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Sildenafil for Male Erectile Dysfunction
A Systematic Review and Meta-analysis
Howard A. Fink, MD, MPH;
Roderick Mac Donald, MS;
Indulis R. Rutks, BS;
David B. Nelson, PhD;
Timothy J. Wilt, MD, MPH
Arch Intern Med. 2002;162:1349-1360.
ABSTRACT
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Objective To determine the efficacy and safety of sildenafil citrate in the treatment
of male erectile dysfunction.
Data Sources The MEDLINE, HealthSTAR, Current Contents, and Cochrane Library databases
(January 1, 1995, through December 31, 2000); bibliographies of retrieved
articles and review articles; conference proceedings abstracts; the Food and
Drug Administration Web site; and the manufacturer.
Study Selection Trials were eligible if they included men with erectile dysfunction,
compared sildenafil with control, were randomized, were of at least 7 days'
duration, and assessed clinically relevant outcomes.
Data Extraction Two reviewers independently evaluated study quality and extracted data
in a standardized fashion.
Data Synthesis Twenty-seven trials (6659 men) met the inclusion criteria. In results
pooled from 14 parallel-group, flexible as-needed dosing trials, sildenafil
was more likely than placebo to lead to successful sexual intercourse, with
a higher percentage of successful intercourse attempts (57% vs 21%; weighted
mean difference, 33.7; 95% confidence interval [CI], 29.2-38.2; 2283 men)
and a greater percentage of men experiencing at least 1 intercourse success
during treatment (83% vs 45%; relative benefit increase, 1.8; 95% CI, 1.7-1.9;
2205 men). In data pooled from 6 parallel-group, fixed-dose trials, efficacy
appeared slightly greater at higher doses. Treatment response appeared to
vary between patient subgroups, although relative to placebo, sildenafil significantly
improved erectile function in all evaluated subgroups. In trials with parallel-group
design and flexible dosing, men randomized to receive sildenafil were less
likely than those receiving placebo to drop out for any reason and no more
likely to drop out due to an adverse event or laboratory abnormality. Specific
adverse events with sildenafil included flushing (12%), headache (11%), dyspepsia
(5%), and visual disturbances (3%); all adverse events were significantly
less likely to occur with placebo. Sildenafil was not significantly associated
with serious cardiovascular events or death.
Conclusions Sildenafil improves erectile function and is generally well tolerated.
Treatment response seems to vary between patient subgroups, although sildenafil
has greater efficacy than placebo in all evaluated subgroups.
INTRODUCTION
ERECTILE DYSFUNCTION (ED) is defined as the persistent "inability to
achieve or maintain an erection sufficient for satisfactory sexual performance."1 While ED is not life threatening, it may result in
withdrawal from sexual intimacy and reduced quality of life.2-6
Although prevalence estimates for ED vary, up to 30 million men in the United
States may be affected.1 A recent study6 found that 7% of men aged 18 to 29 years have trouble
achieving or maintaining an erection, with prevalence rising to 18% for men
aged 50 to 59 years. Elsewhere, half of all men aged 40 to 70 years were found
to have some degree of ED, with nearly 10% of these men having complete ED.7 Furthermore, the prevalence of ED increased with diabetes
mellitus, heart disease, hypertension, smoking, and depression. Erectile dysfunction
also may be caused by spinal cord injury, prostate surgery, and the use of
certain medications.
Normal erectile function relies on the coordination of psychologic,
neurologic, endocrine, vascular, and muscular factors. Problems with any of
these elements—secondary to disease, psychogenic stress, or drug adverse
effects—may contribute to ED. Most cases of ED are believed to be multifactorial.
Treatment options for ED include vacuum constriction devices, penile
implants, vasoactive injection therapy,8-9
transurethral alprostadil therapy,10-11
and oral therapies. Men have demonstrated a strong preference for oral treatments
even if they have lower efficacy,12-13
suggesting that efforts to optimize treatment of ED not only should target
physiologic and clinical measures of improvement but also should address patient
and partner satisfaction and preference.
Sildenafil citrate (Viagra; Pfizer, Inc, New York, NY) is an oral agent
that is approved by the Food and Drug Administration for the treatment of
ED. It affects erectile function by selectively inhibiting phosphodiesterase
type 5, the enzyme responsible for degradation of cyclic guanosine 3',5'-monophosphate
in the corpora cavernosa. This enhances the effect of endogenous nitric oxide,
producing penile smooth muscle relaxation, arterial dilation, and inflow of
blood, leading to penile engorgement. Sildenafil use does not enhance libido
or normal erectile function, and it rarely produces erections in the absence
of sexual stimulation. The manufacturer's recommended treatment dose is 50
to 100 mg taken 30 to 60 minutes before desired sexual activity.
