Erectile Dysfunction: New Agents, New Data CME

Hossein Sadeghi-Nejad, MD

Studies of Efficacy in Currently Available Agents

One of the challenges in treating erectile dysfunction (ED) is the
"rescue" of an initial PDE-5 failure: Will the patient respond to a
higher dose of the same medication or, more importantly, if the dosage
has been maximized, will he respond to another PDE-5 inhibitor? Brisson
and Broderick[1] addressed this topic by prospectively investigating
whether vardenafil can effectively treat patients (n = 327) who had
sildenafil-refractory ED despite dose maximization (100 mg). The
majority of the patients were older than 60 years of age and had severe
arterial insufficiency assessed by intracavernous pharmacotesting (ICI)
and color duplex Doppler ultrasound (CDDU). The authors' "preliminary
experience" revealed that only a small percentage (12%) of sildenafil
failures can be salvaged with vardenafil.
In another study,[2] the efficacy of tadalafil in men with ED who were
naïve to PDE-5 therapy was compared with efficacy in men with ED who
previously responded to sildenafil. This retrospective analysis of 14
double-blind, placebo-controlled, parallel-group trials was designed to
at least partially address the question of whether efficacy outcomes in
various published clinical trials may have been affected significantly
by the exclusion of sildenafil nonresponders. The efficacy of tadalafil
10 mg or 20 mg was assessed in 1349 patients with no prior use of
sildenafil compared to 1440 patients who previously responded to
sildenafil. The authors used a number of validated questionnaires for
this assessment: the International Index of Erectile Function (IIEF),
the Sexual Encounter Profile (SEP) questions 2 and 3, and the Global
Assessment Question (GAQ) 1. Nonresponders to prior sildenafil treatment
were excluded. In this industry-sponsored study (Lilly), the IIEF, SEP3,
and GAQ1 efficacy outcomes for naïve patients were not significantly
different from those for patients with prior sildenafil use (P „ .1).
Tadalafil improved erectile function compared with placebo (P < .001) in
sildenafil-naïve patients and prior sildenafil users. Therefore, the
authors concluded that efficacy outcomes in the trials were unlikely
affected significantly by the exclusion of sildenafil nonresponders.
Long-term safety of sildenafil and the question of whether patients
gradually develop insensitivity to the effects of PDE-5 inhibitor
therapy were addressed in an industry-supported (Pfizer Canada)
multi-institutional Canadian study. The authors studied the maintenance
of long-term efficacy with continued use of sildenafil (3 consecutive
years) taken on-demand by 225 patients (49% with severe ED). This study,
an open-label extension of a double-blind randomized placebo-controlled
trial, reported that 3 years after initiation of on-demand sildenafil
therapy, there was no evidence of tachyphylaxis and that the vast
majority of patients were still satisfied with the effect of sildenafil.
