Download Use of Sildenafil for Safe Improvement of Erectile Function

ORIGINAL INVESTIGATION
Use of Sildenafil for Safe Improvement
of Erectile Function and Quality of Life
in Men With New York Heart Association
Classes II and III Congestive Heart Failure
A Prospective, Placebo-Controlled, Double-blind Crossover Trial
Linda J. Webster, MScN; Evangelos D. Michelakis, MD; Terry Davis, PhD; Stephen L. Archer, MD
Background: Erectile dysfunction (ED) is common in
patients with congestive heart failure (CHF) and is often associated with symptoms of depression. Although
sildenafil citrate, a phosphodiesterase 5 inhibitor, is effective in treating ED, its use is considered a relative contraindication in CHF. We hypothesized that sildenafil is
a safe and effective treatment for ED in patients with New
York Heart Association classes II and III CHF and that
treatment of ED will improve symptoms of depression
and enhance perceived of quality of life.
Methods: We studied 35 patients in a prospective, pla-
cebo-controlled, crossover trial for 12 weeks. Inclusion
required a history of chronic ED and absence of ischemia (negative results from exercise stress test or nuclear
perfusion scan) or nitrate use. The tolerability of sildenafil citrate was established by monitoring the ambulatory blood pressure for 4 hours after a single 50-mg dose.
Improvement in ED, the primary end point, was assessed using the International Index of Erectile Function survey. The effect of improved erectile function on
E
From the Department of
Medicine (Cardiology),
University of Alberta,
Edmonton. Ms Webster and
Dr Michelakis contributed
equally to this study. The
authors have no relevant
financial interest in this article.
quality of life and mood was assessed using the Minnesota Living With Heart Failure Questionnaire, the Beck
Depression Index, and the Center for Epidemiological
Studies–Depression Scale.
Results: Sildenafil caused a mean±SEM asymptomatic
decrease in blood pressure of 6±3 mm Hg, and no patient experienced symptomatic hypotension or other significant adverse effects. Sildenafil improved the International Index for Erectile Function (P⬍.001) and both sets
of depression scores. The Living With Heart Failure Questionnaire index also improved with sildenafil (P=.02).
Conclusion: Sildenafil is a safe and effective treatment
for ED in men with New York Heart Association classes
II and III CHF and provides relief of depressive symptoms, explaining an improvement in the perception of
quality of life.
Arch Intern Med. 2004;164:514-520
RECTILE DYSFUNCTION (ED) IS
the persistent inability to
achieve and/or maintain an
erection sufficient for satisfactory sexual performance.1
Its prevalence is 52% in men aged 40 to 70
years.2 Normal erection involves an arousalinduced release of nitric oxide from nonadrenergic-noncholinergic nerves and endothelium. The resulting activation of
soluble guanylate cyclase increases cyclic
guanosine monophosphate (cGMP) levels in penile arteries and cavernosal smooth
muscle cells; cGMP leads to vasodilatation in large part through a proteinphosphokinase G–mediated activation of
large-conductance calcium-sensitive potassium channels.3 Sildenafil citrate enhances erectile function by inhibiting phosphodiesterase 5 (PDE5), which rapidly
degrades cGMP as it is formed.4
The mechanism of normal erection
seems to be compromised with ageing
(REPRINTED) ARCH INTERN MED/ VOL 164, MAR 8, 2004
514
and vascular disease. Disruption of the
nitric oxide–cGMP system is common in
vascular disease, one of the most common underlying mechanisms in ED of
organic etiology. 5 The association
between vascular disease and ED is so
strong that ED has been proposed to be a
marker of cardiovascular disease.6 In a
cohort of clinic outpatients with congestive heart failure (CHF), three quarters
reported compromised libido and erectile
function. 7 A serious relation exists
between sexual function and the results
of the 6-minute walk (r = 0.32) or New
York Heart Association (NYHA) functional class (r = 0.21).7 This strong association can be explained because, in addition to vascular disease, patients with
CHF have other predisposing factors for
ED, specifically polypharmacy and
depression. Several drugs used in the
treatment of CHF, such as ␤-blockers, are
associated with ED.8 As a result of their
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poor prognosis and the significant impact of CHF symptoms in everyday life, patients with symptomatic CHF
suffer from depression, a well-known predisposing factor of ED.9,10 Conversely, ED itself causes depression,
and may further compromise the quality of life in
patients with CHF. Depression, ED, and cardiovascular
disease have been proposed to form a mutually reinforcing triad.11
Despite the high incidence of ED in patients with
CHF, the effectiveness and the impact of ED treatment
in this patient population are not known. This is unfortunate because the use of sildenafil has revolutionized
the treatment of ED, with efficacy rates exceeding 69%1,12,13
in patients without cardiovascular disease. The reports
of deaths associated with the use of sildenafil soon after
the release of sildenafil14 contributed to the hesitation of
physicians to prescribe this drug to patients with significant cardiovascular disease. However, it is now known
that sildenafil does not increase cardiovascular disease
mortality.15 In patients with stable coronary disease, sildenafil enhances coronary flow reserve16 and does not
worsen cardiac function under exercise conditions.17 The
main contraindication for the use of sildenafil is the interaction between sildenafil and nitrates. This interaction can lead to profound hypotension and is avoidable
by education and by not prescribing sildenafil to patients with evocable ischemia on a conventional exercise stress test. The American College of Cardiology and
American Heart Association released statements suggesting that the use of any form of nitrates and the inability
to perform 5 metabolic equivalents of exercise without
evidence of ischemia are considered absolute contraindications for the use of sildenafil.15 Caution was also raised
for the potential interaction, resulting in hypotension,
of sildenafil with vasodilators commonly used in the treatment of CHF. In this consensus statement, CHF was listed
as a relative contraindication for the use of sildenafil.15
However, a significant percentage of patients with CHF
do not have active ischemia and do not require the use
of nitrates, and could therefore be candidates for treatment of ED with sildenafil.