Many randomized controlled trials have evaluated sildenafil for the
treatment of men with ED. However, we are unaware of any systematic review
and quantitative meta-analysis that has formally evaluated the efficacy and
safety of sildenafil therapy. Therefore, we conducted this systematic review
and meta-analysis to estimate the magnitude of treatment benefits and adverse
effects associated with sildenafil treatment in men with ED, overall and for
those with comorbid conditions.
MATERIALS AND METHODS
LITERATURE SEARCH
Trials were identified by searching the MEDLINE, HealthSTAR, Current
Contents, and Cochrane Library computer databases (January 1, 1995-December
31, 2000). The search strategy included the key terms "impotence" or "erectile
dysfunction," combined with "sildenafil," "Viagra," and "UK-92,480," and limited
by combination with the terms "clinical trial," "controlled trial," "randomized
controlled trial," and "multicenter study." In addition, bibliographies of
retrieved trials and review articles were reviewed, and urology journals and
national meeting abstracts published through December 31, 2000, were hand
searched. The Cochrane Controlled Trials Register also was screened for additional
trials. All trials identified were written in English. Data for unpublished
trials and supplemental data for published trials were obtained from the manufacturer
and the Food and Drug Administration Web site.
SELECTION CRITERIA
Trials were eligible if they (1) included men with ED, (2) were randomized,
(3) compared sildenafil with placebo or active control, (4) were at least
7 days in duration, and (5) assessed clinical outcomes related to ED (eg,
success of sexual intercourse attempts and participant global assessment of
treatment). For each trial, 2 reviewers (H.A.F., R.M., I.R.R.) independently
assessed study eligibility. Differences in eligibility assessments were resolved
by discussion.
OUTCOME MEASURES
Information on trial characteristics, patient demographics, inclusion
and exclusion criteria, dropouts, treatment efficacy, and adverse events were
extracted by 2 independent reviewers (H.A.F., R.M., I.R.R.) in a standardized
fashion.
Because we judged successful sexual intercourse to be the most clinically
relevant measure of treatment efficacy, our primary outcome was the percentage
of all sexual intercourse attempts that were successful. Trials reporting
this measure collected data on intercourse attempts and successes from participants'
event logs. An intercourse attempt constituted each instance when a participant
took the study medication and reported whether he subsequently had successful
sexual intercourse. Sexual intercourse success was defined as vaginal penetration
that the participant found satisfactory (ie, erection was sufficiently hard
and long lasting).
Failure to achieve successful intercourse after use of sildenafil may
not always have been due to failure of the drug to produce an adequate erection
(eg, interruption of sexual activity and drug-associated adverse events).
Therefore, data also were collected to estimate the percentage of successful
intercourse attempts after excluding attempts reported by participants to
have failed for reasons other than an insufficiently hard or long-lasting
erection.
Additional outcomes were the percentage of participants achieving successful
intercourse at least once during treatment; the percentage of participants
reporting improvement in erectile function, with improvement possibly but
not necessarily indicating the ability to reliably achieve successful intercourse;
and responses to questions 3 and 4 of the previously validated International
Index of Erectile Function (IIEF).14
For adverse effects, we examined the percentage of men reporting adverse
effects and the percentage of men withdrawing from the trial. Missing or additional
information was sought from authors and sponsors.
ASSESSMENT OF METHODOLOGIC QUALITY
We assessed the quality of concealment of randomized treatment allocation
according to a scale developed by Schulz et al,15
assigning 1 to poorest quality and 3 to best quality. In addition, we assessed
whether trial participants and investigators were aware of treatment provided,
whether trials used an intention-to-treat analysis, and the percentage of
participants who dropped out or were lost to follow-up.
STATISTICAL ANALYSIS
For assessment of categorical treatment outcomes, we determined the
percentage of men achieving each outcome according to treatment assignment.
For measures of efficacy, we calculated weighted relative benefit increases
(RBIs) and their 95% confidence intervals (CIs) using RevMan 4.0 software.16 For adverse events and withdrawals, we determined
the percentage of men achieving each outcome according to treatment assignment
and the weighted relative risk increases (RRIs) and their 95% CIs. For assessment
of continuous outcomes, we determined the mean value (ie, percentage of successful
attempts and IIEF value) for men in each treatment group and calculated weighted
mean differences (WMDs) and their 95% CIs. Weighted RBIs, weighted RRIs, and
WMDs were estimated using random effects meta-analyses.