Compared to the results 3 months after initiation of sildenafil, a
higher percentage of patients (75% vs 64%) reported that their erection
problems were not (or rarely) a worry in their life.[3]
Two other industry-sponsored studies, which were part of MOMENTUS
(Multiple Observations in Men with ED in National Tadalafil Study in the
US), addressed the efficacy of tadalafil in the treatment of ED. One of
these studies[4] was conducted in men older than 65 years of age; and
the other[5] in patients with exposure to significant other comorbid
factors (diabetes, cardiovascular disease, hypertension, hyperlipidemia,
benign prostatic hypertrophy/prostatectomy, and depression). In keeping
with the results of similar studies with sildenafil in various
subgroups, these studies demonstrated that in patients over the age of
65 without diabetes mellitus or depression, tadalafil 20 mg was
effective and well tolerated.[4] The high prevalence of a number of
potentially serious comorbidities did not preclude a robust response to
tadalafil 20 mg.[5]
Novel Agents
The meeting also highlighted papers on novel PDE5 inhibitors currently
in development. Prince and colleagues[6] presented the results from a
multi-institutional, industry-supported (Surface Logix, Inc.) study of
the preliminary safety and tolerability of SLx-2101, a new long-acting
PDE5 inhibitor. This small study involved 6 volunteer subjects (mean age
35) who received various doses (5, 10, 20, 40, and 80 mg) of SLx-2101
and 2 volunteers who received placebo. The investigators assessed
erectile responses using the RigiScan Plus system and peripheral
arterial tone with the Endo-PAT2000 device. Pharmacokinetic data were
evaluated for 48 hours. The subjects completed the study with no serious
adverse events related to the heart rate, blood pressure, or ECG. As
with other PDE5 inhibitors currently approved for use in the United
States, headache was the most common adverse event. Visual side effects
were noted at the 80-mg dose. RigiScan data showed positive effects at 0
to 6 hours after the dose without Visual Sexual Stimulation (VSS) for
all doses except 5 mg, and at 24 to 24.5 hours post-dose with VSS for
the 20-, 40-, and 80-mg doses. Based on the pharmacokinetic profile
predicting inhibition of PDE5 for at least 36 to 48 hours at all tested
doses, the authors concluded that trials in patients with a variety of
diseases involving underlying endothelial dysfunction were warranted.[6]
On the other side of the effect-duration spectrum, there were a number
of abstracts on the safety and efficacy of avanafil, a new, highly
specific, and rapidly metabolized PDE5 inhibitor with a short duration
of action. In an industry-sponsored study, Kotera and colleagues[7]
compared the PDE5 inhibitory effects of avanafil on the 11 subtypes of
phosphodiesterases with the inhibitory effects of sildenafil,
vardenafil, and tadalafil in anesthetized dogs. The authors found
avanafil to be the most selective PDE5 inhibitor among the four tested
with a tumescence potency that is "almost the same to that of sildenafil
in anesthetized dogs." Because of its higher selectivity, the authors
postulated that avanafil may have weaker adverse effects related to PDE
isozyme inhibition. Kaufman and Dietrich[8] presented the results of a
multicenter, double-blind, randomized phase II study of the safety and
efficacy of various doses of avanafil (supported by Vivus, Inc.). In
this trial, avanafil taken 30 minutes before sexual activity was
associated with highly significant increases in the ability of men with
mild-to-moderate ED to successfully complete intercourse. This effect
was dose-dependent and without regard to food intake. An important
potential benefit of a shorter acting PDE5 inhibitor was highlighted in
a double-blind crossover study by Nehra and coworkers[9] that
investigated the hemodynamic effects of coadministration of avanafil and
glyceryl trinitrate on the systemic blood pressure (SBP) and heart rate
(HR) (supported by a grant from VIVUS, Inc). When hemodynamic effects at
different intervals between administration of the PDE5 inhibitors
(avanafil vs. sildenafil) and glyceryl trinitrate were evaluated,
avanafil was found to be associated with lower SBP decreases and HR
increases compared to sildenafil. When administered 12 hours prior to
nitroglycerin, avanafil had no observable effect on SBP or HR. Given the
shorter duration of interaction and fewer subjects experiencing
clinically significant hypotension, the authors concluded that avanafil
may be a preferable PDE5 inhibitor for patients who are at risk for
using nitroglycerin.
NAION
A much anticipated and widely attended presentation addressed the
incidence of nonarteritic anterior ischemic optic neuropathy (NAION) in
clinical trials and postmarketing experience with sildenafil.[10] The
sudden unilateral visual defect in NAION is potentially attributed to a
lowering of blood flow in the arterioles supplying the optic nervehead
as it enters the eye. The authors emphasized the common risk factors
leading to NAION and ED (increased age, ischemic heart disease,
hypertension, diabetes, and smoking). For men older than 50 years of
age, the estimated annual event rate of NAION has been reported to be
2.5 per 100,000 men with an increased risk in those who have a "disc at
risk," an anatomic variant of the optic nervehead. Laties and colleagues
assessed the occurrence of NAION in sildenafil users participating in
clinical trials and 2 long-term, postmarketing, population-based
observational studies (13,400 men studied for over 13,300 patient-years
of observation in the Pfizer clinical trial database and postmarketing
data from 3813 men in the multinational International Men's Health
Study). They concluded that the incidence of NAION among carefully
monitored patients receiving sildenafil was not higher, and could be
potentially lower, than that reported to occur spontaneously in the
general population.
