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Breakthroughs in Andrology |
From the * Department of Urology, Tulane
University Medical Center, New Orleans, Louisiana;
South Florida Medical Research, Aventura,
Florida; Lawrenceville Urology, Lawrenceville,
New Jersey; Bayer Corporation, Pharmaceutical
Division, West Haven, Connecticut; and || The Male
Clinic, Beverly Hills, California.
| Correspondence to: Dr Wayne Hellstrom, Tulane University Medical Center, Department of Urology, 1430 Tulane Ave, New Orleans, LA 70112 (e-mail: whellst{at}tulane.edu). |
| Received for publication June 27, 2002; accepted for publication July 9, 2002. |
Local treatments for ED, including vacuum constriction devices, penile self-injection therapy, transurethral alprostadil, and penile prostheses (Derouet and Zehl, 1993; Padma-Nathan et al, 1997; Purvis et al, 1999; Lue, 2000; Montague and Angermeier, 2000), can restore erectile function (EF), but no single therapy is satisfactory for every patient (Meinhardt et al, 1999; Lue, 2000). These treatment options may often limit patient satisfaction because of their invasiveness, unappealing technique, or side effects (Burnett, 1998). Oral treatments used with variable success by men with ED in various countries have included sildenafil, apomorphine, phentolamine, trazodone, and yohimbine.
Orally administered phosphodiesterase 5 (PDE5) inhibitors have become the
first-line treatment option for ED. Vardenafil is a potent, highly selective
PDE5 inhibitor that shows promise in the oral pharmacotherapy of ED.
VArdenafil is rapidly absorbed with a tmax as early as 0.7
hour (median, 1 hour) and a t
of approximately 4 hours
(Klotz et al, 2001). In a
phase 2 study involving 601 men with ED, vardenafil significantly improved
erections vs placebo (P < .001)
(Porst et al, 2001), with the
percentage of successful intercourse attempts ranging from 71% to 75%. Among
patients taking the 20-mg dose of vardenafil, 80% experienced improved
erections. Vardenafil was effective in men with ED of all etiologies and
severities and was well tolerated and effective in men who were also taking
antihypertensive medications (Porst and
Schmidt, 2001). In recently completed phase 3 studies, vardenafil
significantly improved EF in men with type 1 or 2 diabetes mellitus
(Goldstein et al, 2001), as
well as in men with a history of radical prostatectomy
(Brock et al, 2002), both of
which are challenging to treat populations.
This pivotal study conducted in the United States and Canada was undertaken to determine the efficacy and safety of vardenafil in a broad population of men with ED of various etiologies and severity.
Study Design
This study was conducted in 54 study centers in the United States and
Canada. This phase 3, multicenter, randomized, double-blind,
placebo-controlled, 4-arm, parallel-group, fixed-dose comparison of vardenafil
5, 10, and 20 mg vs placebo consisted of 3 phases: 1) a 4-week baseline period
in which no treatment or device for ED was allowed; 2) randomization (by
random code generation at Bayer Corporation) to 26 weeks of treatment with
vardenafil or placebo; and 3) a 1-week follow-up for continued monitoring of
adverse events. The study was conducted with Institutional Review
Board/Independent Ethics Committee approval and with signed, written, informed
consent from all patients.
Inclusion Criteria
Eligible patients were men 18 years of age or older experiencing ED, which
was defined as the inability to achieve or maintain a penile erection
sufficient for satisfactory sexual intercourse, for more than 6 months in
duration. To be enrolled in the treatment phase of the study, patients were
required to have experienced a 50% or greater failure rate in maintaining an
erection sufficient to complete intercourse on at least 4 separate attempts
over the 4-week treatment-free baseline period.
