Clinical Medicine Insights: Therapeutics
Review
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Vardenafil in Erectile Dysfunction: The Evidence of Its
Therapeutic Value
Kevin R. Rice and Robert C. Dean
Urology Service, Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307, USA.
Corresponding author email: [email protected]
The opinions and assertions contained herein are the private views of the authors and are not to be considered as
reflecting views of the U.S. Army or the Department of Defense.
Abstract: Erectile dysfunction (ED) is a condition that affects approximately 18 million American men. Phosphodiesterase-5 inhibitors
(PDE5i’s) have revolutionized the treatment of erectile dysfunction by providing the first highly-effective oral medication. Vardenafil
is one of 3 PDE5i’s commercially available for the treatment of ED in the United States. It has demonstrated therapeutic efficacy in
the management of uncomplicated ED as well as more refractory cases associated with diabetes and surgery for prostate cancer. The
physiology, pharmacokinetics, pharmacodynamics, and primary literature evaluating vardenafil are reviewed.
Keywords: erectile dysfunction, phosphodiesterase 5 inhibitors, impotence, vardenafil
Clinical Medicine Insights: Therapeutics 2010:2 965–975
doi: 10.4137/CMT.S3787
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Clinical Medicine Insights: Therapeutics 2010:2
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Rice and Dean
Introduction
Erectile dysfunction (ED) is a condition that affects
approximately 18 million American men.1 The incidence appears to be increasing, although this is
likely related to increased public awareness and
self-reporting. The increased awareness that has taken
place over the last decade is due in no small part to
the discovery of the therapeutic efficacy of phosphodiesterase-5 inhibitors (PDE5i’s) in treating ED as
well as the marketing campaigns of the 3 formulations that are commercially-available in the United
States. PDE5i’s have revolutionized the treatment of
erectile dysfunction. Whereas ED was traditionally
a condition managed by specialists, the introduction
of PDE5i’s has resulted in management of ED in the
primary care setting. PDE5i’s provide arguably the
most physiologic erection of the available treatments
for ED. PDE5i’s have traditionally been prescribed
and studied as on-demand medications for the treatment of ED. However, with the recent exploration
of once daily maintenance therapy as well as postradical prostatectomy penile rehabilitation, there is
potential for new ways to apply these medications to
the management of ED.
Physiology of Penile Erection
In the flaccid state, there is very little blood flow to the
corpora cavernosa. The hemodynamics of the penis in
this setting are the result of baseline sympathetic tone.
This sympathetic input maintains ­vasoconstriction
of the cavernosal arteries as well as contraction of
the cavernosal smooth muscles surrounding the lacunar spaces. The flaccid penis is smaller in this state,
because this sympathetic tone minimizes cavernosal
arterial inflow, corporal cavernosal volume, and ability of the corpora to trap blood. The small amount of
blood that enters the corpora cavernosa exits through
venules that pierce the tunica albuginea of the penile
shaft. This blood then drains through the venous systems of the penis.
The physiologic process of penile erection
involves both cavernosal filling and trapping of
blood. Upon sexual stimulation, cholinergic end neurons of the parasympathetic neurons arising from spinal segments S2-4 produce acetylcholine which acts
through the inositol triphosphate pathway to increase
the conversion of l-arginine to nitric oxide (NO) by
endothelial nitric oxide synthase (eNOS). This results
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in arteriolar dilation and increased cavernosal blood
flow. Simultaneously, the nitrergic end neurons of
parasympathetic nerves S2-4 located in the cavernosal tissue release NO. NO is produced by the cleavage of l-arginine by neuronal nitric oxide synthase
(nNOS). Production of NO results in the conversion
of GTP to cGMP by guanylate cyclase. cGMP interacts with protein Kinase G resulting in calcium shifts
into the sarcoplasmic reticulum and relaxation of
the carvernosal smooth muscles. The result of these
processes is a 20 to 40-fold increase in cavernosal
blood flow. The penis then enlarges in both length
and girth until the tunica albuginea surrounding the
corpora cavernosa reaches its maximum capacity for
stretch. Once this occurs, the intracavernosal pressure increases. This increase in intracavernosal pressure compresses the venules against the underside of
the tunica albuginea, preventing venous outflow of
intracavernosal blood and providing the mechanism
by which blood is trapped in the corpora cavernosa of
the erect penis.