ED and LUTS
Another important study addressed the potential beneficial effects of
PDE5 inhibitors in treating lower urinary tract symptoms (LUTS). McVary
and colleagues[11] conducted a 12-week, double-blind, placebo-controlled
study of sildenafil in men at least 45 years old who scored 25 or lower
on the Erectile Function (EF) domain of the IIEF, had an International
Prostate Symptom Score (IPSS) of at least 12, and prostate-specific
antigen no greater than 10 ng/mL. Men with confirmed or suspected
prostate malignancy were excluded. Subjects were instructed to take
sildenafil (50 or 100 mg) or placebo each night at bedtime or 30 minutes
to 1 hour before anticipated sexual activity. The primary endpoint was
the change in EF domain score from baseline to week 12. Changes in the
Self-Esteem (SE) domain of the Self-Esteem and Relationships
Questionnaire (SEAR), total IPSS, IPSS subscores for irritative and
obstructive symptoms, quality of life (QoL), BPH impact index (BPHII),
and maximum urinary flow rate (Qmax) were also assessed. In this study
of 366 men, those on sildenafil demonstrated significant improvements in
EF domain scores and significant improvements in SEAR SE domain scores.
Importantly, there were significant beneficial effects on LUTS as
assessed by the total IPSS, irritative, and obstructive subscores as
well as the IPSS QoL question and the BPHII. Interestingly, increases in
maximal flow rate (Qmax) for the sildenafil group were not significantly
different from those for placebo. Taken together, the results suggested
that sildenafil taken daily improved EF and ameliorated LUTS. The
observed improvements in IPSS were comparable to those achieved using
alpha1-blockers and were accompanied by significant improvements in QoL
measures. The improvements in LUTS with no significant change in Qmax
suggest that a new pathophysiology paradigm may be needed to explain the
etiology of LUTS.[11]
Yet another BPH-related abstract was a preliminary pilot study to
evaluate the effects of alpha-blockers on sexual function. Sadeghi-Nejad
and colleagues[12] identified a cohort of 21 patients (mean age 74.1
years) who had been on combination therapy with terazosin and
finasteride for at least 1 year. The patients' symptoms were evaluated
at identification and 1 month after discontinuing terazosin. Assessments
were made using the IPSS, QoL score, and the Sexual Health Inventory for
Men (SHIM). Patients were asked if they wished to remain off terazosin
after the 1-month period. A matched-pair t-test was applied to the
before and after scores. Discontinuation of terazosin in patients
resulted in worsening of IPSS from a mean of 10.67 ± 5.56 to a mean of
14.81 ± 6.25 (t = 2.50). Changes in QoL scores and sexual function
were not statistically significant after alpha-blocker discontinuation.
Approximately 60% of the patients in this small pilot study elected to
resume combination therapy with alpha-blockers and finasteride. It was
concluded that in patients with severe ED and LUTS, terazosin does not
appear to have a significant effect on EF. These findings await
corroboration in larger randomized studies. Epidemiology, Screening, and
Prognosis
Kupelian and colleagues[13] investigated the relationship between ED and
total testosterone (TT), bioavailable testosterone (BT), sex-hormone
binding globulin (SHBG), and luteinizing hormone (LH). Data were
obtained from the baseline examination of the Massachusetts Male Aging
Study (MMAS), a population-based prospective cohort study of 1709 men
aged 40 to 70 years. The investigators found no association between ED
and TT, BT, or SHBG. An increased risk of ED with higher LH levels was
observed, but the authors suggested that the finding may be indicative
of a relationship between decreased testicular function and ED
independent of testosterone levels.