Exclusion Criteria
Conditions that precluded study entry included anatomic abnormalities of
the penis that could impair EF, hypoactive sexual desire, a history of radical
prostatectomy, ED after spinal cord injury, retinitis pigmentosa, unstable
angina pectoris, uncontrolled atrial tachyarrhythmia, or, within the previous
6 months, any myocardial infarction, stroke, electrocardiographic ischemia, or
life-threatening arrhythmia. Patients were excluded if they had symptomatic
postural hypotension within 6 months prior to screening, resting hypotension
(systolic blood pressure [SBP] <90 mm Hg), hypertension (resting SBP
>170 mm Hg or diastolic blood pressure [DBP] >110 mm Hg), a history of
hepatitis B surface antigen or hepatitis C, severe chronic liver disease or
abnormalities, chronic hematologic disease, bleeding disorder, poorly
controlled diabetes mellitus (hemoglobin A1c >12%), inadequately treated
hyperthyroidism or hypothyroidism, or a history of peptic ulcer disease within
1 year of screening. Also excluded were patients with a history of malignancy
within the previous 5 years, low serum testosterone levels (defined as the
lower limit of normal, according to the range of laboratories that
participated in the study, which was at least 10 nmol/L), serum creatinine
values >2.5 mg/dL, any investigational drug usage within 30 days of
screening, and sildenafil or other therapy for ED within 7 days of screening.
Previous sildenafil treatment was allowed if patients reported improvements in
EF while on sildenafil. Nitrate medication was strictly contraindicated.
Antiandrogens, anticoagulants, androgens, and trazodone hydrochloride were not
allowed.
Treatment
Patients were instructed to take study medication approximately 1 hour
before intended sexual intercourse and were given no special instruction in
regard to food or alcohol use. Not more than a single dose of the study drug
was permitted per calendar day. Medication use was monitored from the
patients' medication/outcome diaries and pill counts performed by study
personnel during assessment visits.
Efficacy Variables
The intent-to-treat (ITT) population consisted of all patients who had
received at least 1 dose of study medication and who had received at least 1
efficacy assessment. The primary efficacy measures were EF domain score
(questions 1-5 and 15) of the International Index of Erectile Function (IIEF)
questionnaire after 12 weeks of treatment and patients' responses to 2 diary
questions ("Were you able to insert your penis into your partner's
vagina?" and "Did your erection last long enough for you to have
successful intercourse?"). The mean success rate for each patient was
calculated from the start of the study drug to week 12, the a priori primary
endpoint. In addition, as secondary endpoints, these variables were determined
at weeks 4, 8, 18, and 26. The additional secondary efficacy measure reported
here was the response by patients completing weeks 12 and 26 of treatment to
the following Global Assessment Question (GAQ): ("Has the treatment you
have taken over the past 4 weeks improved your erections?").
Safety
All patients who had received at least 1 dose of study medication and had
postbaseline safety data were evaluated for adverse events. For each adverse
event, the investigator assessed its seriousness, intensity (mild, moderate,
or severe), and relationship to study medication (none, unlikely, possible,
probable, or indeterminate). A full physical examination was performed at
screening, and abbreviated examinations (including a 12-lead
electrocardiogram) were performed at weeks 12 and 26 following commencement of
therapy. Routine laboratory tests and vital sign determinations were performed
at screening, at baseline, and during treatment (weeks 4, 12, 18, and 26 or at
premature discontinuation). On certain office visits, patients were asked to
take vardenafil prior to being seen in the office in order to take
measurements within an optimal window of drug activity defined as 11 minutes
to 5 hours after oral ingestion.
Statistical Methods: Efficacy Analysis
The primary IIEF efficacy variables were tabulated, followed by analysis of
covariance testing with baseline values as a covariate and terms for center
and treatment. The interactions between treatment and center by treatment were
determined to be insignificant. Testing of hypotheses included comparisons of
each vardenafil dosage group vs placebo; therefore, a Bonferroni adjustment
was used, with statistical significance being considered a P value
less than .0167. Least-squares mean EF domain scores were assessed as last
observation carried forward (LOCF) to account for patient dropouts. The mean
value for each treatment group was calculated from each individual's success
rate for each diary question. Responses to the GAQ were analyzed using
logistic regression. Retrospective analysis was also performed to determine
the percentage of patients reaching EF domain scores consistent with normal EF
(
26), stratified by treatment group and baseline EF score
(Cappelleri et al, 1999).