We hypothesized that in patients with moderately
severe CHF who undergo appropriate screening and selection, sildenafil is safe and effective. To study safety,
we used ambulatory blood pressure monitors and observed the patients for several hours after the intake of
sildenafil. To study efficacy, we used the standard International Index for Erectile Function (IIEF)18 to compare the effects of sildenafil vs placebo in patients with
NYHA classes II and III CHF in a prospective crossover
trial. In addition to its effectiveness in treating ED, we
also hypothesized that sildenafil would be useful in decreasing symptoms of depression that stem from lack of
a satisfactory sex life in these patients. We used 2 different and well-validated indices of depression: the Beck Depression Index (BDI)19-22 and the Center for Epidemiologic Studies–Depression Scale (CES-D).23-26 To determine
whether the treatment of ED and decrease in ED-related
depressive symptoms in these patients would improve
quality of life and lead to an improvement in the perception of their disease, we used the Minnesota Living With
Heart Failure Questionnaire (LihFE).27-30
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515
METHODS
The human ethics board of the University of Alberta, Edmonton, approved the protocol, and each participant signed an informed consent form.
SCREENING
Initial contact was made by a letter offering participation to men
with NYHA classes II and III CHF who were not taking nitrates in our heart function clinic. The 41 patients who responded underwent further screening and were excluded from
the study if they (1) had symptomatic hypotension or systolic
blood pressure of less than 80 mm Hg at baseline, (2) had a
positive stress test result within the past year or a history consistent with ongoing myocardial ischemia, (3) were receiving
psychotropic therapy (anxiolytics or antidepressants), (4) had
significant valvular disease, and (5) had a recent history of alcohol and/or other drug abuse. Three patients were excluded
based on those criteria. The remaining 38 patients underwent
further screening with an exercise stress test (Bruce protocol)
to ensure adequate functional capacity (⬎5 metabolic equivalents, a level of cardiovascular fitness necessary for most sexual
activity15) and exclude ischemia. Overall, 3 patients were excluded because they had active ischemia. Four patients failed
to achieve the target heart rate (85% of maximal [220 beats/
min−age of participant]), and 21 patients had abnormal findings on the baseline electrocardiogram that compromised the
interpretation of the exercise electrocardiogram (atrial fibrillation [n=13], left bundle branch block [n=5], and nonspecific ST-T wave changes [n=3]). Among these 25 patients who
required further assessment to exclude coronary ischemia, 18
underwent nuclear imaging studies and 7, dobutamine stress
echocardiogram (n=7). Evidence of an old myocardial infarction was found in 18 patients, but none had reversible ischemia. Thirty-five patients entered the study.
STUDY DESIGN
The study was a 12-week randomized, placebo-controlled, crossover study. The randomization to placebo vs sildenafil followed successful completion of the safety protocol.
SAFETY PROTOCOL
After a single 50-mg dose of sildenafil, the patients were observed in the clinic for 5 hours under ambulatory blood pressure monitoring (Del Mar Pressurometer model P6; Del Mar
Avionics, Irvine, Calif). The blood pressure and heart rate were
recorded at 15-minute intervals, and data were analyzed at the
end of the session. All patients took their morning medications before 8 AM, and all studies were performed from 10 AM
and 2 PM. Patients were excluded from the study if they manifested a fall in mean arterial pressure (seated, at rest for 5 minutes) of more than 10% that was sustained for more than 30
minutes or was associated with hypotensive symptoms (dizziness, angina, and diaphoresis).