Laumann and colleagues estimated the effect of sociodemographic status,
health, relationship/psychological, and lifestyle variables on the odds
of having ED by race/ethnicity, based on results from the
cross-sectional population based "Male Attitudes Regarding Sexual
Health" (MARSH) survey, the first nationally representative probability
survey of ED in black, white, and Hispanic men aged 40 years or
older.[14] The authors demonstrated that the relationship between the
variables and ED varied by race/ethnicity; furthermore, the odds ratio
(OR) for ED increased significantly with age, diabetes (2.1),
hypertension (1.6), and moderate (1.6) or severe (6.0) LUTS, and was
decreased significantly by exercise (0.98) and by college vs less than
high school education (0.4).
Gilhooly and colleagues[15] addressed the reliability of homocysteine as
a potential diagnostic marker for ED. Patients suffering from ED (SHIM <
17) and controls (SHIM 22 or higher) were queried for comorbidities
relating to medical and surgical history, medication/ dietary supplement
use, smoking/alcohol history, and other risk factors. Fasting morning
blood specimens for homocysteine, vitamin B6, vitamin ± 2, folate,
copper, testosterone, cholesterol, triglycerides, and HDL/LDL were
collected for each patient. The authors reported that of the 11
predictor variables included in the first regression model, only 1
variable (age) was statistically significant (P = .0066), after
adjusting for the other 10 variables. In this pilot study of 47 patients
with ED and 39 normal controls, there was no significant difference
between mean homocysteine levels in a group of patients with or without
ED. It was concluded that homocysteine is not a good independent
predictor of ED.
Sun and coworkers[16] analyzed a nationally representative managed care
claims database (51 health plans with 28 million members in the United
States) to determine whether ED could be used as an early marker for
diabetes mellitus (DM). To do so, the investigators compared the odds
ratio of having DM between men with ED (n = 285,436) and those without
ED (n = 1,584,230). After adjustment for age, region, and concurrent
diseases, the odds ratio of having DM between men with ED and without ED
was found to be 1.60 (P < .0001). They concluded that ED is a strong
marker of DM in men 45 years of age or younger, a "likely" marker for
men aged between 46 and 65, but not a marker of DM for men older than 66
years.
Longitudinal results from the Massachusetts Male Aging Study on the
natural progression and remission of ED were presented by Travison and
colleagues.[17] They reported that initial ED severity is significantly
associated with the likelihood of progression or remission (total
remission occurred more frequently among men with mild ED than with
moderate or complete (32% vs 23%, P = .04) and full progression was more
common among men with moderate ED than with mild (32% vs 20%, P = .02).
Age, body mass index, and availability of a sexual partner were
associated with remission when controlling for other covariates.
Importantly, however, they noted that even some men with complete ED may
experience total remission, particularly younger men with lower BMI, or
who gain a sexual partner. Priapism
Burnett and colleagues[18] examined the role of long-term oral PDE5
inhibitor therapy in the management of recurrent priapism. These
patients, whose recurrent episodes and frequent emergency department
visits are a major disruptive element in their lives, pose an exquisite
challenge to clinicians who manage ED, priapism, and related
pathologies. The authors have proposed dysregulation of PDE5 as a factor
in the pathogenesis of the disorder and investigated the role of
sildenafil or tadalafil in the management of this difficult problem in
men who had priapism episodes as long as 3 to 5 hours daily. Sildenafil
citrate at a 25- or 50-mg oral daily dose in the morning, or tadalafil
at a 5-mg oral dose 3 times weekly in the morning, was administered to 3
men with sickle cell disease-associated priapism recurrences and 1 man
with idiopathic priapism recurrences. With a duration of therapy from 3
to 11 months, the authors observed that episodes of priapism were
reduced to "rare or occasional." The authors concluded that the
beneficial effects of long-term PDE5 therapy for recurrent priapism
proved consistent with the concept of PDE5 dysregulation as a pathogenic
basis for idiopathic and hematologic dyscrasia-related priapism.
Resetting of the erectile regulatory function of PDE5 was suggested as a
potential mechanism for the effects of PDE5 inhibitors in this setting.

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