Statistical significance was defined as P less than or equal to .05
for all secondary efficacy variables.
The number of patients evaluated in this study was based on all 3 primary efficacy variables. Sample size calculations assumed a standard deviation of 10.3 for EF domain scores and 35% for the diary questions. Treatment differences considered to be clinically significant were 5 points for the EF domain score and 18% for the diary questions. With approximately 143 valid patients per group, this study had the power of approximately 95% for the EF domain score and the power of approximately 97.5% for the diary questions. This yielded a lower bound to the power of the study of 90%. Allowance of a 10% dropout rate in the first month required 159 randomized patients for the efficacy analysis. However, to obtain 6-month safety data on 150 patients at the highest dose, the number of patients randomized was increased to 200 patients per group (assuming an overall 25% dropout rate).
Statistical Methods: Safety Analysis
Rates of discontinuations, adverse events, and laboratory and
electrocardiographic abnormalities, as well as measurements and changes from
baseline in blood pressure and heart rate, were recorded.
Patient Population and Demographics
This study was conducted from March 29, 2000 (first patient, first visit),
to March 2, 2001 (last patient, last visit). Eight hundred five men at 54
study centers completed baseline evaluations and were randomized to treatment
with either placebo (n = 197) or vardenafil 5 mg (n = 205), 10 mg (n = 206),
or 20 mg (n = 197). Over the course of 26 weeks of therapy, 37% of all
patients (297 of 805) discontinued (Figure
1). Of patients randomized to placebo, 54% discontinued, most
commonly because of insufficient therapeutic effect (20%). Of patients
randomized to vardenafil, 31% discontinued, with the most common cause being
insufficient therapeutic effect (13%) in the 5-mg group, lost to follow-up
(10%) in the 10-mg group, and adverse events (8%) in the 20-mg group. Seven
hundred sixty-two men were valid for safety, and 749 men were valid for the
ITT analysis.
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At baseline, there were no clinically meaningful differences between treatment groups with respect to any demographic or clinical variables (Table 1). Overall, patients were diagnosed with ED a mean of 3.6 years prior to screening and experienced symptoms of ED an average of 2.3 years before the clinical diagnosis was made (time of first noticed ED minus time since ED first diagnosed). Sildenafil had been used previously by 71% (544 of 762), all of whom experienced improved erections during this treatment. Only 15 of 506 screening failures were due to failure to respond to sildenafil. Prior use of other medications for ED or devices for erectile enhancement was infrequent. The treatment groups were well balanced in terms of medical history (Table 1). Findings at screening with overall rates greater than 10% were hypertension (37%), pure hypercholesterolemia (24%), prostatic hyperplasia (20%), type 2 diabetes (18%), esophageal reflux (12%), and allergy (12%).
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Efficacy: EF Domain, Penetration Success, and Intercourse
Completion
At baseline, the mean EF domain score ranged between 13 and 14 and was
consistent with moderate ED. At baseline, less than 10% of patients had mild
ED, while the proportion of patients with severe ED ranged between 30% and 45%
of the population in each treatment arm
(Table 1).
The primary efficacy measures, the EF domain and mean success rates of
penetration and maintained erections to completion of intercourse after 12
weeks of treatment, indicated significant superiority of all vardenafil doses
over placebo (P < .0001) (Figures
2 and
3). For those receiving
vardenafil 20 mg, the mean EF domain score increased from 12.8 at baseline to
21.4 at week 12, the mean successful penetration rate increased from 40.9% at
baseline to 80.5% at week 12, and the mean ability to maintain an erection for
successful intercourse increased from 14.7% at baseline to 64.5% at week 12.
Similar results were obtained for comparisons of EF domain items and diary
responses at other postbaseline assessments. All groups showed continued
improvements vs baseline throughout the 26-week treatment period, and
differences between scores for placebo-treated patients and those randomized
to vardenafil remained significant at 26 weeks (P 
.001).