EFFICACY PROTOCOL
Patients were randomized to 1 of the following 2 arms: placebo for the first 6 weeks with a switch to sildenafil citrate (50
mg) at the midpoint, or sildenafil for the first 6 weeks with a
switch to placebo thereafter. The appearance of the placebo pills
was similar but not identical to that of the sildenafil pills in shape
and color, and they were supplied by the pharmacy services of
the University of Alberta Hospitals. Patients were instructed to
ingest the medication approximately 1 hour before anticiWWW.ARCHINTERNMED.COM
©2004 American Medical Association. All rights reserved.
Patient Characteristics*
Characteristic
Age, mean ± SEM, y
Serum creatinine level, mean ± SEM, mg/dL
Ejection fraction, mean ± SEM, %
NYHA class II
NYHA class III
Ischemic
Idiopathic
Other
Hypertension
Diabetes
ACE
␤-Blocker
Diuretic
ASA
Coumadin
Digoxin
Calcium channel blocker
Score, mean ± SEM
IIEF†
BDI
CES-D
LihFE
60 ± 2
113 ± 5
26 ± 1
25 (71)
10 (29)
21 (60)
9 (26)
5 (14)
24 (69)
9 (26)
33 (94)
33 (94)
31 (89)
23 (66)
22 (63)
22 (63)
4 (11)
9±1
9±1
5±1
37 ± 2
Abbreviations: ACE, angiotensin-converting enzyme; ASA, acetylsalicylic
acid; BDI, Beck Depression Inventory; CES-D, Center for Epidemiological
Studies–Depression Scale; IIEF, International Index of Erectile Function;
LihFE, Minnesota Living With Heart Failure Questionnaire; NYHA, New York
Heart Association.
SI conversion factor: To convert creatinine to micromoles per liter,
multiply by 88.4.
*Unless otherwise indicated, data are expressed as number (percentage)
of patients.
†Indicates erectile function domain (questions 1-5 and 15).
110
110
STATISTICAL ANALYSIS
100
105
90
100
80
Heart Rate, Beats/min
Mean Blood Pressure, mm Hg
Mean Blood Pressure
Heart Rate
previous 4 weeks (IIEF), symptoms of depression during the
previous week (BDI and CES-D), and perception of heart failure symptoms during the past month (LihFE).
The IIEF was developed during the Massachusetts Male
Aging Study, and consists of 15 questions that address the domains of efficacy of erectile function, achievement of orgasm,
sexual desire, and satisfaction with intercourse. It is a wellvalidated, multidimensional, self-administered questionnaire
used for the clinical assessment of erectile function.18 The primary domain of erectile function (questions 1, 2, 3, 4, 5, and
15, with answers scored on a 0- to 5-point scale) was used in
this trial.
The BDI was developed for assessment of depression in
psychiatric populations and detecting symptoms of depression in healthy populations.19-22 The scale consists of 21 questions that investigate 4 categories of symptoms addressing emotion, cognitive ability, motivation, and physical symptoms.
The CES-D is a 20-item self-report instrument that is widely
used as a screening tool to designate depressed and nondepressed subjects in clinical studies. It is an internally consistent, valid measurement tool that assesses depressive symptoms with emphasis on depressed mood.23-26,31
The BDI and the CES-D were advantageous in that the patient was able to complete the questionnaire alone. These tools
are best used to screen for depressive symptoms and not as a
diagnostic tool for the presence of clinical depression. They can
only detect the presence of depressive symptoms and cannot
distinguish their source (perceived vs situational).32 Participants who indicated significant scores on either depression index (BDI, ⬎13; CES-D, ⬎16) at any point during the study were
also interviewed by a psychologist, and none had clinical depression.
The LihFE is a well-validated 21-item questionnaire used
as a standard measure in CHF studies to assess the participants’ subjective feelings about their limitations imposed by the
disease. It assesses the areas of somatic, depressive, and active
functions of daily life and, as such, is a quality-of-life indicator.27-30
95
Results of power calculations indicated that a sample size of
35 in each group was required to achieve a power of more than
0.81, based on previous publications studying the effects of sildenafil vs placebo and using the IIEF index.12 The data are expressed as mean±SEM and analyzed with repeated-measures
analysis of variance, with a post hoc analysis using a Fisher probable least-significant differences test (StatView; SAS Institute,
Cary, NC). P⬍.05 was considered statistically significant.