Mechanism of Phosphodiesterase-5
Inhibitors
Phospodiesterases (PDEs) are intracellular enzymes
that regulate breakdown of cyclic nucleotides.2 PDE5
is one of eleven mammalian PDE families. Inhibition
of PDE5 prevents the breakdown of cGMP, which
promotes calcium sequestration into the sarcoplasmic
reticulum of cavernosal smooth muscle cells. This
results in potentiated smooth muscle relaxation and
cavernosal engorgement (Fig. 2).3
Vardenafil (Levitra®) was the second PDE5i to
receive FDA approval for the treatment of ED in the
United States (Fig. 1). Vardenafil is the most potent
of the commercially-available PDE5i’s, although
this has not been demonstrated to result in a clinical
advantage over other PDE5i’s. The IC50 is the in vitro
O
O
O
N
HN
S
N
N
N
N
O
Figure 1. Chemical structure of vardenafil.
Clinical Medicine Insights: Therapeutics 2010:2
Vardenafil
Corpus cavernosum
Cell Me
mbrane
Guanylate
Cyclase
cGMP
GTP
GMP
ERECTION
Smooth
Muscle
Relaxation
O
O
O
N
N
HN
S
N
N
N
O
VARDENAFIL
Figure 2. Mechanism of vardenafil.
concentratration at which 50% of phosphodiesterase
5 is inhibited. The IC50 for vardenfil is 0.1 to 0.7 nM.
The IC50 of sildenafil is 3.9 nM.4 The IC50 of tadalafil is 0.94 nM.5 The maximal plasma concentration
(Cmax) for vardenafil 20 mg 20.9 ng/ml vs. 327 and
378 ng/ml for sildenafil 100 mg and tadalafil 20 mg,
respectively. The time to reach Cmax for vardenafil
is similar to sildenafil at 0.7 to 0.9 hours and considerably shorter than that of tadalafil (2 hours). The
half life of vardenafil is similar to sildenadfil at 4 to
5 hours, but shorter than the half life of tadalafil, which
is 17.5 hours.5,6 As with sildenfail, consumptions of a
high fat meal prior to taking vardenafil prolongs the
time to reach Cmax. Unlike sildenafil, consumption
of a high-fat meal does not alter is relative bioavailability. The delay in reaching Cmax has not been
observed in low to moderate fat meals.7 Tadalafil’s
absorption and bioavailability does not appear to be
altered by high-fat meals.8
With regard to selectivity, the affinity of vardenafil for PDE5 versus PDE6 is .15:1. This is higher
than that of sildenafil (10:1) but lower than that of
tadalafil (.700:1). Crossreactivity with PDE6 is
responsible for the blurred vision that some patients
may experience when taking PDE5i’s. Indeed, comparative evaluation of side effects by patients taking
Clinical Medicine Insights: Therapeutics 2010:2
once of the 3 PDE5i’s has demonstrated increased
blurred vision in patients taking sildenafil versus the
other two PDE5i’s.9 Vardenafil’s affinity for PDE5 vs.
PDE11 is .300:1, which is less than that of Sildenafil
(.700:1), but more than that of tadalafil (20 to 40:1).
This may explain why there is a higher incidence of
musculoskeletal pain in patients taking tadalafil.9
Clinical Efficacy of Vardenafil
In 2001, Klotz et al performed a pharmacokinetic
and pharmacodynamic study of vardenafil in 21 men
with ED. The study was a prospective randomized,
double-blind, placebo-controlled crossover trial. Outcomes were measured with a RigiScan. A Rigiscan
is a device that consists of two cuffs worn at the base
and tip of the penis. These cuffs measure radial penile
rigidity at these two locations. This is then expressed
as percentage of total rigidity (100%). The subjects
in this trial wore the device 0.5 hour prior to dosing
and then 2.5 hours after dosing. The subjects watched
sexually explicit videos and RigiScan measurements
were taken. The primary endpoint of the study was
the length of time that penile rigidity was .60%.