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Improvements in primary efficacy scores were dose related. Notably, at week 12 following randomization, improvements in EF domain scores were significantly higher for the 10- and 20-mg vardenafil dosing groups than for the 5-mg group (P < .01 and P < .001, respectively). The superior efficacy of vardenafil 10 and 20 mg over the 5-mg dose was maintained at week 26 (P < .0001).
Efficacy: Return to Normal EF
The ability of vardenafil to bring patients with ED to normal function (EF
domain score 26) was apparent irrespective of baseline severity
(Figure 4). For patients having
mild ED (EF domain scores of 22-25), between 79% and 89% of those receiving
vardenafil 20 and 10 mg, respectively, returned to normal function.
Importantly, 39% of patients with severe ED (EF domain scores 10) achieved
normal EF after receiving 20 mg vardenafil compared to only 4% on placebo.
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Efficacy: GAQ
The proportion of responders, defined as those in the ITT population who
affirmatively answered the GAQ, was significantly higher for all groups of
patients treated with vardenafil than for those treated with placebo
(P < .0001) (Figure
5). For this variable, there was also a dose-related difference in
response between 5, 10, and 20 mg. At 12 weeks, 64.5% of those receiving
vardenafil 5 mg, 72.9% of those receiving vardenafil 10 mg, and 80.9% of those
receiving vardenafil 20 mg described a positive response to the GAQ vs 38.6%
of those receiving placebo (P .0001). Corresponding results for
those who completed 26 weeks of therapy were 64.9% for those who received 5 mg
vardenafil, 79.8% for those who received 10 mg vardenafil, and 85.2% for those
who received 20 mg vardenafil compared with 27.6% of men who received placebo
(Figure 5).
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Safety
In general, treatment with vardenafil was well tolerated. Most of the
treatment-emergent adverse events (TEAEs), regardless of cause, were mild or
moderate in intensity. The incidence of TEAEs considered possibly or probably
related to study treatment increased with the vardenafil dosage with 7%, 19%,
33%, and 42% for patients treated with placebo or vardenafil 5, 10, or 20 mg,
respectively. The most commonly reported TEAEs included headache, rhinitis,
cutaneous flushing, and dyspepsia and are shown in
Table 2. No type of visual
change occurred in more than 2% of patients, with no blue color vision
reported.
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The incidence of serious TEAEs was nearly constant across all groups: 5%, 5%, 3%, and 4% of patients treated with placebo or vardenafil 5, 10, or 20 mg, respectively. One myocardial infarction was reported, which occurred in a patient receiving placebo; no deaths were reported in this study. Discontinuations due to adverse events were infrequent and not obviously related to vardenafil dose (Figure 1). Very few single adverse events led to discontinuations of study medication in more than 1 patient per group (headache [2 patients receiving vardenafil 5 or 20 mg], abnormal liver function tests [3 patients receiving vardenafil 10 mg], nausea [2 patients receiving vardenafil 20 mg], hypesthesia [2 patients receiving vardenafil 10 mg], and kidney calculus [2 patients receiving vardenafil 20 mg]).
Clinical laboratory evaluations revealed sporadic occurrences of low or high values outside the normal range at some interval during the course of treatment, but no clear dose or group relationship was observed. Analysis of laboratory values, changes from baseline, and time-dependent alterations during the 26-week treatment period indicated no relationship between vardenafil treatment and any laboratory abnormalities.
Analysis of vital signs revealed only minor changes from baseline that were generally similar across treatment groups. Mean changes from baseline in heart rate, measured within 11 minutes and 5 hours after taking the treatment, were minor and appeared unrelated to the dose of vardenafil. Mean blood pressure decreases in patients taking 5, 10, or 20 mg vardenafil were small, ranging from -3.6 to -6.6 mm Hg for supine SBP, from -3.5 to -6.5 mm Hg for standing SBP, from -3.5 to -4.8 mm Hg for supine DBP, and from -2.1 to -4.5 mm Hg for standing DBP. For placebo, changes in baseline were -0.4 mm Hg for supine and standing SBP, -0.7 for supine DBP, and -1.3 for standing DBP.
