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 DiseaseA Randomized Crossover Trial. JAMA. 2002;287(6):719-725. doi:10.1001/jama.287.6.719
Author Affiliations: Division of Cardiovascular Diseases and Internal Medicine (Drs Arruda-Olson and Pellikka and Ms Leckel) and Departments of Biostatistics (Mr Mahoney) and Urology (Dr Nehra), Mayo Clinic and Mayo Foundation, Rochester, Minn.
Context The relationship between sildenafil citrate use and reported adverse
cardiovascular events in men with coronary artery disease (CAD) is unclear.
Objective To evaluate the cardiovascular effects of sildenafil during exercise
in men with CAD.
Design, Setting, and Subjects Randomized, double-blind, placebo-controlled crossover trial conducted
March to October 2000 at a US ambulatory-care referral center among 105 men
with a mean (SD) age of 66 (9) years who had erectile dysfunction and known
or highly suspected CAD.
Interventions All patients underwent 2 symptom-limited supine bicycle echocardiograms
separated by an interval of 1 to 3 days after receiving a single dose of sildenafil
(50 or 100 mg) or placebo 1 hour before each exercise test.
Main Outcome Measures Hemodynamic effects of sildenafil during exercise (onset, extent, and
severity of ischemia) assessed by exercise echocardiography.
Results Mean (SD) resting ejection fraction was 56% (7%) (range, 39%-68%). After
sildenafil use, resting systolic blood pressure was reduced from 135 (19)
mm Hg to 128 (17) mm Hg, for a mean change of −7 mm Hg (95% confidence
interval [CI], −9 to −4 mm Hg; P<.001).
After placebo use, the mean (SD) change was from 135 (20) mm Hg to 133 (19)
mm Hg, a difference of −2 mm Hg (95% CI, −6 to 0.3 mm Hg; P = .08). The difference between mean change after sildenafil
and placebo use was 4.3 (95% CI, 0.9-7.7; P = .01).
Resting heart rate, diastolic blood pressure, and wall motion score index
(a measure of the extent and severity of wall motion abnormalities) did not
change significantly in either group. Exercise capacity was similar with sildenafil
use (mean [SD], 4.5 [1.0] metabolic equivalents) and placebo use (mean [SD],
4.6 [1.0] metabolic equivalents; mean difference, 0.07; 95% CI, −0.06
to 0.19; P = .29). Exercise blood pressure and heart
rate increments were similar. Dyspnea or angina developed in 69 patients who
took sildenafil and 70 patients who took placebo (P
= .89); exercise electrocardiography was positive in 12 patients (11%) who
took sildenafil and 17 patients (16%) who took placebo (P = .09). Exercise-induced wall motion abnormalities developed in similar
numbers of patients after sildenafil and placebo use (84 and 86 patients,
respectively; P = .53). Wall motion score index at
peak exercise was similar after sildenafil and placebo use (mean [SD], 1.4
[0.4] vs 1.4 [0.4]; mean difference, 0.01; 95% CI, −0.01 to 0.03; P = .40).
Conclusion In men with stable CAD, sildenafil had no effect on symptoms, exercise
duration, or presence or extent of exercise-induced ischemia, as assessed
by exercise echocardiography.
Erectile dysfunction affects 30 million men in the United States1 and frequently coexists with coronary artery disease.
Since the Food and Drug Administration approved the use of sildenafil citrate
for the treatment of erectile dysfunction, millions of prescriptions have
been issued.2 Reported adverse cardiac events
associated with sildenafil use include acute myocardial infarction, ventricular
tachycardia, hypotension, and death,3- 7
raising concerns about the safety of this agent in patients with coronary
Sildenafil is a cyclic guanosine monophosphate–specific type 5
phosphodiesterase inhibitor. Phosphodiesterase 5 is located not only in the
corpus cavernosum, but also in other vascular tissue, including arteries and
veins.6 Adverse cardiovascular events associated
with sildenafil may be due to myocardial ischemia during sexual activity,
with aggravation of ischemia by a vasodilator effect. Published guidelines
regarding the management of cardiac patients with erectile dysfunction suggest
that sildenafil may be hazardous in patients with ischemic heart disease and
that clinicians should use caution in prescribing this medication.7
However, it is also possible that the concern regarding adverse events
associated with sildenafil may instead stem from the cardiovascular demands
of sexual activity, the health of the population for whom sildenafil is prescribed,
an adverse interaction with nitrates, or reporting bias. Hence, the purpose
of this study was to assess the hemodynamic effects of sildenafil during exercise,
including the effect on the onset, extent, and severity of electrocardiographic
and echocardiographic evidence of ischemia in men with known coronary artery
disease or high pretest probability of coronary artery disease.