Results presented for each outcome measure are those directly available
from articles reviewed and from the manufacturer. However, because available
results excluded randomized participants not reporting data for a particular
outcome, sensitivity analyses were performed for all efficacy outcome measures.
In these analyses, men with missing data were assumed, on average, to have
experienced no change in erectile function between baseline and the end of
treatment. Specifically, the distributions of missing baseline and end-of-treatment
values were assumed to be equivalent to the distribution of baseline values
for men assigned to the same treatment group who provided baseline data. These
imputed outcome distributions for men with no data were then pooled with the
outcome distributions for men with data, and the analyses described in this
subsection were repeated.
Data from fixed-dose studies suggested the presence of a meaningful
dose-response effect for at least some treatment outcomes. Therefore, different
fixed doses were not pooled in meta-analyses. In addition, a clinical decision
was made to perform meta-analysis between trials of similar design only. Trials
that used a parallel-group design, flexible dosing, and administration on
an as-needed basis (PRN) are emphasized in the text primarily because this
is the manner in which sildenafil is used in clinical practice. Efficacy data
for specific subgroups also are derived from parallel-group, flexible-dose
PRN studies. Results were tested for heterogeneity at a significance level
of P<.10.
RESULTS
CHARACTERISTICS OF TRIALS
Twenty-seven trials involving 6659 men met all eligibility criteria
and are included in this systematic review (Table 1). Eleven trials were published in peer-reviewed journals,17-26
4 as abstracts,27-30
and 2 in conference symposiums,31-32
while 3 were available on the Food and Drug Administration Web site as part
of the manufacturer's new drug application.33
Data from the remaining unpublished trials were available only from the manufacturer.
Supplemental data were obtained from the manufacturer for all published trials
except for 1 conducted independently of their sponsorship.23
Although all published trials reported that they were randomized, double blind,
and placebo controlled, just two20, 25
detailed a clearly adequate method of random allocation and concealment of
treatment assignment. Study protocols, obtained from the manufacturer, documented
adequate measures to conceal allocation for 26 trials. In no trial was sildenafil
compared with another active treatment. The most frequent trial design involved
parallel treatment groups and flexible PRN dosing (n = 14). Twenty-six trials
indicated treatment duration (range, 1-26 weeks). Common trial inclusion criteria
were age 18 years and older; ED of at least 3 to 6 months' duration; and involvement
in a stable heterosexual relationship for 6 months or longer. Exclusion criteria
used in most trials included genital anatomic deformity; primary nonerectile
sexual disorder (eg, hypoactive sexual disorder); hyperprolactinemia; hypogonadism;
major psychiatric disorders not well controlled with therapy (including schizophrenia
and major depression); alcohol or substance abuse; major hematologic, renal,
or hepatic abnormalities; spinal cord injury; poorly controlled diabetes mellitus;
recent cardiovascular events (stroke, myocardial infarction, congestive heart
failure exacerbation, unstable angina, or life-threatening arrhythmia within
6 months); uncontrolled hypertension or hypotension (eg, blood pressure >170/100
or <90/50 mm Hg, respectively); active peptic ulcer disease; history of
bleeding disorder; current treatment with nitrates, trazodone hydrochloride,
or androgens; retinitis pigmentosa; intention to donate blood products during
or within 1 month of treatment; and unwillingness to discontinue use of other
treatments for ED.
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Table 1. Characteristics of Included Sildenafil Citrate Trials*
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DEMOGRAPHICS OF PATIENTS
Men in these trials had a mean age of 55 years, with 21% aged 65 years
or older (Table 2). Mean ED duration
was 4.8 years. Baseline ED severity was estimated in 20 trials from scores
of enrolled participants (n = 6161) on the IIEF erectile function domain (range,
0-30). Men scoring 0 to 10 were rated as having severe ED (47%), those scoring
11 to 25 were rated as having mild to moderate ED (45%), and those scoring
26 to 30 were considered to have no ED (3%). Based on their weighted mean
baseline scores for IIEF questions 3 and 4, on average, men were able to achieve
or maintain erections much less than half of the time (IIEF question 3 mean
score, 1.99; IIEF question 4 mean score, 1.68). Approximately half of the
men had purely organic ED, whereas 19% had purely psychogenic ED and nearly
30% had a mixed cause (ie, organic plus psychogenic). The most common comorbid
conditions in men participating in these trials were hypertension (28%), diabetes
mellitus (22%), and ischemic heart disease (10%).
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Table 2. Baseline Characteristics of 6659 Participants*
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EFFICACY OUTCOMES
Overall Efficacy
Use of sildenafil produced a large and statistically significant improvement
in erectile function compared with use of placebo. Treatment benefit was found
for all outcome measures in all patient subgroups evaluated and across all
studies.