The percentage of patients with electrocardiographic abnormalities was similar across treatment groups; there was no evidence of an increase in abnormalities from placebo to vardenafil 20 mg and no clinically notable differences in electrocardiographic parameters between the vardenafil groups and the placebo group. Results obtained within 5 hours of dosing indicated no dose-dependent abnormalities in electrocardiographic parameters. Moreover, at the 26-week visit, changes from baseline in PR, QRS, and QT intervals were similar across all treatment groups.
Comment
The results of this study indicate that vardenafil dosages of 5, 10, and 20
mg were significantly superior to placebo for the treatment of ED, on the
basis of the primary study endpoints of the EF domain score of the IIEF and
diary-recorded success rates for penetration and maintenance of erection
during intercourse. In addition, all vardenafil doses were nearly always
significantly superior to placebo on the basis of the secondary study
endpoints and the GAQ. For those receiving vardenafil 20 mg, the mean EF
domain score increased from 12.8 (moderate, on average) at baseline to 21.4
(mild level of ED, on average) at week 12. Of note, in patients taking 20 mg
vardenafil, the perpatient success rate of penetration nearly doubled from 41%
at baseline to 80% at week 12, and the ability to maintain an erection for
successful intercourse increased fourfold from 15% at baseline to 65% at week
12 (all P < .0001 vs placebo). In addition, 81% of those receiving
vardenafil 20 mg gave a positive response to the GAQ at week 12 vs 39% of
those receiving placebo (P < .0001). Efficacy was maintained over
the next 14 weeks, resulting in 85% of men using vardenafil 20 mg having
reported improved erections at 26 weeks. Importantly, vardenafil 20 mg enabled
a considerable percentage of patients to achieve normal EF: 79% of patients
with mild ED and up to 39% of patients with severe ED who received vardenafil
20 mg achieved normal EF (based on EF domain scores 26)
(Cappelleri et al, 1999).
The results of the current study extend previous findings for vardenafil. Pharmacokinetic/pharmacodynamic studies demonstrated the rapid absorption of vardenafil and a doubling of the duration of penile rigidity over placebo (Klotz et al, 2001; Stark et al, 2001). In phase 2 studies, vardenafil 5, 10, and 20 mg significantly improved erectile functioning, including vaginal penetration and maintenance of erection, in men with mild to severe ED of all etiologies (Porst et al, 2001). Vardenafil has also been shown to be effective in men with either type 1 or 2 diabetes mellitus (Goldstein et al, 2001).
Vardenafil was well tolerated. The adverse events noted most often with its use—headache, rhinitis, cutaneous flushing, and dyspepsia—were expected based on the pharmacology of PDE5 inhibitors and on clinical trials with other PDE5 inhibitors (Padma-Nathan et al, 2001; Padma-Nathan and Giuliano, 2001). Importantly, only small percentages of patients discontinued during the 6-month study period because of adverse events. These results are consistent with those previously reported for vardenafil (Porst et al, 2001). Nearly all of the adverse events recorded for patients in the trial reported here were mild or moderate in severity and typically resolved with continued use of vardenafil.
Although PDE5 inhibitors have demonstrated good safety and tolerability in a large number of controlled clinical trials, as well as in clinical practice, the vasodilatory effects of these drugs may have safety implications in patients with ED and cardiovascular disease. In this study, changes in vital signs with vardenafil were minor and were generally similar across treatment groups.
