind, placebo-controlled trial. Eur Urol. 2006;50:351–359.

Porst H, Glina S, Ralph D, Zeigler H, Wong DG, Woodward B.

Durability of response following cessation of tadalafil taken once

daily as treatment for erectile dysfunction. J Sex Med. 2010;

7:3487–3494.

Rajfer J, Aliotta PJ, Steidle CP, Fitch WP III, 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.

Ralph D, Eardley I, Kell P, Dean J, Hackett G, Collins O, Edwards D.

Improvement in erectile function on vardenafil treatment correlates

with treatment satisfaction in both patients and their partners.

Br J Urol Int. 2007;100:130–136.

Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg

D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA.

Aging, progenitor cell exhaustion, and atherosclerosis. Circulation.

2003;108:457–463.

Ridker PM. C-reactive protein and the prediction of cardiovascular

events among those at intermediate risk: moving an inflammatory

hypothesis toward consensus. J Am Coll Cardiol. 2007;49:2129–

2138.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr,

Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG,

Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER

Study Group. Rosuvastatin to prevent vascular events in men and

women with elevated C-reactive protein. N Engl J Med. 2008;

359:2195–2207.

Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic

treatment with tadalafil improves endothelial function in men with

increased cardiovascular risk. Eur Urol. 2005;47:214–220.

Rosen RC, Allen KR, Ni X, Araujo AB. Minimum clinically important

differences in the erectile function domain of the International Index

of Erectile Function Scale. Eur Urol. 2011;60:1010–1016.

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;

49:822–830.

Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE,

Pumper GM, Lerman LO, Lerman A. Assessment of endothelial

function by non-invasive peripheral arterial tonometry predicts late

cardiovascular adverse events. Eur Heart J. 2010;31:1142–1148.

Rubio-Aurioles E, Kim ED, Rosen RC, Porst H, Burns P, Zeigler H,

Wong DG. 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;6:1314–1323.

Salama N. Nocturnal electrobioimpedance volumetric assessment in

diabetic men with erectile dysfunction before and after tadalafil

intake. Int J Impot Res. 2004;16:441–447.

Seftel A, Goldfischer E, Kim ED, Dula E, Zeigler H, Burns P. Onset of

efficacy of tadalafil once daily in men with erectile dysfunction:

a randomized, double-blind, placebo controlled trial. J Urol.

2011;185:243–248.

Seftel AD, Buvat J, Althof SE, McMurray JG, Zeigler HL, Burns PR,

Wong DG. Improvements in confidence, sexual relationship and

satisfaction measures: results of a randomized trial of tadalafil 5 mg

taken once daily. Int J Impot Res. 2009;21:240–248.

Shimizu M, Kario K. Role of the augmentation index in hypertension.

Ther Adv Cardiovasc Dis. 2008;2:25–35.

Skoumal R, Chen J, Kula K, Breza J, Calomfirescu N, Basson BR,

Kopernicky V. Efficacy and treatment satisfaction with on-demand

tadalafil (Cialis) in men with erectile dysfunction. Eur Urol.

2004;46:362–369.

Steidle CP, Stecher VJ, Pace C, Tseng LJ. Correlation of improved

erectile function and rate of successful intercourse with improved

emotional well-being assessed with the Self-Esteem And Relationship

questionnaire in men treated with sildenafil for erectile dysfunction

and stratified by age. Curr Med Res Opin. 2006;22:939–948.

Suzuki K, Sato Y, Horita H, Adachi H, Kato R, Hisasue S, Itoh N,

Tsukamoto T. The correlation between penile tumescence mea-

sured by the erectometer and penile rigidity by the RigiScan.

Int J Urol. 2001;8:594–598.

Tamler R, Bar-Chama N. Assessment of endothelial function in the

patient with erectile dysfunction: an opportunity for the urologist.

Int J Impot Res. 2008;20:370–377.

Udelson D, Park K, Sadeghi-Nejad H, Salimpour P, Krane RJ,

Goldstein I. Axial penile buckling forces vs. Rigiscan radial rigidity

as a function of intracavernosal pressure: why Rigiscan does not

predict functional erections in individual patients. Int J Impot Res.

1999;11:327–337.

Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM,

Dimmeler S. Increase in circulating progenitor cells by statin

Porst et al N Once-Daily Tadalafil in PDE5I-Naive Men 1321

therapy in patients with stable coronary artery disease. Circulation.

2001;103:2885–2890.

Yalcin I, Bump RC. Validation of two global impression question-

naires for incontinence. Am J Obstet Gynecol. 2003;189:98–101.

Yinon D, Lowenstein L, Suraya S, Beloosesky R, Zmora O, Malhotra

A, Pillar G. Pre-eclampsia is associated with sleep-disordered

breathing and endothelial dysfunction. Eur Respir J. 2006;27:

328–333.

1322 Journal of Andrology N November �December 2012