All study subjects were men older than 40 years with erectile dysfunction
and either known coronary artery disease (≥50% diameter stenosis of a major
epicardial vessel or one of its major branches, history of myocardial infarction,
prior positive stress imaging test result, or prior coronary artery bypass
surgery or angioplasty) or a high (>70%) pretest probability of coronary artery
disease, according to the presence of typical angina pectoris.8
Subjects werw recruited via posted advertisements, Mayo Clinic newsletter
announcements, and physician referrals; in all cases, primary care physicians
agreed to the subjects' participation. All subjects had adequate resting echocardiographic
images, were able to exercise, and agreed to participate in the study. No
subject had asthma, severe aortic stenosis, hypertrophic obstructive cardiomyopathy,
unstable angina, recent myocardial infarction (within 1 month), significant
arrhythmia or atrial fibrillation, congestive heart failure, hepatic insufficiency,
renal insufficiency, or a systolic blood pressure less than 90 mm Hg. No subjects
were receiving therapy with dipyridamole, theophylline, erythromycin, or cimetidine,
nor had they used sildenafil within the previous 24 hours. The use of long-acting
nitrates was discontinued at least 72 hours before testing; the use of other
cardioactive medications was continued. The sildenafil citrate dose was 50
mg, unless another dose was recommended by the man's physician. The study
was approved by the institutional review board of the Mayo Clinic, Rochester,
Minn. Written informed consent was obtained from all subjects.
All patients underwent 2 symptom-limited exercise echocardiograms separated
by an interval of 1 to 3 days. Cardioactive medications were not changed between
the 2 tests. Subjects were randomized in a double-blind crossover design to
receive a single dose of sildenafil or placebo 1 hour before the exercise
test. The order of administration was determined by a randomization schedule
in blocks of 10, generated within the Section of Biostatistics, Mayo Clinic,
so that half of the study population underwent the initial test after receiving
sildenafil and half after receiving placebo. Sildenafil and placebo preparations,
identical in appearance, were prepared in the institution's pharmacy and labeled
"first test" and "second test" for each study, according to the randomization
schedule. Unblinding was performed only after the database was closed.
Baseline echocardiographic images (parasternal long-axis and short-axis
views and apical 4-chamber and 2-chamber views) were obtained and repeated
1 hour after the administration of sildenafil or placebo. The exercise echocardiogram
was performed with a supine bicycle (Medical Positioning, Kansas City, Mo)
attached to a table tilted 30° to 45° to the left. Subjects began
exercising at 25 W, with a 25-W increase in the resistance at 2-minute stages.
Workload in metabolic equivalent tasks (METs) was calculated with a standard
equation for ergometer exercise.9 Echocardiographic
imaging was performed continuously during each stage of the exercise protocol
by using an ultrasound system (Acuson Sequoia, Mountain View, Calif) with
a 3-MHz transducer and harmonic-imaging mode. The study was recorded on videotape,
and representative cardiac cycles were acquired, digitized, and stored for
each standard view at rest, 25 W, peak exercise, and immediate recovery. The
criteria for test termination were development of symptoms, including fatigue,
a systolic blood pressure decrease greater than 10 mm Hg, ventricular dilation
or global reduction of systolic function, or significant arrhythmia.