­Vardenafil was evaluated at single doses of 10 and
20 mg. Compared to placebo, subjects receiving
10 mg demonstrated an increase in duration of .60%
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Rice and Dean
rigidity of 24.4 and 24.8 minutes at the base and tip
of the penis, respectively. Subjects receiving 20 mg
vardenafil demonstrated an increase in duration of 37.2
and 28.7 minutes at the base and tip, respectively. With
regard to pharmacokinetics, vardenadil demonstrated a
Tmax (time from administration to maximal plasma concentration) of 0.7 to 0.9 hours and a serum half life of
4.2 hours.10 This study confirmed the therapeutic efficacy and specific pharmacokinetics of vardenafil.
Porst et al performed the first at home evaluation
of vardenafil in 601 men. This was a multicenter,
randomized, double-blind, placebo-controlled trial
evaluating vardenafil at 5, 10, and 20 mg doses over
a 12-week treatment period. Primary endpoints were
answers to questions 3 (When you attempted intercourse, how often were you able to penetrate your
­partner?) and 4 (During intercourse, how often were
you able to maintain your erection after you entered
your ­partner?) of the International Index of Erectile
Function (IIEF). The IIEF is a validated 15-item questionnaire designed to measure the degree of erectile
dysfunction. Each question is answered on a 0–5 scale,
with a score 5 indicating better ­function. All three
doses of vardenafil demonstrated a ­statistically significant increase in positive responses to questions
3 and 4. Additionally, patients receiving vardenafil
demonstrated statistically significant increases in all
domain scores of the IIEF. Eighty percent of men
receiving the 20 mg dose responded positively to
the global assessment question (Has the treatment
you have been taking for the last 4 weeks improved
your erections?) compared to 30% for men receiving
placebo. Treatment-emergent adverse events were
dose-related and included headache (7%–15%),
flushing (10%–11%), dyspepsia (1%–7%), and rhinitis (3%–7%).11 This was the first study to report the
efficacy of vardenafil in enabling men with ED to
engage in successful sexual intercourse as determined utilizing a validated instrument.
In 2003, Hellstrom et al published a phase III,
multi-center, randomized, double-blind, placebocontrolled, four-arm, parallel-group, fixed dose comparison study. Eight hundred and five patients were
treated with of vardenafil 5 mg, 10 mg, 20 mg, or
placebo for 26 weeks. Efficacy was determined
through utilization of several metrics. Subjects were
asked to answer IIEF questions 1–5 and 15 (IIEF-ED)
after 12 weeks of treatment. They were also asked to
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answer the sexual encounter profile question 2 (SEP2)
“Were you able to insert your penis into your partner’s
vagina?” as well as the sexual encounter profile question 3 (SEP3) “Did your erection last long enough
for you to have successful intercourse?” Secondary
outcomes included answers to the above questions
at 26 weeks as well as a global assessment question.
All vardenafil treatment arms demonstrated statistically significant improvements in primary outcomes.
Mean EF domain score improved from 12.5 to 18.4,
from 13.4 to 20.6, and from 12.8 to 21.4 from baseline to 12 week follow-up for vardenafil 5, 10, and
20 mg treatment groups, respectively (P , 0.0001
vs. ­placebo). The placebo arm did not demonstrate
a significant change in EF domain score over the
study period. The mean successful penetration rate
improved from 42.8 to 65.5%, 45.4 to 75.5%, and
40.9 to 80.5% from baseline to 12 week follow-up
in the vardenafil 5, 10, and 20 mg treatment groups
(P , 0.0001 vs. placebo). The mean ability to maintain an erection for successful intercourse improved
from 14.0 to 50.6%, 14.6 to 64.5%, and 14.7 to 64.5%
in the vardenafil 5, 10, and 20 mg treatment groups,
respectively (P , 0.0001). These statistically significant improvements were maintained at 26 week
follow-up.12 This study confirmed vardenafil’s efficacy and safety in treating ED.
Erectile Dysfunction
and Comorbid Conditions
The presence of ED has been suggested to be associated
with an increased risk of future cardiac events. In two
large scale analyses, the presence of ED was found
to be a harbinger for future cardiac events.13,14 This is
thought to be due to the common vascular pathology
contributing to these two conditions. This has led to
the investigation of the effect of cardiovascular risk
factors, comorbid conditions, medications, and their
relationship to the management of ED with PDE5i’s.