70
0
0
30
60
90
120
150
180
210
RESULTS
240
Time After Sildenafil Administration, min
Figure 1. Mean heart rate and blood pressure for 4 hours after a 50-mg dose
of sildenafil citrate.
pated sexual activity and not more than once a day. A participant diary was completed with the times the drugs were ingested, the time to effect (if erection was achieved), and optional personal comments about the effect and experience.
Follow-up visits were completed at 2, 4, 6, 8, 10, and 12
weeks. At each follow-up visit, the diary was reviewed, and vital signs were measured. A careful history was taken to detect
adverse effects of sildenafil or exacerbation of CHF symptoms. In addition to these assessments, the participants completed self-report questionnaires at baseline and weeks 4 and
10. These questionnaires quantified erectile function during the
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516
CLINICAL CHARACTERISTICS
All participants completed the 12-week protocol. The
baseline hemodynamic measurements, basic clinical variables, and baseline scores in all indices used are outlined in the Table.
SAFETY
The mean hemodynamic data (heart rate and blood pressure) for 4 hours after a 50-mg dose of sildenafil citrate
are shown in Figure 1. Mean heart rate and blood pressure did not decrease significantly after the ingestion of
sildenafil. At no time did the mean arterial pressure deWWW.ARCHINTERNMED.COM
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EFFICACY
18
16
14
12
IIEF Score
crease more than 10% from the baseline level. Furthermore, the heart rate did not significantly change during
the 4 hours after the ingestion of the initial dose of sildenafil. No patient reported any adverse effects, including
dizziness, weakness, nausea, hot flushes, or visual and
color vision disturbances.
10
8
6
Erectile Function
The erectile function scores at baseline and 6 and 12 weeks
for the placebo-sildenafil crossover protocol are shown
in Figure 2. Erectile function significantly improved at
week 4 for those who first received sildenafil (P⬍.001).
With the crossover to placebo, their scores returned to
baseline. The group that received placebo initially did not
show statistically significant improvement of their erectile function scores (P = .67) until they received sildenafil during the latter part of the study (P⬍.001). The
overall response to sildenafil did not differ between the
2 groups (sildenafil first vs placebo first; P = .98).
4
Sildenafil First
Placebo First
2
0
Baseline
Week 4
Week 10
Figure 2. International Index of Erectile Function (IIEF) scores at baseline
and 6 and 12 weeks for the placebo–sildenafil citrate crossover protocol.
These patients underwent successful outpatient treatment of the symptoms with diuresis in the heart function clinic. There were no reports of blurry vision or altered color vision, flushing, headaches, or nausea, all
known adverse effects of sildenafil.13
Depression
COMMENT
Figure 3A illustrates the scores measured using 2 sepa-
rate indices. All indices showed improvement during the
period that sildenafil was used, in contrast to placebo.
Quality of Life
Figure 3B shows the scores using the LihFE index at baseline and after sildenafil and placebo treatments. In the
sildenafil-first group, the use of sildenafil caused a significant decrease in the score (P= .008), and switching
to placebo caused an increase in the score (P =.04) that
reached the baseline levels. In the placebo-first group,
there was no change in the score until the patients received sildenafil in week 4, which again caused a decrease in the score (P=.003 vs baseline; P=.02 vs placebo).
Again, there was no difference in the responses to the
LihFE questionnaire, whether the patients received placebo or sildenafil first.
The major finding of this study is that sildenafil is safe
and effective in treating ED in men with moderate (NYHA
classes II-III) heart failure who undergo appropriate
screening. There was also a remarkably clear beneficial
effect of treating ED for symptoms of depression and quality of life in this CHF cohort. To our knowledge, this is
the first report on the safety and efficacy of this commonly used drug in a population with moderately severe CHF. It is also one of few studies to examine the
potentially beneficial effect of treating ED in patients with
advanced cardiovascular disease. Although the use of sildenafil in patients with CHF at present is considered a relative contraindication,15 our findings suggest that this drug
can be prescribed in patients with moderately severe CHF,
provided that they are not taking nitrates and they have
no evidence of active myocardial ischemia.
SAFETY IN NYHA CLASSES II AND III CHF
ADVERSE EVENTS
There were no significant hemodynamic effects during
the course of the study. No participant was hospitalized
during their participation in the study or during the 30
days after participation. Two deaths were reported to study
personnel, one 4 months and the second 5 months after
the end of the patient’s participation in this study. Atrial
fibrillation developed in 2 patients during the trial period, and neither was taking sildenafil at the time the arrhythmia was detected. These dysrhythmias were noted
at 2 and 4 weeks of the placebo phase of the study. The
atrial fibrillation was asymptomatic on both occasions and
was discovered only on electrocardiograms obtained at
routine visits. One patient experienced worsening symptoms of heart failure (dyspnea and limited exercise tolerance) during the fifth week of the placebo phase (placebo-first group), thought to be due to volume overload.