Baseline blood pressure and heart rate were recorded before sildenafil
or placebo administration and immediately before the exercise test. During
exercise, blood pressure and pulse were recorded at the end of each stage,
a 12-channel electrocardiogram was obtained each minute, and 3-channel monitoring
of cardiac rhythm was performed continuously.10,11
After termination of exercise testing, subjects were monitored for 15 minutes.
Oxygen via nasal cannula and intravenous esmolol hydrochloride were available
for treatment of persistent symptoms and evidence of marked ischemia.
Interpretation of the echocardiographic studies was performed by a single
experienced reviewer (P.A.P.) blinded to clinical information, subject identity,
and results of the other stress echocardiogram. Each study was scored semiquantitatively
with a 16-segment model.12 Each segment was
analyzed individually and scored by motion and systolic thickening at rest,
1 hour after medication, and with exercise. Wall motion was scored according
to a 5-point grading system (1 = normal or hyperdynamic, 2 = hypokinetic,
3 = akinetic, 4 = dyskinetic, and 5 = aneurysm).10,11
The wall motion score index (WMSI) was calculated at rest and with exercise
as the sum of the scores divided by the number of segments visualized. The
normal response to exercise was an increase in contractility. Myocardial ischemia
was diagnosed when the exercise echocardiographic images documented a new
regional wall motion abnormality or worsening of preexisting wall motion.10,11 Resting wall motion abnormalities
were classified as infarction. For assessment of the number of vascular regions
with echocardiographic abnormalities, the anterior, anteroseptal, midinferoseptal,
and apical segments were attributed to the left anterior descending coronary
artery, the anterolateral and inferolateral segments to the circumflex, and
the inferior and basal inferoseptal segments to the right coronary artery.
The percentage of ischemic segments was determined at peak exercise. The heart
rate at the onset of new or worsening wall motion abnormalities was recorded.
Left ventricular ejection fraction and end systolic volume were assessed at
baseline, 1 hour after administration of sildenafil or placebo, and at peak
exercise by using the biplane Simpson method.13
Exercise electrocardiography results were considered positive for ischemia
if there was horizontal or downsloping ST-segment depression of 1 mm or more
at 80 milliseconds after the J point, nondiagnostic if the baseline ST segment
was abnormal, or negative for ischemia in the absence of these criteria. The
heart rate at which the electrocardiogram result became positive was recorded.
Continuous variables were summarized as the mean (SD). Categorical variables
were summarized as percentages. In the first step of the analysis, a test
for residual carryover effects of sildenafil was conducted for each variable
and none were significant (all P>.05).14
For continuous variables, treatment effects were assessed by calculating the
difference between first and second study data. These differences were then
compared between the subjects randomized to receive placebo and then sildenafil
vs sildenafil and then placebo by using the 2-sample test with corresponding
95% confidence intervals (CIs).15 The matched-pairs
paired t test was used to evaluate differences between
premedication and postmedication data (ie, before vs after sildenafil administration
and before vs after placebo administration). To evaluate differences in categorical
data, variables were categorized as follows: −1, positive result in
the first study and negative result in the second study; 0, positive result
in both studies or negative result in both studies; and 1, negative result
in the first study and positive result in the second study. The linear trends
test for percentages was then used to assess significant treatment differences
by comparing these categorizations between the subjects randomized to placebo
and then sildenafil vs sildenafil and then placebo.16
Odds ratios and corresponding 95% CIs for these comparisons were estimated
with the method of Gart17 and converted to
relative risk estimates by using methods described by Zhang and Yu.18
The sample size for this study was based on detectable differences of
exercise WMSI between the 2 treatments. Our initial estimate of the SD for
exercise WMSI for this study was 0.6 and was based on treadmill stress echocardiographic
studies conducted in men who were older than 40 years and had known or high
pretest probability of coronary artery disease between January 1990 and September
1998. A conservative estimate of the SD of the paired difference in exercise
WMSI between the 2 examinations would be approximately 0.85 (ie, √2
× 0.6), which is considered conservative because observations on the
same subject under the different treatments will be positively correlated,
thus reducing the SD of paired differences. Given the estimates, this study
had approximately 80% power to detect a mean increase in exercise WMSI of
0.24 between the 2 treatments, assuming a 2-sided significance level of .05
with 100 subjects (analyses performed with SAS software version 6.12 [SAS
Institute Inc, Cary, NC]). In at least 3 of the 16 segments, this increase
corresponds to 1 or more levels on average per subject (eg, 3 or more segments
that change from hypokinesis to akinesis).