For the primary efficacy outcome measure, results indicated that in
the 4 weeks before the end-of-treatment assessment, the mean percentage of
participants' sexual intercourse attempts that were successful was 57% for
men receiving sildenafil compared with 21% for men receiving placebo (WMD,
33.7; 95% CI, 29.2-38.2) (Table 3
and Figure 1). For secondary efficacy
outcome measures, during the 4 weeks before the end-of-treatment assessment,
83% of men in the sildenafil group reported at least 1 successful sexual intercourse
attempt compared with 45% of those receiving placebo (RBI, 1.8; 95% CI, 1.7-1.9)
(Table 3 and Figure 2), and 78% of men receiving sildenafil reported that treatment
"improved" their erections compared with 25% of men allocated to the placebo
group (RBI, 3.1; 95% CI, 2.7-3.5) (Table
3 and Figure 3).
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Table 3. Efficacy Outcomes for Parallel-Group, Flexible-Dose PRN Trials
According to Participant Subgroup*
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Figure 1. Weighted mean differences (WMDs)
in the percentage of sexual intercourse attempts that were successful per
participant. CI indicates confidence interval.
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Figure 2. Relative benefit increases (RBIs)
in the percentage of men reporting at least 1 successful sexual intercourse
attempt during treatment. CI indicates confidence interval.
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Figure 3. Relative benefit increases (RBIs)
in the percentage of men reporting improvement in erections. CI indicates
confidence interval.
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In analyses excluding sexual intercourse attempts reported by the participant
to have failed for reasons other than an insufficiently hard or long-lasting
erection, the percentage of successful attempts was 66% in men receiving sildenafil
and 25% in those receiving placebo (WMD, 39.4; 95% CI, 35.6-43.2) (Table 3). Analyses in which men with missing
end-of-treatment data were assumed, on average, to have experienced no change
from baseline erectile function, and were included with men reporting end-of-treatment
data, produced results similar to the main results for the mean percentage
of successful intercourse attempts and for improvement in erections.
Participants' weighted mean end-of-treatment scores for IIEF question
3 (n = 3291) were 3.8 in men randomized to receive sildenafil vs 2.3 for those
allocated to receive placebo (WMD, 1.4; 95% CI, 1.3-1.5). These scores indicate
that, on average, sildenafil use provided "erections sufficient to penetrate
one's partner" much more than half of the time (compared with much less than
half of the time for the placebo group). For IIEF question 4, mean closeout
scores were 3.6 for men randomized to receive sildenafil vs 2.1 for men allocated
to the placebo group (WMD, 1.5; 95% CI, 1.4-1.6), indicating that "maintenance
of erections during intercourse" was possible more than half of the time for
men receiving sildenafil and much less than half of the time for those receiving
placebo.
Efficacy by Treatment Dose
In data from trials that used a parallel design with fixed PRN dosing,
efficacy of sildenafil across the dosing range used in clinical practice (25-100
mg) appeared slightly greater at higher doses for some efficacy measures (Table 4). The mean percentage per participant
of intercourse attempts that were successful appeared greater at 50 or 100
mg compared with at 25 mg but no different between the 2 higher doses. In
contrast, the percentage of men that reported at least 1 successful sexual
intercourse attempt in the 4 weeks preceding the end-of-treatment assessment
appeared the same with each sildenafil dose. Improvement in erections was
reported more frequently with each increase in treatment dose.
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Table 4. Efficacy Outcomes by Dose for Parallel-Group, Fixed-Dose Studies*
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Efficacy in Patient Subgroups
Subgroup efficacy data are derived mainly from 14 trials that used a
parallel-group design with flexible PRN dosing (Table 3). Data on the likelihood of successful sexual intercourse
attempts are available from 9 of the 14 trials, whereas improvement in erections
was assessed in all 14 trials. Subgroup data for IIEF questions 3 and 4 were
assessed in all 14 trials and are available on request from the authors. Not
all subgroups were represented in every trial. Data for men with spinal cord
injury and men with spina bifida are available only from crossover or fixed-dose
trials. All subgroup data for intercourse success outcomes are presented using
the primary analysis method that considered all intercourse attempts. Analyses
in examined subgroups that excluded intercourse attempts reported to have
failed for reasons other than an insufficiently hard or long-lasting erection
generated WMDs for the percentage of successful attempts that were increased
in favor of sildenafil treatment by 4% to 11% compared with the primary method
(data not shown).