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517
The primary safety end point used to ensure that these
patients could tolerate sildenafil, a weak vasodilator, was
the absence of hypotension for 4 hours after a single ingestion of 50 mg of sildenafil citrate. Using an ambulatory recording system, we were able to measure blood
pressure and heart rate at multiple points. We showed
that at no point did the blood pressure drop more than
10% from baseline, although there was a small decrease
at 60 minutes that was not associated with any symptoms.
Our findings are in agreement with those reported
by Vardi et al,33 who used ambulatory blood pressure
monitoring for 6 hours after sildenafil use in 22 hypertensive and 27 normotensive patients. These authors reported a small and asymptomatic decrease in the mean
arterial pressure (mean decrease, –5.3 mm Hg) that did
not differ between the normotensive and hypertensive
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A
B
8
P = .67
BDI Scores
14
P = .02
12
10
8
4
P = .005
6
P = .46
7
P <.001 vs Midline
P = .003 vs Baseline
6
CES-D Scores
16
P = .04
5
4
3
2
1
2
0
P = .003
P = .01 vs Midline
P = .03 vs Baseline
Week 4
Week 10
0
Baseline
Week 4
Week 10
Placebo First
Sildenafil First
45
P = .80
40
LihFE Scores
18
35
30
P = .008 P = .003 vs Baseline
P = .02 vs Midline
25
Baseline
P = .04 vs Midline
Baseline
Week 4
Week 10
Figure 3. Depression (A) and quality-of-life scores (B) at baseline and 6 and 12 weeks for the placebo–sildenafil citrate crossover protocol. BDI indicates Beck
Depression Inventory; CES-D, Center for Epidemiological Studies–Depression Scale; LihFE, Minnesota Living With Heart Failure Questionnaire.
groups. Arruda-Olson et al17 studied the hemodynamic
effects of sildenafil in 105 men with known or probable
coronary artery disease. They reported a small and asymptomatic decrease in the systolic blood pressure measured once, 1 hour after oral sildenafil citrate administration (50 or 100 mg) (mean change of −7 vs –2 mm Hg
in the placebo group; P⬍.001) but not in the diastolic
blood pressure (P⬍.16) or the heart rate (P⬍.08). In
that study, the mean ejection fraction of the patients
studied was 60%, and thus the results could not be
extrapolated in patients with significant left ventricular
dysfunction.
The decrease in blood pressure that we reported was
associated with a small increase in heart rate (Figure 1).
This increase in heart rate is likely due to the decrease
in blood pressure. Alternatively, sildenafil can cause an
increase in heart rate because it has been proposed to cause
an increase in sympathetic activation. Phillips et al34 recently reported that in 14 healthy volunteers, a single oral
dose of sildenafil citrate (100 mg) caused a significant
increase in muscle sympathetic nerve activity and plasma
norepinephrine levels. Despite this sympathetic activation, the blood pressure, heart rate, and forearm vascular resistance did not change in these healthy volunteers. Senzaki et al 35 have shown that the cGMP
modulation of ␤-adrenergic stimulation in healthy dog
myocardium is blunted in dogs with heart failure, perhaps due to alterations in PDE5 localization and reduced synthesis. Whether the PDE5 expression and function are altered in the hearts of humans with CHF remains
unknown.
The peak biological and hemodynamic effects of
sildenafil are known to occur from 50 to 60 minutes, and
this has been confirmed in several recent studies by our
group36 (REF) and others (REF—the circulation coronary paper).15,16 Sildenafil is metabolized and cleared hepatically,36 and it is possible that liver congestion alters
the normal metabolism of sildenafil and thus causes an
exaggerated or late hemodynamic response. However, in
a recently published study37 that included 13 patients with
severe right heart failure due to pulmonary hypertension, sildenafil did not significantly decrease the invasively measured mean arterial pressure. On the other hand,
sildenafil increased the cardiac output and lower capillary wedge pressure and decreased the pulmonary vascular resistance.37
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518
Finally, the minimal hemodynamic effects that we
report may also be a result of the expected action of background CHF medications, because all of the studies were
performed in the morning, and at a time coinciding with
the peak effect times of antihypertensive therapy and diuretics (2-3 hours). This is important because in many
studies, the medications are held the morning of the study.
Our study suggests that sildenafil is safe to prescribe to
patients taking all the currently indicated medications
for CHF (Table).