ED develops in greater than 50% of patients within
10 years of being diagnosed with diabetes. In the
Massachusetts Male Aging Study, the age-adjusted
probability of developing ED was three times high
in patients with diabetes compared to those without
this condition.15 In diabetic patients, ED is often associated with peripheral vascular disease and diabetic
neuropathy.16,17 Reported success rates of PDE5i’s
in treating ED in diabetic patients have been lower
Clinical Medicine Insights: Therapeutics 2010:2
Vardenafil
than those reported evaluating their use in the ­general
population.18 Goldstein et al examined the efficacy
of vardenafil in treating ED in diabetic patients in
a phase III multi-center prospective randomized
double-blind placebo-controlled trial published in
2003. In this trial 452 diabetic males were randomized to receive placebo, vardenafil 10 mg, or vardenafil 20 mg for 12 weeks. Primary outcomes were
improvement in the IIEF-EF and answers to SEP2 and
SEP3 questions. The mean improvement in the IIEF
erectile function domain was 5.9 and 7.8 for vardenafil 10 and 20 mg (P = 0.03), respectively compared
to 1.4 for placebo (P , 0.0001). The percentage of
subjects self-reporting successful vaginal penetration
was 36, 61, and 64% for placebo, vardenafil 10 mg,
and 20 mg respectively (P , 0.0001 vs. placebo). The
self-reported ability to maintain an erection until the
end of intercourse was 23, 49, and 54% in the placebo,
vardenafil 10 mg, and 20 mg groups, respectively
(P , 0.0001).19 This was the first study demonstrating
the efficacy of vardenafil in treating diabetic males.
Subsequent studies have confirmed vardenafil’s
efficacy in treating ED in diabetic patients with success
rates similar to those reported for sildenafil in treating this patient population.20,21 In 2006, Ziegler et al
evaluated the efficacy of vardenafil in treating ED
in men with type 1 diabetes mellitus. In this multicenter, double-blind, placebo-controlled trial, 302
PDE5i-naïve men were randomized to receive placebo or flexible dose vardenafil. Primary outcomes
were answers to SEP2 and SEP3. ­Secondary outcomes were IIEF scores. Patients receiving vardenafil demonstrated significant improvements in SEP2
and SEP3 regardless of level of glycemic control
(P , 0.0001).20 The percentage of men responding
positively to SEP2 and SEP3 was 71 and 50% after
12 weeks of treatment. These numbers are similar
to that reported by Goldstein et al in their study on
the use of vardenafil in diabetic patients,19 but lower
than those reported in the general population of men
with ED. This seems to indicate that diabetic patients
tend to have more refractory ED than patients without diabetes, but that this may not be a function of
level of glycemic control.
The efficacy of vardenafil in the treatment of men
with dyslipidemia was demonstrated by Miner et al
in 2008.22 In this multicenter, randomized, doubleblind, placebo-controlled study of 712 men who had
Clinical Medicine Insights: Therapeutics 2010:2
been on statin therapy for at least 3 months were
given flexible dose vardenafil or placebo. Significant
improvements in IIEF-EF, SEP2, and SEP3 were
demonstrated. In a follow-up randomized, doubleblind placebo-­controlled, parallel group study, the
same investigators evaluated the relationship between
severity of ­dysplipidemia and efficacy of flexible dose
­vardenafil. Once again, outcomes included IIEF-EF,
SEP2, and SEP3. In addition, a stopwatch-assessed
duration of erection was performed. Subgroup analysis
was performed based low density lipoprotein cholesterol (LDL-C) levels, total cholesterol to high density
lipoprotein cholesterol ratio (TC/HDL-C), and the
presence or absence of the metabolic syndrome. Once
again, vardenafil treatment was associated with a significant improvement in all outcome measures regardless of subgrouping. Interestingly, patients with higher
LDL-C experienced a greater increase in IIEF-EF
despite similar baseline scores (P = 0.033). However,
neither TC/HDL-C nor the presence of metabolic syndrome were associated with significant changes in
IIEF-EF scores. Response to SEP2 did not differ significantly between subgroups. Response to SEP3 followed
a similar pattern to the IIEF-EF score, with high
LDL-C being associated with a significantly increased
positive response rate (P = 0.019). The mean duration
of erection sufficient for penetration was significantly
longer in the patients of a TC/HDL-C greater than or
equal to 3.5 (P = 0.028).23 While the findings of this
study fail to demonstrate a clear pattern of therapeutic
efficacy among subgroups, all significant associations
seem to be paradoxical. This may be explained by the
fact that all patients in this study were on stable statin
therapy. Thus, the lipoprotein levels used to stratify
patients do not necessarily reflect baseline severity
of dyslipidemia. Additionally, given the flexible-dose
study design, patients with more severe dyslipidemia
may have been receiving higher doses of vardenafil.