AGE
Although men younger than 65 years appeared to be more likely than older
men to experience improved erections and successful sexual intercourse when
compared within treatment groups, in both age categories, sildenafil treatment
resulted in significantly better outcomes than placebo use. Of men younger
than 65 years, those receiving sildenafil had successful sexual intercourse
during 60% of their attempts (vs 23% for the placebo group; WMD, 34.5; 95%
CI, 29.5-39.5; n = 1836), 85% had at least 1 successful sexual intercourse
attempt during treatment (vs 47% for the placebo group; RBI, 1.7; 95% CI,
1.6-1.9, n = 1779), and 80% reported improved erections with treatment (vs
27% for the placebo group; RBI, 2.9; 95% CI, 2.5-3.3; n = 2777). In comparison,
older men receiving sildenafil had successful intercourse during 46% of attempts
(vs 14% for the placebo group), 74% had at least 1 successful intercourse
attempt during treatment (vs 36% for the placebo group), and 69% reported
improved erections (vs 18% for the placebo group); all differences were statistically
significant (Table 3).
ETHNICITY
Compared with placebo treatment, sildenafil treatment significantly
enhanced intercourse success and improved erections in all ethnic groups evaluated,
with treatment response seeming to be roughly comparable between different
ethnic groups. Among white men, those randomized to receive sildenafil had
successful sexual intercourse during 45% of attempts vs 15% of attempts for
those allocated to the placebo group (WMD, 29.3; 95% CI, 23.3-35.3; n = 755).
Also, 75% of white men receiving sildenafil reported 1 or more successful
attempts at intercourse during treatment (vs 40% for the placebo group; RBI,
1.8; 95% CI, 1.5-2.3; n = 731), and 70% reported improved erections with treatment
(vs 17% for the placebo group).
Asian men receiving sildenafil had successful sexual intercourse during
61% of attempts vs 24% of attempts in those allocated to the placebo group,
with nearly 90% of Asian men in the sildenafil group reporting 1 or more successful
attempts at intercourse during treatment (vs 49% in men receiving placebo)
(Table 3).
Data on intercourse success were available for few black men because
black participants constitute fewer than 5% of all participants in completed
sildenafil trials. Consequently, for all outcome measures, CIs around the
point estimates for the difference in results for black men receiving sildenafil
vs those receiving placebo are wide. Nevertheless, results indicate that black
men randomized to sildenafil use had significantly greater intercourse success
and improvement in erections than did those randomized to placebo use (Table 3).
SEVERITY
Men categorized at baseline as having severe ED appeared less likely
than those with mild to moderate ED to experience improved erections and successful
sexual intercourse when compared within treatment groups. However, for men
in both categories of ED severity, sildenafil treatment produced significantly
better results than placebo treatment for all efficacy outcomes. Men with
mild to moderate ED at baseline who received sildenafil had successful sexual
intercourse during 63% of attempts (vs 28% for the placebo group; WMD, 35.3;
95% CI, 31.7-38.9; n = 1359), with 88% having at least 1 successful intercourse
attempt during treatment (vs 56% for the placebo group) and 87% reporting
improved erections with treatment (vs 36% receiving placebo). Men with severe
ED who received sildenafil had successful sexual intercourse during 47% of
their attempts vs 11% of attempts for men receiving placebo, and they were
more likely to experience at least 1 successful intercourse attempt during
treatment (74% vs 26% for the placebo group) (Table 3). Men with severe ED receiving sildenafil also were more
than 4-fold more likely to report improved erections compared with such men
receiving placebo (RBI, 4.2; 95% CI, 3.5-5.1).
HYPERTENSION AND VASCULAR DISEASE
Men with a self-reported history of hypertension who received sildenafil
had successful sexual intercourse during a mean of 50% of attempts vs 16%
of attempts for men receiving placebo (WMD, 33.3; 95% CI, 26.6-40.0; n = 628)
(Table 3). Three quarters of men
allocated to the sildenafil group experienced at least 1 successful intercourse
attempt during treatment compared with 39% of those randomized to receive
placebo.
Men with ischemic heart disease were significantly more likely to experience
improved erectile function with sildenafil use compared with placebo use for
all measured efficacy outcomes (Table 3). The mean percentage of sexual intercourse attempts that were
successful was 42% for men with ischemic heart disease receiving sildenafil
vs 14% in those receiving placebo (WMD, 23.8; 95% CI, 2.1-45.6; n = 202).