EFFECTIVENESS IN TREATING ED
IN PATIENTS WITH CHF
The efficacy of treatment was shown by the improvement of the IIEF scores during the sildenafil arm of the
trial (Figure 2). The efficacy of sildenafil in treating ED
in the general population exceeds 80%,12,38,39 but this has
never been studied in CHF. In our study, only 1 patient
had no response at all to sildenafil (Figure 2).
The IIEF scores were not significantly altered by placebo in either of our study groups. This is in agreement
with recent large trials showing that placebo did not alter
the erectile function domain of the IIEF.12 We do not known
what percentage of our study patients had mainly organic
vs mainly psychogenic ED, because invasive erectile function studies were not performed. However, given the very
high prevalence of endothelial dysfunction and overt vascular disease in CHF, it is likely that most of our study participants had a major organic component in their ED.
Although the placebo pill was not identical to the
sildenafil pill, it was very similar in shape and color. Because sildenafil has been reported to cause hot flashes,
it is possible that patients aware of this adverse effect
would be able to identify the sildenafil pill. However, none
of the patients reported hot flashes in the sildenafil group,
and only 2 patients in our study had previously used sildenafil.
Furthermore, the crossover design of our study
strengthens our interpretation of the data and limits potential weaknesses in the randomization and blinding process. As expected, the IIEF scores after sildenafil ingestion returned to baseline during the placebo phase of the
study (Figure 2). In addition to the IIEF, this return to baseline after the placebo phase was observed in all of the indices used (ie, the CES, BDI, and LihFE) (Figure 3).
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The assessment of the initial hemodynamic variables in combination with the erectile improvement indicates that the vasodilatory effect of sildenafil primarily affects the penile circulation during arousal, without
significant impact on the systemic blood pressure.
DECREASE IN DEPRESSIVE SYMPTOMS AND
IMPROVEMENT IN QUALITY OF LIFE
A potentially important benefit of effective treatment of
ED in these older, chronically ill patients with CHF is
the observed improvement of quality of life and relief of
depressive symptoms. Indices assessing depression and
perceptions of quality of life of those living with heart
failure showed significant improvement in scores during the period of sildenafil treatment and reversion to basal
levels during the placebo phase of the study (Figure 3).
The beneficial effects of treatment of ED with sildenafil
in regard to depressive symptoms are in agreement with
previously reported studies, using the same40 and different depression indices.41 In a placebo-controlled study,
Seidman et al41 reported that sildenafil effectively treated
ED, and this was associated with improvements in depression and quality-of-life indices. These authors used
the Hamilton Depression Rating Scale. We used 2 separate self-reported instruments to study depression in our
study, both of which have been well validated in multiple patient groups, including elderly patients, outpatients, and populations with chronic disease. To our
knowledge, our study is the first to study the association between the treatment of ED and depression.
Phosphodiesterase inhibitors have been used in the
treatment of depression. For example, rolipram, a PDE4
inhibitor, has been used to treat depression, perhaps a
reflection of the high expression of PDE4 in the brain.42-44
Although PDE5 is also expressed in the brain,45-47 only
limited data suggest any effects of sildenafil on brain function.48
Although the effects on the depression and qualityof-life indices are interesting and cited as a secondary end
point in our study, it should not be assumed that the effective treatment of ED cures depression. Depression in
this population subsides and exacerbates with the natural progression of heart failure symptoms. The etiology of
depression is often multifactorial,49,50 and the effective treatment of ED in these patients addresses but one cause. Nonetheless, there was a clear correlation between effective treatment of ED and perceived quality of life.
Effective treatment of ED with sildenafil has been
shown to improve several indices of quality of life in the
general population38 and in patients with chronic illness such as spinal cord injury.51 We show that quality
of life improved by treating ED in patients with CHF, one
of the most common chronic diseases, by using the LihFE,
an index developed to assess quality of life specifically
in CHF. We speculate that the mechanism for this improvement is the decrease in depressive symptoms.
In conclusion, this study provides new evidence that
it is safe and effective to treat men with ED and moderate heart failure with sildenafil. It is necessary to complete baseline safety measurements to ensure adequate
physical fitness for sexual activity and absence of myo(REPRINTED) ARCH INTERN MED/ VOL 164, MAR 8, 2004
519
cardial ischemia that would necessitate nitrate use. Sildenafil is a reasonable alternative to the invasive solutions
of the past (eg, penile implants, intracavernosal injections of vasodilators) for many CHF patients with ED.
Accepted for publication March 28, 2003.
This study was supported by a grant from the University of Alberta Hospital Foundation, Edmonton. Drs Michelakis and Archer are supported by Alberta Heritage Foundation for Medical Research, Edmonton, Canadian Institutes
of Health Research, Ottawa, Ontario, the Heart and Stroke
Foundation of Canada, Ottawa, and the Canadian Foundation for Innovation, Ottawa.