Furthermore, no information was available regarding
comorbid medical conditions as well as concomitant
medications, all of which can have significant effects
on erectile and sexual function.
Eardley et al performed a retrospective analysis of
13 randomized, double-blind, placebo-controlled trials investigating the use of vardenafil in patients with
diabetes mellitus, hypertension, dyslipidemia, and/or
the metabolic syndrome. Outcome measures were
change in IIEF-EF score and answers to SEP2 and
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Rice and Dean
SEP3 questions. The investigators found ­significant
improvement in all outcome measures regardless of
underlying medical condition(s). Interestingly, the
authors found that the level of glycemic control as
well concomitant use of medications for the treatment
of diabetes mellitus, hypertension, and dyslipidemia
had no significant effect on efficacy of vardenafil.24
Antihypertensive medications in particular have been
demonstrated to adversely affect erectile function.25
Given that sexual side effects can have a negative
effect on patient compliance with these medications,
the ability to minimize these effects can improve
compliance and potentially prevent untoward cardiac
events. Indeed, McLaughlin et al has demonstrated
that prescribing sildenafil can improve patient compliance with antihypertensives, oral hypoglycemics,
and antidepressants.26
Sexual dysfunction, to include ED, is known to
occur with significant frequency in patients with
schizophrenia.27 Whether ED in these patients is
a consequence of symptoms of schizophrenia or
antipsychotic medications is unclear.28 In 2006,
Gopalakrishnan et al performed a randomized,
double-blind, placebo-controlled trial that demonstrated sildenafil to significantly improve erectile
function in men with antipsychotic-induced ED.29
Mitsonis et al performed a 12-week, open-label
study of the efficacy of flexible-dose vardenafil in
the treatment of ED in patients with ­schizophrenia.
The IIEF was used to measure sexual function outcomes. A schizophrenia-specific Quality of Life
Scale (QLS)30 was administered to evaluate the
effect of vardenafil on the patients’ overall quality
of life. Vardenafil resulted in a statistically significant improvement in all IIEF domains as well as in
the QLS when compared to baseline.31 The strength
of these results is weakened by the study’s small
size and lack of a control group. However, the significant improvement in overall quality of life as
well as in all domains of the IIEF experienced by
patients after being treated with vardenafil highlights the profound effect that PDE5i’s can have on
patients suffering from schizophrenia. Further large
scale placebo-controlled studies are needed to confirm these findings.
Erectile dysfunction and lower urinary tract symptoms related to benign prostatic ­enlargement are both
conditions that commonly affect the aging male patient.
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Concomittant management of these ­conditions has
raised concern as PDE5i’s and α-blockers can both
result in hypotension. ­Simultaneous administration
of vardenafil and α-blockers to healthy ­volunteers
resulted in clinically significant decreases in blood
pressure. Thus, the simultaneous use of alpha blockers and vardenafil was initially contraindicated.32
Subsequent studies demonstrated that this effect
was mitigated by separating the dosing of these two
­medications by at least 6 hours. Additionally, the use
of the α1a receptor blocker ­tamsulosin further reduced
the incidence of hypotension.33 Thus, the contraindication on simultaneous administration was lifted
by the FDA. It is now recommended that patients
should be stable on α-blocker therapy before being
started on the lowest vardenafil dose that is clinically
effective.34
Comparative Studies
In a prospective, randomized, double-blind, crossover study performed in 2006, investigators compared
vardenafil and sildenafil in treating patients with diabetes mellitus, hypertension, and/or hyperlipidemia.