Data on the efficacy of sildenafil treatment relative to placebo treatment
are available for few men with peripheral vascular disease (Table 3). Nevertheless, compared with men receiving placebo, those
receiving sildenafil reported a significantly higher mean percentage of successful
sexual intercourse attempts (57% vs 13%; WMD, 38.8; 95% CI, 18.2-59.4; n =
49) and more often reported improved erections with treatment (70% vs 14%
for the placebo group). Men allocated to receive sildenafil were not significantly
more likely to experience at least 1 successful intercourse attempt during
treatment than were men receiving placebo, although the magnitude of treatment
effect in this small sample was similar to that seen in men overall (86% for
sildenafil vs 40% for placebo; RBI, 1.8; 95% CI, 0.9-3.6; n = 44).
DIABETES MELLITUS
Two trials consisted entirely of men with diabetes mellitus,24-25 whereas a total of 14 trials that
used a parallel-group design and flexible PRN dosing provided subgroup data
on men with diabetes mellitus. In pooled data from the larger group of trials
(Table 3), men receiving sildenafil
had a mean of 44% successful sexual intercourse attempts compared with 16%
for men receiving placebo (WMD, 26.9; 95% CI, 19.9-33.9; n = 551). Seventy
percent of men receiving sildenafil were able to have successful intercourse
at least once during treatment, significantly more than the 34% of men who
received placebo. Men with diabetes mellitus receiving sildenafil also were
significantly more likely to report improved erections than those treated
with placebo (63% vs 19%; RBI, 3.0; 95% CI, 2.5-3.7).
DEPRESSION OR PSYCHOGENIC ED
In men with depression, those receiving sildenafil had a significantly
higher mean percentage of intercourse successes than those randomized to receive
placebo (58% vs 24%; n = 51) and a greater likelihood of experiencing 1 or
more successful intercourse attempts during treatment (86% vs 43%; RBI, 1.8;
95% CI, 1.1-2.9; n = 49) (Table 3). Men receiving sildenafil also were more than 3-fold more likely to report
that treatment improved their erections than were men receiving placebo (RBI,
3.4; 95% CI, 2.4-4.7).
Men with ED entirely attributed to a psychogenic cause appeared to more
frequently experience improved erections and successful intercourse than did
men with nonpsychogenic ED (ie, organic ED). Of men with psychogenic ED, those
receiving sildenafil reported a significantly higher percentage of successful
sexual intercourse attempts (66% vs 29% for the placebo group; n = 453) and
a greater likelihood of experiencing at least 1 successful intercourse attempt
during treatment (91% vs 61% for the placebo group; RBI, 1.4; 95% CI,1.2-1.6)
(Table 3). In comparison, men
with organic ED receiving sildenafil had successful sexual intercourse during
50% of attempts (vs 17% for the placebo group; WMD, 31.9; 95% CI, 26.0-37.9),
whereas 76% of these men who received sildenafil had at least 1 successful
intercourse attempt during treatment (vs 37% for the placebo group; RBI, 2.0;
95% CI, 1.8-2.3), with both treatment group differences achieving statistical
significance.
HISTORY OF RADICAL PROSTATECTOMY
Relatively little information is available regarding the efficacy of
sildenafil treatment for men with a history of radical prostatectomy. These
data indicate that although these men do significantly better with sildenafil
use than with placebo use for all efficacy outcomes (Table 3), they seem considerably less likely to respond to either
sildenafil or placebo use than all other groups of men with ED. Compared with
men randomized to receive placebo, those who received sildenafil had a significantly
higher mean percentage of successful intercourse attempts (25% vs 3%; n =
42) and a greater likelihood of experiencing 1 or more successful intercourse
attempts during treatment (47% vs 14%; n = 37).
SPINAL CORD DISORDERS
Two trials20-21 enrolled
men with ED secondary to traumatic spinal cord injury, of which only one20 provided data on the likelihood of successful sexual
intercourse with treatment. In this crossover design, flexible PRN dosing
trial, the mean percentage of successful intercourse attempts with sildenafil
use was significantly greater than the mean percentage with placebo use (53%
vs 8%; n = 178 men randomized) (Table 3). Men receiving sildenafil also were significantly more likely
to experience at least 1 successful intercourse attempt during treatment than
were men receiving placebo (81% vs 26%). In data from both trials, 83% of
men receiving sildenafil reported improved erections compared with 12% receiving
placebo (RBI, 7.2; 95% CI, 4.7-10.9).
One trial23 comprised young men with
spina bifida and used a crossover design and fixed PRN dosing. Participants
receiving sildenafil had a significant improvement in erectile function, as
measured by "erectile score" (P<.05 vs placebo;
n = 17 men randomized). No data were reported regarding success of intercourse
attempts.