There are 2 potential limitations of this study. First, patients with a history of failing sildenafil therapy were specifically excluded from the trial. However, this represented only 15 of 257 men who were specifically excluded by the study investigators prior to randomization. It is therefore unlikely that exclusion of this low percentage of subjects from the study would have significantly affected the overall study findings. The second limitation may be the imbalance between the large number of patients in the placebo group who discontinued because of lack of treatment efficacy and the much smaller number of vardenafil-treated patients who stopped treatment for this reason. This difference could potentially have biased the results to demonstrate a placebo effect in those patients completing the study. However, for the measurement of the EF domain, the LOCF approach to analysis of the data was employed to address this limitation.
In conclusion, in a broad population of men with ED of various etiologies and severity, vardenafil safely and consistently improved all efficacy parameters of EF, improving erections and satisfaction in up to 85% of men treated for 26 weeks and restoring normal EF in up to 89% of men with mild ED and in 39% of men with severe ED.
Acknowledgments
Data Access and Responsibility: All authors of this study have had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis (see accompanying statements).
Funding/Support: This research was supported by Bayer Corporation, Pharmaceutical Division, West Haven, Conn, and Bayer Inc, Toronto, Calif.
Members of the Vardenafil Study Group: Randall P. Abele, MD (Edmonton Prostate Centre, Edmonton, Alberta); Gerald L. Andriole, MD (Washington University School of Medicine, St Louis, Mo); Stephen M. Auerbach, MD (California Professional Research, Newport Beach, Calif); Jack Barkin, MD (Toronto, Ontario); Winston Barzell, MD (Urology Treatment Center, Sarasota, Fla); Donald Bergner, MD (Tampa Bay Medical Research Inc, Clearwater, Fla); Richard Casey, MD (Male Health Centres, Oakville, Ontario); Stacy Childs, MD (Wyoming Research Foundation, Cheyenne, Wyo); Selwyn Cohen, MD (Clinical Research Consultants Inc, Trumbull, Conn); David O. Cook, MD (Piedmont Medical Research Associates Inc, Winston-Salem, NC); Jeoffrey Deeths, MD (Nebraska Clinical Research Center, Omaha, Neb); Craig F. Donatucci, MD (Duke University Medical Center, Durham, NC); Mostafa M. Elhilali, MD (Royal Victoria Hospital, Montreal, Quebec); Pamela I. Ellsworth, MD (Dartmouth Hitchcock Medical Center, Division of Urology, Lebanon, NH); Howard B. Epstein, MD (University of Florida, Jacksonville, Health Science Center, Jacksonville, Fla); Robert A. Feldman, MD (Urology Specialists, PC, CT Clinical Research Center, Waterbury, Conn); Louis Fields, MD (Thornhill, Ontario); Roger Fincher, MD (Spokane, Wash); William Fitch III, MD (Urology Consultants, PA, San Antonio, Tex); Jenelle E. Foote, MD (Midtown Urology, Atlanta, Ga); Jeffrey Frankel, MD (Seattle, Wash); Harold A. Fuselier, MD (Ochsner Foundation Hospital, Ochsner Clinic, Department of Urology, New Orleans, La); Larry I. Gilderman, DO (University Clinical Research Associates Inc, Pembroke Pines, Fla); Marc Gittelman, MD (South Florida Medical Research, Aventura, Fla); Evan Goldfischer, MD (Hudson Valley Urology Center, Poughkeepsie, NY); James E. Gottesman, MD (Seattle Urological Associates, Seattle, Wash); Fred Govier, MD (Virginia Mason Medical Center, Department of Urology, Seattle, Wash); Michael Greenspan, MD (Hamilton & District Urology Association, Hamilton, Ontario); Wayne J. Hellstrom, MD (Tulane University Medical Center, New Orleans, La); Charles B. Herring, MD (New Hanover Medical Research Associates, Wilmington, NC); Gary S. Karlin, MD (Lawrenceville Urology, Lawrenceville, NJ); Joel M. Kaufman, MD (Urology Research Options, Aurora, Colo); Robert J. Krane, MD (Massachusetts General Hospital, Department of Urology, Boston, Mass); John N. Krieger, MD (A Puget Sound Health Care System, Section of Urology, Seattle,Wash); Alan Lau, MD (University of Illinois at Chicago, Chicago, Ill); William A. Leitner, MD (Urology Centers of Alabama, PC, Birmingham, Ala); Joel Lilly, MD (Seattle Urological Associates, Seattle, Wash); Jack Lubensky, MD (Radiant Research Inc, Center for Clinical Research, Austin, Tex); Nizamuddin Maruf, MD (MidAtlantic Clinical Research Center, Rockville, Md); Keith Matthews, MD (Uromed, Montreal, Quebec); Andrew McCullough, MD (New York University Medical Center, Urology Research, New York, NY); Kevin T. McVary, MD (Northwestern Center for Clinical Research, Chicago, Ill); Arnold Melman, MD (Montefiore Medical Center, Department of Urology, Bronx); William B. Monnig, MD (The Urology Group, Cincinnati, Ohio); Craig Niederberger, MD (University of Illinois at Chicago, Chicago, Ill); Harin Padma-Nathan, MD (The Male Clinic, Beverly Hills, Calif); Allan B. Patrick, MD (Fredericton, New Brunswick); Jon Lee Peterson, MD (Health Advance, nTouch Research, Houston, Tex); Peter J. Pommerville, MD (Victoria, British Columbia); V. Gary Price, MD (North Texas Clinical Research, Fort Worth, Tex); George Raad, MD (Metrolina Medical Research Associates, Charlotte, NC); Paul R. Sieber, MD (Urological Associates of Lancaster, Lancaster, Pa); Alan W. Skolnick, MD (Health Advance Touch Research, Houston, Tex); Christopher P. Steidle, MD (Northeast Indiana Research, Fort Wayne, Ind); Cecile Storrie, MD (MDS Harris Inc, Dallas, Tex); David Talley, MD (Urology San Antonio Research, PA, San Antonio, Tex); Joseph J. Tepas, MD (University of Florida, Jacksonville Health Science Center, Jacksonville, Fla); Timothy S. Truitt, MD (Health Advance Institute, Melbourne, Fla); Luc Valiquette, MD (Hopital St Luc, Montreal, Quebec); Alexander Vukasin, MD (Urology Group of Princeton, PA, Princeton, NJ); Mitchell Wiatrak, MD (Midwest Research Specialists, Milwaukee, Wis); John Williams, MD (University of Florida, Jacksonville Health Science Center, Jacksonville, Fla); Rafael Wurzel, MD (Grove Hill Medical Center, New Britain, Conn); Joseph Zadra, MD (Barrie, Ontario).
The authors thank Kenneth Pomerantz, PhD, and HeĞle`ne Dassule, PhD, for editorial assistance.
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A. Tsertsvadze, H. A. Fink, F. Yazdi, R. MacDonald, A. J. Bella, M. T. Ansari, C. Garritty, K. Soares-Weiser, R. Daniel, M. Sampson, et al. Oral Phosphodiesterase-5 Inhibitors and Hormonal Treatments for Erectile Dysfunction: A Systematic Review and Meta-analysis Ann Intern Med, November 3, 2009; 151(9): 650 - 661. [Abstract] [Full Text] [PDF]
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A. Tsertsvadze, H. A. Fink, F. Yazdi, R. MacDonald, A. J. Bella, M. T. Ansari, C. Garritty, K. Soares-Weiser, R. Daniel, M. Sampson, et al. Oral Phosphodiesterase-5 Inhibitors and Hormonal Treatments for Erectile Dysfunction: A Systematic Review and Meta-analysis Ann Intern Med, October 19, 2009; (2009) 0000605-200911030-00150v1. [Abstract] [Full Text]
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A. Qaseem, V. Snow, T. D. Denberg, D. E. Casey Jr., M. A. Forciea, D. K. Owens, P. Shekelle, and for the Clinical Efficacy Assessment Subcommittee Hormonal Testing and Pharmacologic Treatment of Erectile Dysfunction: A Clinical Practice Guideline From the American College of Physicians Ann Intern Med, October 19, 2009; (2009) 0000605-200911030-00151v1. [Abstract] [Full Text]