A total of 931 men were included in the intent to treat
population. The two drugs were assessed for patient
preference, efficacy, and adverse events. With regard
to preference, 683 (73.4%) of patients responded to
the question. Vardenafil was preferred by 38.9% of
patients, sildenafil by 34.5% of patients, and 26.6%
of patients had no preference. This difference was not
statistically significant. The IIEF-EF, SEP2, SEP3, and
GAQ were used to evaluate efficacy, and responses to
the treatment satisfaction scale (TSS). Vardenafil demonstrated statistical superiority in the included IIEF-EF,
SEP2, SEP3, GAQ, and 12 of 19 TSS items. No significant differences were noted for the remaining 7 TSS
items. Incidence of adverse events was low and similar
between vardenadil and sildenafil. This was the first
study to suggest that vardenafil may have increased
therapeutic efficacy when compared to sildenafil.
However, it should be noted that nominal significance
does not necessarily translate into clinical significance.
Indeed, no statistical difference in patient preference
was demonstrated. 35 Further similarly-designed studies will be necessary in order to compare the efficacy
of all 3 PDE5i’s. Additionally, subgroup analysis with
regard to medical comorbidities may help to identify
specific therapeutic niches for each medication.
Clinical Medicine Insights: Therapeutics 2010:2
Vardenafil
In 2009 Jannini et al reported on an open-label,
randomized, multicenter crossover study comparing
sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg,
and vardenafil 20 mg in the treatment of ED.36 Of
note, data from the crossover portion of this study
were not presented in this publication. These data will
likely be published in subsequent manuscripts. One
hundred thirty-four men were randomized to one of
the four study arms. Primary outcome was efficacy
as determined by IIEF-ED scores after 8 weeks of
treatment. Secondary outcomes were penile hemodynamic parameters as determined by penile duplex
after intracavernosal injection of alprostadil. Of note,
hemodynamic studies were not performed during the
therapeutic window for the assigned PDE5i. No significant differences in primary outcomes were demonstrated between any of the 4 study groups. Sildenafil
50 and 100 mg were both associated with improvements in cavernosal peak systolic velocity when compared to baseline. Only patients receiving sildenafil
100 mg demonstrated a significant improvement in
resistive index when compared to baseline. The clinical implications of these hemodynamic findings are
not clear. Additionally, the findings of this study are
weakned by the open label nature and a high attrition
rate (25%).
Vardenafil in the Treatment
of Postprostatectomy
Erectile Dysfunction
ED can occur in over one third of patients undergoing radical prostatectomy for the treatment of prostate
cancer. The cavernosal nerves course posterolateral
to the prostate bilaterally before piercing the pelvic
diaphragm and entering the corpora cavernosa. These
nerves are responsible for releasing NO in response to
sexual arousal leading to cavernosal engorgement as
described above. The cavernosal nerves are vulnerable
to injury during the posterolateral dissection performed
during radical prostatectomy. Nerve-sparing techniques
utilized in open, laparoscopic, and ­robotic-assisted
prostatectomies are aimed at ­minimizing permanent
ED. However, even patients who go on to experience
a full recovery of erectile function tend to experience
a variable period of severe ED following surgery. In
these cases, the etiology of this transient ED is thought
to be related to surgery-­induced neuropraxia rather
than complete transection.
Clinical Medicine Insights: Therapeutics 2010:2
In 2003, Brock et al published the first study
examining the efficacy of vardenafil in treating postprostatectomy ED. This was a randomized, placebocontrolled, double-blind, fixed-dose, parallel group
study examining the efficacy of vardenafil in restoring
erectile function in men with postprostatectomy ED
having undergone either bilateral or unilateral nervesparing radical retropubic prostatectomy. Efficacy
was assessed using a GAQ. 65.2, 59.4, and 12.5% of
patients receiving vardenafil 20 mg, 10 mg, and placebo reported improvement in erections, respectively.
The strongest predictor of therapeutic efficacy was
pretreatment ED rather than whether nerve sparing
was unilateral or bilateral.37 While this study clearly
demonstrates improved erections in the patients having received vardenafil, findings are weakened by the
lack of a validated instrument for assessing erectile
function.