Corresponding author and reprints: Stephen L. Archer,
MD, Department of Medicine (Cardiology), University of
Alberta, WMC 2C2.36, 8440112th St, Edmonton, Alberta,
Canada T6G 2B7 (e-mail: [email protected]).
REFERENCES
1. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802-1813.
2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence
and its medical and psychosocial correlates: results of the Massachusetts Male
Aging Study. J Urol. 1994;151:54-61.
3. Michelakis E, Tymchak W, Archer S. Sildenafil: from the bench to the bedside.
CMAJ. 2000;163:1171-1175.
4. Medina P, Segarra G, Vila JM, Domenech C, Martinez-Leon JB, Lluch S. Effects
of sildenafil on human penile blood vessels. Urology. 2000;56:539-543.
5. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol. 1999;161:5-11.
6. Kirby M, Jackson G, Betteridge J, Friedli K. Is erectile dysfunction a marker for
cardiovascular disease? Int J Clin Pract. 2001;55:614-618.
7. Jaarsma T, Dracup K, Walden J, Stevenson LW. Sexual function in patients with
advanced heart failure. Heart Lung. 1996;25:262-270.
8. Buffum J. Pharmacosexology update: prescription drugs and sexual function.
J Psychoactive Drugs. 1986;18:97-106.
9. Seidman SN, Roose SP. The relationship between depression and erectile dysfunction. Curr Psychiatry Rep. 2000;2:201-205.
10. Seidman SN. Exploring the relationship between depression and erectile dysfunction in aging men. J Clin Psychiatry. 2002;63:5-12, 23-25.
11. Goldstein I. The mutually reinforcing triad of depressive symptoms, cardiovascular disease, and erectile dysfunction. Am J Cardiol. 2000;86:41F-45F.
12. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA, Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl
J Med. 1998;338:1397-1404.
13. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction: 1998. J Urol. 2002;167:1197-1204.
14. Feenstra J, van Drie-Pierik RJ, Lacle CF, Stricker BH. Acute myocardial infarction associated with sildenafil. Lancet. 1998;352:957-958.
15. Cheitlin MD, Hutter AM Jr, Brindis RG, et al, American College of Cardiology/
American Heart Association. ACC/AHA expert consensus document: use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol. 1999;
33:273-282.
16. Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med. 2000;342:16221626.
17. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary
artery disease: a randomized crossover trial. JAMA. 2002;287:719-725.
18. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment
of erectile dysfunction. Urology. 1997;49:822-830.
19. Gallagher D, Nies G, Thompson LW. Reliability of the Beck Depression Inventory with older adults. J Consult Clin Psychol. 1982;50:152-153.
20. Stewart RB, Blashfield R, Hale WE, Moore MT, May FE, Marks RG. Correlates of
Beck Depression Inventory scores in an ambulatory elderly population: symptoms, diseases, laboratory values, and medications. J Fam Pract. 1991;32:497502.
21. Robinson BE, Kelley L. Concurrent validity of the Beck Depression Inventory as
a measure of depression. Psychol Rep. 1996;79:929-930.
WWW.ARCHINTERNMED.COM
©2004 American Medical Association. All rights reserved.
22. Ambrosini PJ, Metz C, Bianchi MD, Rabinovich H, Undie A. Concurrent validity
and psychometric properties of the Beck Depression Inventory in outpatient adolescents. J Am Acad Child Adolesc Psychiatry. 1991;30:51-57.
23. Zich JM, Attkisson CC, Greenfield TK. Screening for depression in primary care
clinics: the CES-D and the BDI. Int J Psychiatry Med. 1990;20:259-277.
24. Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in
well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. 1994;10:77-84.
25. Beekman AT, Deeg DJ, Van Limbeek J, Braam AW, De Vries MZ, Van Tilburg W.
Criterion validity of the Center for Epidemiologic Studies Depression Scale (CESD): results from a community-based sample of older subjects in the Netherlands. Psychol Med. 1997;27:231-235.
26. Lewinsohn PM, Seeley JR, Roberts RE, Allen NB. Center for Epidemiologic Studies Depression Scale (CES-D) as a screening instrument for depression among
community-residing older adults. Psychol Aging. 1997;12:277-287.
27. Rector TS, Cohn JN, Pimobendan Multicenter Research Group. Assessment of
patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial
of pimobendan. Am Heart J. 1992;124:1017-1025.
28. Rector TS, Kubo SH, Cohn JN. Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo.
Am J Cardiol. 1993;71:1106-1107.