ADVERSE EVENTS
In data from 14 parallel-group, flexible-dose PRN trials (n = 3780),
men randomized to sildenafil use were less likely than those allocated to
placebo use to drop out of trials for any reason (7% vs 14%; RRI, 0.6; 95%
CI, 0.5-0.9) and no more likely to drop out due to an adverse event or laboratory
abnormality (1.3% vs 1.2%; RRI, 1.3; 95% CI, 0.7-2.3) (Table 5). In fixed-dose studies, dropouts also were reduced relative
to placebo at each treatment dose (25-100 mg), with no substantial difference
between the sildenafil doses or between the results for fixed-dose and flexible-dose
studies.
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Table 5. Discontinuations and Adverse Events by Treatment Dose*
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Nearly half of the men (48%) randomized to sildenafil use reported at
least 1 adverse event compared with 36% of men randomized to placebo use (RRI,
1.4; 95% CI, 1.3-1.6) (Table 5).
The most commonly reported adverse events in men receiving sildenafil were
headache (11% vs 4% for the placebo group), flushing (12% vs 2% for the placebo
group), dyspepsia (5% vs 1% for the placebo group), and visual disturbances
(3% vs 0.8% for the placebo group); all differences were statistically significant.
Data from fixed-dose trials indicated that all of these adverse effects were
more frequent at higher doses. Most adverse events were mild or moderate in
severity. The incidence of these adverse events appeared comparable across
different subgroups of patients (data not shown).
The incidence of death and serious cardiovascular events, such as angina
pectoris and myocardial infarction, were infrequent in individuals enrolled
in these randomized trials. In data available from 24 of 27 eligible trials,
the combined outcome of angina or chest pain of possible cardiac origin was
reported by 0.8% of men receiving sildenafil compared with 0.5% of men receiving
placebo (P = .08). In all 27 trials (4240 men in
sildenafil treatment arms and 2707 in the placebo arm), myocardial infarction
occurred in 0.1% of men receiving sildenafil (n = 6) and 0.2% of men receiving
placebo (n = 6), and deaths occurred in 0.1% of men randomized to receive
sildenafil (n = 4) and 0.1% of men randomized to receive placebo (n = 2).
All deaths occurred more than 7 days after the last treatment dose. In results
restricted to men with ischemic heart disease not taking nitrates (664 men
from 24 of 27 eligible trials), angina was reported by 2.4% of men receiving
sildenafil vs 0.4% of men receiving placebo (P =
.06).
COMMENT
This systematic review and quantitative meta-analysis summarizes the
evidence from randomized controlled clinical trials regarding the efficacy
and safety of sildenafil for the treatment of ED. Overall, compared with men
receiving placebo, those allocated to the sildenafil group had a higher percentage
of successful sexual intercourse attempts, were more likely to have successful
intercourse at least once during follow-up, and were more likely to report
improved erections. Treatment benefit was found across all trials and for
all evaluated patient subgroups. Although each of the sildenafil doses used
in clinical practice (25, 50, and 100 mg) had significantly greater efficacy
than placebo, the difference between these active treatment doses appeared
modest and was not present for all outcomes.
When data were analyzed excluding intercourse attempts reported to have
failed for reasons other than an insufficiently firm or long-lasting erection,
overall and subgroup results appeared comparable to those derived using the
primary analysis method, although with an apparent increase in the relative
benefit of sildenafil use over placebo use. Additional analyses suggested
that overall results change little when men without outcomes data are assumed
to have had no change from baseline erectile function and are included in
the analyses.
In data from trials that used a parallel-group design and flexible PRN
dosing, the response to treatment, as measured by mean percentage of successful
intercourse attempts per participant, in subgroups ranged from 42% to 66%,
except in men with a history of radical prostatectomy (25%). Although the
potential role of differences in the pathophysiologic characteristics of ED
between subgroups in explaining variation in efficacy outcomes cannot be evaluated
with meta-analytic techniques, other factors may be important. Some differences
in treatment outcome may be related to the level of baseline erectile function.
For example, men with a history of radical prostatectomy had among the lowest
levels of intercourse success during the open run-in periods that preceded
most trials (data not shown). Differences in treatment outcome also may be
related to variation in placebo responsiveness. We estimated placebo effect
for each subgroup by comparing its mean percentage of successful intercourse
attempts during the run-in phase with its success rate during the double-blind
phase among the men who received placebo. In these comparisons, men with depression
and psychogenic ED achieved a 15% to 20% improvement in the intercourse success
rate with placebo therapy, and men with a history of radical prostatectomy
or peripheral vascular disease experienced essentially no improvement with
placebo use. Finally, differences between specific subgroups also may be affected
by confounding due to other patient variables, a possibility that could not
be investigated in this trial-level meta-analysis.