In recent years, several investigators have evaluated the role for penile rehabilitation in the treatment
of postprostatectomy ED. This practice of penile
rehabilitation is based on muscular rehabilitation programs that have proven beneficial in treating striated
muscle denervation injuries. The regular oxygenation
of the corpora cavernosa that occurs during sexual
arousal as well as during nocturnal penile tumescence (NPT) may serve to maintain healthy corporal
tissue. Corporeal oxygen tension has been demonstrated to increase from 25–40 mmHg in the flaccid
state to 90–100 mmHg during erection.38 This oxygen
may be necessary for the efficient synthesis of NO.
Furthermore, the results of several animal models
have demonstrated that prolonged lack of cavernosal
engorgement with its associated relative hypoxia may
be associated with elevated levels of TGF-β resulting
in corporeal fibrosis.39 Thus, in theory, early intervention may prevent cavernosal smooth muscle atrophy
and apoptosis as well as corporal fibrosis. This is
thought to lead to a corporal veno-occlusive disorder
(CVOD) where cavernosal arterial inflow is intact, but
the emissary veins are never completely compressed
against the tunica of the corpora cavernosa resulting
in continuous venous leak.
Montorsi et al described the first prospective,
randomized trial evaluating the therapeutic efficacy
of restoring erections in the early postprostatectomy period. In this study 30 men having undergone
nerve-sparing radical retropubic prostatectomy were
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Rice and Dean
r­ andomized to receive intracavernosal alprostadil
three times a week for twelve weeks or to be observed
over the same time period. Patients were then evaluated six months after surgery with a detailed sexual
history, penile Doppler examination, and RigiScan.
Twelve of the 15 (80%) patients in the treatment arm
completed the study. Of these patients, 8 of 12 (67%)
reported recovery of spontaneous erections sufficient
for vaginal penetration compared to 2 of 15 (20%)
in the control arm (P , 0.01). Ten of the 12 (83%)
patients in the treatment group, including all complete
responders and 2 partial responders, had normal penile
hemodynamics, while 2 of the partial responders demonstrated CVOD on Doppler examination. Within
the control group, all 3 men with recovery of spontaneous erections and 2 of the failures demonstrated
normal penile hemodynamics. However, 8 (67%) of
the failures in this group demonstrated CVOD and 2
demonstrated arterial insufficiency. Thus, there was
a 33% incidence of normal penile hemodynamics, a
14% incidence of arterial insufficiency, and a 53%
incidence of CVOD in the control group. This study
demonstrated both clinical and radiologic evidence
of a potential benefit of early restoration of erections after prostatectomy. The striking difference in
the incidence of CVOD between the treatment and
control groups (17 vs. 53%, respectively) would seem
to indicate that this is the penile vascular pathology
prevented by early restoration of erections.40 The
impressive results of this study are tempered by its
small numbers as well as the 20% attrition rate in the
treatment group. To date, these results have not been
replicated in a large prospective study.
The role for PDE5i’s in the treatment of postprostatectomy ED has been well-established. However,
their utilization in the setting of postprostatectomy
penile rehab is more controversial. The main argument
against their ability to restore spontaneous erections
in these patients is that PDE5i’s require the production
of NO in order to have their effect. Thus, they would
not be expected to be particularly effective in patients
who have ED resulting from postsurgical cavernosal
neuropraxia or injury. However, the results of several
animal models as well as clinical studies have offered
potential mechanisms for the efficacy of PDE5i’s in
this setting. In a study performed by Ferrini et al the
administration of vardenafil to rats after cavernosal
972
neurotomy reduced the incidence of smooth muscle
loss and cavernosal fibrosis. This is thought to be due
to an increase in intracellular cGMP in smooth muscle cells.41 In another animal model study, administration of sildenafil to rats within 24 hours of stroke was
associated with increased neurogenesis and decreased
neurologic deficits. This study suggests that PDE5i’s
may possess neuroprotective properties.42 Additionally, there is evidence PDE5i’s can promote endothelial health as demonstrated by an increase in the
number of circulating endothelial progenitor cells in
humans as well as increasing cavernous endothelial
cells in diabetic rats.43,44
Much of the initial interest regarding the use of
PDE5i’s in postprostatectomy penile rehabilitation
was in response to a study by Padma-Nathan et al presented at the 2003 American Urological Association
(AUA) Annual Meeting. In this study, 76 men with
normal preoperative erectile function (defined as a
combined score of 8 when answering SEP2 and SEP3
as well as normal NPT testing by RigiScan) having
undergone radical retropubic prostatectomy with
bilateral nerve-sparing were randomized to receive
nightly sildenafil 50 mg (n = 23), sildenafil 100 mg
(n = 28), or placebo (n = 25) starting 4 weeks postoperatively and continuing for 36 weeks. The patients
were then reassessed 8 weeks after the treatment
period (postop week 48) with SEP2, SEP3, and their
response to the following question: “Over the past 4
weeks, have your erections been good enough for satisfactory sexual activity?” Fourteen of the fifty-one
(27%) patients who received nightly sildenafil compared to 1 of 25 (4%) patients in the placebo group
reported the return of spontaneous erectile function
(P = 0.0156).45 The authors propose that the sevenfold increase in the incidence of spontaneous erections when compared to the placebo group offers
definitive evidence of the efficacy of nightly sildenafil. However, the rates of erectile function in both
groups are far lower than those reported on prostate
cancer outcomes studies. Thus, the applicability of
these data is questionable.