From March 4, 1999, through October 4, 2000, 110 men were randomized
into the study (Figure 1). Of the
105 subjects with evaluable data, the mean (SD) age was 66 (9) years (range,
43-87 years). Ninety-three (89%) had known coronary artery disease and 29
(28%) had typical angina pectoris. Ninety-seven men (92%) received 50 mg of
sildenafil citrate; 8 (7%) received 100 mg. The median interval between tests
was 24 hours (range, 22-77 hours). The use of long-acting nitrates was discontinued
in 21 subjects (20%) 72 hours before exercise testing. Subjects' clinical
characteristics are summarized in Table
The baseline electrocardiogram result was abnormal in 59 patients (56%):
15 (14%) had previous Q-wave myocardial infarction, 42 (40%) had ST-segment
abnormalities, 1 (1%) had left ventricular hypertrophy, 7 (7%) had right bundle-branch
block, 1 (1%) had left bundle-branch block, and 13 (12%) had other conduction
Resting wall motion abnormalities were present in 60 patients (57%),
whereas the mean (SD) resting WMSI was 1.2 (0.3). The mean (SD) resting ejection
fraction was 56% (7%) (range, 39%-68%). A resting ejection fraction of less
than 50% was present in 16 men (15%) and less than 40% in only 2 men (2%).
Resting heart rate did not change significantly after sildenafil administration
(mean difference, 1/min; 95% CI, −0.1 to 2.1; P
= .08). Systolic blood pressure decreased significantly after sildenafil administration
(mean [SD], 135  mm Hg to 128  mm Hg; mean difference, −7 mm
Hg; 95% CI, −9 to −4 mm Hg; P<.001);
this significant decrease was not observed with placebo (mean [SD], 135 
mm Hg to 133  mm Hg; mean difference, −3 mm Hg; 95% CI, −6
to 0.3 mm Hg; P = .08). Diastolic blood pressure
did not change significantly after sildenafil administration (mean difference, −2
mm Hg; 95% CI, −4 to 0.1 mm Hg; P = .16) or
Exercise hemodynamic data are summarized in Table 2. After exercise, the rate of recovery for heart rate and
systolic and diastolic blood pressure was similar for sildenafil and placebo.
The average rate of decrease in heart rate from peak exercise was 3% (1%)
per minute for both sildenafil and placebo (mean difference, 0%/min; 95% CI, −0.1%
to 0.1%; P = .88). For systolic blood pressure, the
rate of decrease was 3.6 (1.5) mm Hg/min with sildenafil and 3.3 (1.5) mm
Hg/min with placebo (mean difference, −0.3 mm Hg/min; 95% CI, −0.5
to 0.02; P = .07). Diastolic blood pressure decreased
1.0 (0.8) mm Hg/min with sildenafil and 0.9 (0.8) mm Hg/min with placebo (mean
difference, −0.1 mm Hg/min; 95% CI, −0.3 to 0.1; P = .30).
The resting WMSI did not change significantly after administration of
sildenafil (mean difference, 0; 95% CI, −0.005 to 0.003; P = .53) or placebo (mean difference, 0; 95% CI, −0.005 to 0.005; P>.99). The resting ejection fraction did not change significantly
(56% [7%] before and 57% [7%] after sildenafil; mean difference, 0.3%; 95%
CI, −0.5% to 1.0%; P = .43) or placebo administration.
Symptoms of dyspnea or angina developed in 69 men taking sildenafil
and in 70 men taking placebo (P = .89). Reasons for
termination of exercise and electrocardiographic interpretations were similar
with sildenafil and placebo use (Table 3). One subject developed hypotension with exercise after taking
100 mg of sildenafil citrate. This subject's blood pressure decreased from
114/70 to 90/60 mm Hg at peak exercise. Blood pressure in recovery was 70/50
mm Hg. The subject was asymptomatic and was treated with a 500-mL intravenous
bolus of isotonic sodium chloride solution. Hypotension persisted for 22 minutes.