Safety data from the trials in this meta-analysis suggest that sildenafil
administration was generally well tolerated. Although adverse events were
significantly more frequent with sildenafil use than with placebo use, they
were mostly mild or moderate in severity, and dropout rates due to adverse
events or to laboratory abnormalities occurred no more frequently with sildenafil
use than with placebo use. All adverse effects were more frequent at higher
sildenafil doses. Differences in reports of angina or chest pain of cardiac
origins between men receiving sildenafil and those allocated to placebo use
did not reach statistical significance, and myocardial infarction and death
were uncommon and appeared to be no more likely in men receiving sildenafil
than in those receiving placebo.
Although even large meta-analyses such as the present one may have limited
power to detect modest increases (eg, <2-fold) in relatively uncommon events
such as myocardial infarction or death (eg, 0.1%-1.0%),34
postmarketing data do not provide any conclusive evidence for an excess cardiovascular
risk with sildenafil use as prescribed in the United States and England. Through
January 14, 2000, the Adverse Event Reporting System of the Food and Drug
Administration listed 635 US deaths possibly associated with sildenafil use.35 However, because of limitations in data obtained
from these types of postmarketing reports,36
it cannot be determined whether these deaths are related to sildenafil use,
sexual activity, patients' underlying disease, or a combination of these factors.
Preliminary postmarketing surveillance data from the UK Drug Safety Research
Unit37 indicated that in nearly 6000 men prescribed
sildenafil from whom questionnaires were returned, the mortality rate related
to myocardial infarction or ischemic heart disease was not greater than expected
for an age-adjusted population of English men. The authors caution that the
possibility of differences between the cohort of sildenafil users and men
in the general population of England limits the conclusions that may be drawn
from these data.
Although these trials provide clinically meaningful information on the
treatment efficacy and adverse events associated with sildenafil treatment,
overall and for most important subgroups, only limited efficacy data are available
for black or Hispanic men and for men with a history of radical prostatectomy,
peripheral vascular disease, depression, or spina bifida. In addition, efficacy
and safety results from this systematic review and meta-analysis should not
be extrapolated to the categories of patients excluded from most evaluated
trials with the probable exception of men with ED secondary to spinal cord
injury for whom there are data from trials that enrolled only such individuals.
In addition, none of these trials lasted longer than 26 weeks, so long-term
efficacy and safety data from randomized controlled trials are not available.
In conclusion, the evidence from this systematic review and meta-analysis
indicates that sildenafil use significantly improves erectile function and
is well tolerated by men with ED. However, several questions remain. Longer-term
trials would help clarify the degree to which efficacy and safety of sildenafil
are maintained over time. Additional data are needed to more precisely determine
the efficacy and safety of sildenafil treatment in black and Hispanic patients
and in men with a history of radical prostatectomy, peripheral vascular disease,
or depression. Appropriately, trials in black and Hispanic patients are ongoing.
In addition, it is important to more fully elucidate the safety of sildenafil
treatment in men possibly at increased risk for cardiovascular events, such
as those with stable ischemic heart disease. Ongoing prescription adverse
event monitoring37 and other database surveillance
may provide additional information that further evaluates the apparent safety
of sildenafil use in appropriate populations of men. Randomized trials should
compare sildenafil with other treatments for ED and sildenafil monotherapy
vs combined therapy with sildenafil and other active treatment(s). End points
should include intercourse success, patient and partner preference, sexual
function–related quality of life, and adverse effects, including cardiovascular
events.
AUTHOR INFORMATION
Accepted for publication October 22, 2001.
This study was supported in part by a grant from the Technology Assessment
Program of the Management Decision and Research Center, Health Services Research
and Development Service of the Veterans Health Administration's Office of
Research and Development, and by the Center for Chronic Disease Outcomes Research
and the Cochrane Review Group in Prostate Diseases and Urologic Malignancies,
Veterans Affairs Medical Center.
The views expressed in this article are those of the authors and do
not necessarily represent the views of the Department of Veterans Affairs.
Corresponding author and reprints: Howard A. Fink, MD, MPH, Veterans
Affairs Medical Center, 1 Veterans Dr, PO Box 11G, Minneapolis, MN 55417 (e-mail: howard.fink{at}med.va.gov).
From the Geriatric Research Education and Clinical Center (Dr Fink),
the Section of General Internal Medicine (Drs Fink and Wilt), and the Center
for Chronic Disease Outcomes Research and the Veterans Affairs Coordinating
Center of the Cochrane Review Group in Prostate Diseases and Urologic Malignancies
(Drs Fink, Nelson, and Wilt and Messrs Mac Donald and Rutks), Veterans Affairs
Medical Center, Minneapolis, Minn.
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