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 A. Nehra Erectile Dysfunction and Cardiovascular Disease: Efficacy and Safety of Phosphodiesterase Type 5 Inhibitors in Men With Both Conditions Mayo Clin. Proc., February 1, 2009; 84(2): 139 - 148. [Abstract] [Full Text] [PDF]
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 E. C. Serefoglu, A. F. Atmaca, B. Dogan, S. Altinova, Z. Akbulut, and M. D. Balbay Problems in Understanding the Turkish Translation of the International Index of Erectile Function J Androl, July 1, 2008; 29(4): 369 - 373. [Abstract] [Full Text] [PDF]
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 F. Giuliano, E. Rubio-Aurioles, M. Kennelly, F. Montorsi, E. D. Kim, A. E. Finkbeiner, P. J. Pommerville, M. W. Colopy, H. J. Wilkins, B. H. Wachs, et al. Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury Neurology, January 24, 2006; 66(2): 210 - 216. [Abstract] [Full Text] [PDF]
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L. Valiquette, J. M. Young, I. Moncada, H. Porst, J.-G. Vezina, B.-N. Stancil, K. Edmunds, F. Montorsi, and Vardenafil Study Group Sustained Efficacy and Safety of Vardenafil for Treatment of Erectile Dysfunction: A Randomized, Double-Blind, Placebo-Controlled Study Mayo Clin. Proc., October 1, 2005; 80(10): 1291 - 1297. [Abstract] [PDF]
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W. J. G. Hellstrom, M. Elhilali, M. Homering, T. Taylor, and M. Gittleman Vardenafil in Patients With Erectile Dysfunction: Achieving Treatment Optimization J Androl, September 1, 2005; 26(5): 604 - 609. [Abstract] [Full Text] [PDF]
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 R. A. Kloner Cardiovascular Effects of the 3 Phosphodiesterase-5 Inhibitors Approved for the Treatment of Erectile Dysfunction Circulation, November 9, 2004; 110(19): 3149 - 3155. [Full Text] [PDF]
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 S. Hood and M. Kirby Review: PDE-5 inhibitors -- a summary The British Journal of Diabetes & Vascular Disease, November 1, 2004; 4(6): 383 - 386. [Abstract] [PDF]
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 C. C. Carson Erectile Dysfunction: Evaluation and New Treatment Options Psychosom Med, September 1, 2004; 66(5): 664 - 671. [Abstract] [Full Text] [PDF]
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 New oral drugs for erectile dysfunction DTB, July 1, 2004; 42(7): 49 - 52. [Abstract] [Full Text] [PDF]
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 A. Morgentaler A 66-Year-Old Man With Sexual Dysfunction JAMA, June 23, 2004; 291(24): 2994 - 3003. [Full Text] [PDF]
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 S. M Crowe and D. S Streetman Vardenafil Treatment for Erectile Dysfunction Ann. Pharmacother., January 1, 2004; 38(1): 77 - 85. [Abstract] [Full Text] [PDF]
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 I. Goldstein, J. M. Young, J. Fischer, K. Bangerter, T. Segerson, and T. Taylor Vardenafil, a New Phosphodiesterase Type 5 Inhibitor, in the Treatment of Erectile Dysfunction in Men With Diabetes: A multicenter double-blind placebo-controlled fixed-dose study Diabetes Care, March 1, 2003; 26(3): 777 - 783. [Abstract] [Full Text] [PDF]
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 P. Rajagopalan, A. Mazzu, C. Xia, R. Dawkins, and P. Sundaresan Effect of High-Fat Breakfast and Moderate-Fat Evening Meal on the Pharmacokinetics of Vardenafil, an Oral Phosphodiesterase-5 Inhibitor for the Treatment of Erectile Dysfunction J. Clin. Pharmacol., March 1, 2003; 43(3): 260 - 267. [Abstract] [Full Text] [PDF]
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