This subject was taking a calcium channel blocking agent, an α1-adrenergic receptor blocking agent, and aspirin.
There were no deaths, acute myocardial infarction, or ventricular fibrillation
associated with exercise studies. Nasal oxygen was administered during the
recovery period in 6 men (6%) taking sildenafil and 2 (2%) taking placebo
(P = .16). No subjects required treatment with an
intravenous β-blocker during recovery.
The interpretation of exercise echocardiograms was similar for sildenafil
and placebo (P = .49). The overall summary of interpretations
of exercise echocardiograms was as follows (Table 4): results were normal in 16 subjects (15%) taking sildenafil
and 14 (13%) taking placebo, ischemia was present in 25 subjects (24%) taking
sildenafil and 27 (26%) taking placebo, infarction was present in only 5 subjects
(5%) taking each, and infarction with ischemia was present in 59 men (56%)
taking sildenafil and placebo. In sildenafil and placebo groups, there was
no difference in the numbers of subjects with any ischemia (84 and 86 subjects,
respectively; p = .53) or multivessel ischemia (59
and 57 subjects, respectively; P = .62) or in WMSI
during exercise, ejection fraction, or heart rate at onset of ischemia.
In this prospective, randomized, double-blind crossover study in men
with erectile dysfunction and known or probable coronary artery disease, sildenafil
administered 1 hour before maximal, symptom-limited exercise testing was well
tolerated and did not change the onset, extent, or severity of ischemia, as
assessed by exercise electrocardiography or echocardiography.
Risk factors for erectile dysfunction and coronary artery disease are
similar and include age, diabetes mellitus, hypertension, and smoking.19 The coexistence of coronary artery disease and sexual
dysfunction in middle-aged and older men is common. Phase 2/3 studies of sildenafil
include predominantly patients without coronary artery disease and patients
at low risk for coronary artery disease. In those studies, sildenafil improved
erectile function and was well tolerated, and the incidence of severe adverse
effects was low.20- 22
However, in patients who have used sildenafil, 130 deaths have been reported
to the Food and Drug Administration.23 Seventy-seven
had cardiovascular events, including 41 with definite or suspected myocardial
infarction, 27 with cardiac arrest, 6 with cardiac symptoms, and 3 with coronary
artery disease. Accordingly, there has been concern regarding the safety of
sildenafil in patients with ischemic heart disease.7
The men in our study are likely representative of many seeking treatment for
This is the first report, to our knowledge, to describe exercise testing
with sildenafil monitored by both electrocardiography and an imaging technique.
Exercise echocardiography is a well-validated, noninvasive technique to evaluate
patients with known or suspected coronary artery disease.24- 26
It is safe, sensitive, and specific, with an overall accuracy similar to that
observed with other imaging techniques and higher than that of exercise electrocardiography.25 In our study, bicycle exercise echocardiography allowed
continuous echocardiographic imaging throughout exercise, which enhanced the
safety of the study. It also permitted assessment of the heart rate at which
new wall motion abnormalities, indicative of ischemia, first developed.
In most of our subjects, exercise echocardiography demonstrated exercise-induced
myocardial ischemia. However, exercise was no more likely to induce ischemia
after sildenafil use than after placebo use. The extent and severity of ischemia
and the heart rate at which it developed were similar. In this study group
of 105 men, despite frequent ischemia after either placebo or sildenafil use,
there were no clinically significant events. However, the study was powered
only to assess the impact of sildenafil on extent and severity of ischemia.
Larger numbers would be needed to assess any potential impact on clinical
Despite the randomized, double-blind design of the study, subjects may
have been able to determine when they received sildenafil. However, the paramedical
staff members who administered the test were not told which drug the subject
had received. The physician who interpreted the tests was not present during
the performance of the tests. Therefore, it is unlikely that nonblinding could
have affected the results of this study.