29. Hulsmann M, Berger R, Sturm B, et al. Prediction of outcome by neurohumoral
activation, the six-minute walk test and the Minnesota Living with Heart Failure
Questionnaire in an outpatient cohort with congestive heart failure. Eur Heart J.
2002;23:886-891.
30. Riegel B, Moser DK, Glaser D, et al. The Minnesota Living With Heart Failure Questionnaire: sensitivity to differences and responsiveness to intervention intensity
in a clinical population. Nurs Res. 2002;51:209-218.
31. Schroevers MJ, Sanderman R, van Sonderen E, Ranchor AV. The evaluation of
the Center for Epidemiologic Studies Depression (CES-D) Scale: depressed and
positive affect in cancer patients and healthy reference subjects. Qual Life Res.
2000;9:1015-1029.
32. Fechner-Bates S, Coyne JC, Schwenk TL. The relationship of self-reported distress to depressive disorders and other psychopathology. J Consult Clin Psychol. 1994;62:550-559.
33. Vardi Y, Klein L, Nassar S, Sprecher E, Gruenwald I. Effects of sildenafil citrate
(Viagra) on blood pressure in normotensive and hypertensive men. Urology. 2002;
59:747-752.
34. Phillips BG, Kato M, Pesek CA, et al. Sympathetic activation by sildenafil. Circulation. 2000;102:3068-3073.
35. Senzaki H, Smith CJ, Juang GJ, et al. Cardiac phosphodiesterase 5 (cGMPspecific) modulates beta-adrenergic signaling in vivo and is down-regulated in
heart failure. FASEB J. 2001;15:1718-1726.
36. Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of
(REPRINTED) ARCH INTERN MED/ VOL 164, MAR 8, 2004
520
sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica. 1999;29:297-310.
37. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002;
105:2398-2403.
38. Giuliano F, Pena BM, Mishra A, Smith MD. Efficacy results and quality-of-life measures in men receiving sildenafil citrate for the treatment of erectile dysfunction.
Qual Life Res. 2001;10:359-369.
39. Steers W, Guay AT, Leriche A, et al. Assessment of the efficacy and safety of
Viagra (sildenafil citrate) in men with erectile dysfunction during long-term treatment. Int J Impot Res. 2001;13:261-267.
40. Muller MJ, Benkert O. Lower self-reported depression in patients with erectile
dysfunction after treatment with sildenafil. J Affect Disord. 2001;66:255-261.
41. Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC. Treatment of erectile dysfunction in men with depressive symptoms: results of a placebocontrolled trial with sildenafil citrate. Am J Psychiatry. 2001;158:1623-1630.
42. O’Donnell JM. Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by
differential reinforcement of low response rate. J Pharmacol Exp Ther. 1993;
264:1168-1178.
43. Scuvee-Moreau J, Giesbers I, Dresse A. Effect of rolipram, a phosphodiesterase
inhibitor and potential antidepressant, on the firing rate of central monoaminergic neurons in the rat. Arch Int Pharmacodyn Ther. 1987;288:43-49.
44. Zhu J, Mix E, Winblad B. The antidepressant and antiinflammatory effects of rolipram in the central nervous system. CNS Drug Rev. 2001;7:387-398.
45. Uckert S, Kuthe A, Stief CG, Jonas U. Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. World J Urol.
2001;19:14-22.
46. Yanaka N, Kotera J, Ohtsuka A, et al. Expression, structure and chromosomal
localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A
gene. Eur J Biochem. 1998;255:391-399.
47. Kotera J, Yanaka N, Fujishige K, et al. Expression of rat cGMP-binding cGMPspecific phosphodiesterase mRNA in Purkinje cell layers during postnatal neuronal development. Eur J Biochem. 1997;249:434-442.
48. Schultheiss D, Muller SV, Nager W, et al. Central effects of sildenafil (Viagra) on
auditory selective attention and verbal recognition memory in humans: a study
with event-related brain potentials. World J Urol. 2001;19:46-50.
49. Cleland JG, Wang M. Depression and heart failure: not yet a target for therapy?
Eur Heart J. 1999;20:1529-1531.
50. Majani G, Pierobon A, Giardini A, et al. Relationship between psychological profile and cardiological variables in chronic heart failure: the role of patient subjectivity. Eur Heart J. 1999;20:1579-1586.
51. Hultling C, Giuliano F, Quirk F, Pena B, Mishra A, Smith MD. Quality of life in
patients with spinal cord injury receiving Viagra (sildenafil citrate) for the treatment of erectile dysfunction. Spinal Cord. 2000;38:363-370.
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