In 2008, Montorsi et al reported on a large multicenter, prospective, randomized, double-blind,
placebo-controlled, crossover trial evaluated the efficacy of nightly versus on-demand ­vardenafil in the
treatment of postprostatectomy erectile ­dysfunction.
Clinical Medicine Insights: Therapeutics 2010:2
Vardenafil
60
Patients with IIEF-EF
score 22 (%)
*
50
40
Placebo
Vardenafil nightly
30
Vardenafil on demand
20
10
0
n = 152 143 149
End of double-blind
treatment period
153 143 149
148 138 142
End of 2-mo
single-blind
washout period
End of open-label
on-demand period
Figure 3. Percentage of patients with IIEF-EF score $22 at the end of double-blind, single-blind washout, and open label on demand periods.
Reproduced with permission from Elsevier.
In this study 668 men with normal preoperative
erectile function scheduled to undergo bilateral
nerve-sparing radical prostatectomy were randomized receive vardenafil 10 mg nightly with placebo
on-demand, nightly placebo with flexible dose vardenafil on-demand, or placebo nightly and on-demand
for 9 months. Following the initial 9 months, there
was a 2 month washout period with placebo. Finally,
patients entered a 2-month period open-label vardenafil on demand. This study was designed to both
evaluate the efficacy of vardenafil on demand versus
nightly administration in restoring function erections. Additionally, the washout period followed
by an open label period was designed to determine
whether early administration nightly or on-demand
vardenafil could improve long term erectile function
rates. Four hundred twenty-three men completed the
study. As depicted graphically in Figure 3, at the end
of the initial 9-month double-blind treatment period,
the proportion of patients reporting an IIEF score
of $22 was 24.8%, 32.0%, 48.2% in those receiving placebo, nightly vardenafil and vardenafil on
demand, respectively (P , 0.0001 for vardenafil on
demand vs. placebo). Additionally, the difference in
patients reporting an IIEF score of $22 was statistically higher in the on-demand versus nightly vardenafil groups at several points during the double-blind
period (P = 0.0065). No significant difference in the
proportion of men reporting an IIEF Score of $22
Clinical Medicine Insights: Therapeutics 2010:2
was appreciated between the three groups at the end
of the single-blind washout or open label on demand
periods of the study.46 Thus, this study provides powerful evidence against the efficacy of vardenafil (and
other PDE5i’s) in restoring spontaneous erections in
men with initial postprostatectomy ED.
Conclusion
Over a decade after initial FDA approval, PDE5is
remain the first line treatment for erectile dysfunction. This is due to excellent efficacy in the setting
of relatively few adverse effects. Vardenafil has
been associated with excellent success in treating
ED in the setting of multiple medical and surgical
comorbidities. The superior potency and selectivity
for PDE5 when compared to the other two commercially available PDE5i’s has not been demonstrated
to translate into clinical superiority. However, further
comparative studies are necessary.
Disclosure
This manuscript has been read and approved by all
authors. This paper is unique and is not under consideration by any other publication and has not been
published elsewhere. Dr. Dean has received a research
grant from Pfizer Co. Dr. Rice and the peer reviewers of this paper report no conflicts of interest. The
authors confirm that they have permission to reproduce any copyrighted material.
973
Rice and Dean
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