In our study subjects, there was a slight decrease in blood pressure
at rest after sildenafil administration, without changes in heart rate. A
discrete blood pressure reduction at rest after sildenafil administration
has been attributed to vasodilation and described both in healthy subjects
and patients with stable angina.27,28
The peak plasma concentration following an oral dose occurs approximately
1 hour after sildenafil administration.27 The
maximum decrease in blood pressure occurs at this time.27,29
Therefore, to maximize any potential adverse effects of the drug, stress testing
was performed 1 hour after administration of the drug.
Exercise, including sexual activity, may trigger acute coronary events
in patients with coronary artery disease.30- 32
In our subjects, the exercise-induced increments in blood pressure and heart
rate with exercise were similar with and without sildenafil use. During sexual
intercourse, heart rate and blood pressure increase as with other forms of
exertion.33,34 Hellerstein and
Friedman35 monitored middle-aged men with known
or suspected coronary artery disease during sexual intercourse with their
spouses at home and observed a mean peak heart rate of 117/min. The mean (SD)
peak exercise heart rate of patients in our study was slightly less (110 /min).
Our observations suggest that myocardial ischemia during sexual activity may
be common in men with stable coronary artery disease.
The typical maximum workload during coitus is approximately 3.3 to 3.4
METs for less than 30 seconds.34,35
Guidelines from the American College of Cardiology and the American Heart
Association suggest that if a patient can exercise more than 5 to 6 METs without
demonstrating ischemia on exercise electrocardiography testing, the risk of
ischemia during sexual intercourse is probably low.7
In our study, which included only men who could exercise, the mean (SD) exercise
capacity was not affected by sildenafil use (4.5 [1.0] METs with sildenafil
and 4.6 [1.0] METs with placebo, P = .29).
In this study, men were not taking nitrates or had discontinued the
use of nitrates 72 hours before exercise testing. Both nitrates and sildenafil
promote increased cyclic guanosine monophosphate levels. An interaction during
concomitant administration of sildenafil and nitrates promotes marked reductions
in blood pressure because of vasodilation in both animal models and humans.29,36 Of the cardiovascular deaths reported
to the Food and Drug Administration, some involved a possible interaction
between sildenafil and nitrates.7,23
Therefore, the coadministration of nitrates and sildenafil was assiduously
avoided in our study.
Oral sildenafil increases coronary flow reserve in severely stenotic
coronary arteries to an extent comparable to the increase in normal coronary
arteries, thus preserving the ratio of flow reserve in stenotic and normal
vessels.28 In another study37
of patients with chronic heart failure, oral sildenafil increased epithelium-dependent,
flow-mediated vasodilation when compared with placebo. These studies, albeit
in small numbers of patients, support our conclusions that oral sildenafil
does not have an adverse effect on stress-induced myocardial ischemia in patients
with ischemic heart disease.
The number of men with left ventricular dysfunction included in our
study was limited. Although a variety of medications were taken by the subjects
in this study, numbers were too small to permit subgroup analysis. Significant
hypotension developed in a single subject who had taken 100 mg of sildenafil
citrate. Numbers of men receiving the 100-mg dose were too small for conclusions
to be drawn about the safety of this dose in this population.
Patients with known or suspected coronary artery disease and erectile
dysfunction should have an individualized assessment before sildenafil prescriptions
are issued. Exercise testing can be performed after sildenafil administration
and may be indicated for risk stratification of some patients. Patients with
stable coronary artery disease who are able to exercise to 4.5 METs without
angina or hypotension and with a negative or mildly positive stress test result
can probably safely take sildenafil. Further research will be needed, though,
to clarify what levels of functional capacity and severity of ischemia can
be considered truly safe for men with coronary disease who wish to use sildenafil.
In men who had known or probable coronary artery disease and were able
to exercise, sildenafil had no effect on the presence or extent of exercise-induced
regional wall motion abnormalities, symptoms, exercise duration, or arrhythmias.
In patients who have stable coronary artery disease and are not taking nitrates,
sildenafil did not potentiate myocardial ischemia.