Safety concerns related PDE-5 inhibitors have been
alleviated by data from clinical studies in general
and coronary artery disease (CAD) populations conducted
in the last 5 years. High-risk patients with CAD were
excluded from initial safety studies. A study by DeBusk
and colleagues in 150 patients with manifest CAD comparing
placebo and sildenafil concurred with the other studies
that there were no significant safety concerns. Mechanistic
studies uniformly demonstrated that PDE-5 inhibitors
do not worsen myocardial ischemia in patients undergoing
exercise testing. Hence, the overall conclusion is
that sildenafil is safe, even in patients with CAD.
The Metabolic Equivalent of the Task (MET) is the
standard clinical measure of physical exertion. The
resting state is associated with 1 MET and the Bruce
treadmill test, walking at 4.2 miles per hour at 16%
gradient, with 13 METs. Sexual activity pre-orgasm
is established at 2-3 METs and during orgasm at 3-4
METs. However, the values for sexual activity were
established in very young persons and may not directly
relate to the experience of older persons commonly
evaluated for erectile dysfunction (ED).
Arousal and exertion represent 2 distinct domains
of sexual activity. The adrenergic surge and cathecholamine
response in arousal may increase risk, even in the
absence of substantial physical exertion. Bohlen and
colleagues reported in 1984 a well-conducted study
to characterize the effects of various types of sexual
activity in healthy men (mean age 33 years, range
25-43 years) and their wives carrying out 4 distinct
types of sexual activity to orgasm in the laboratory
(coitus, man-on-top; coitus, woman-on-top; self-stimulation;
partner stimulation). Oxygen uptake, heart rate, and
blood pressure were measured during sexual activity
and a treadmill exercise test performed after sexual
activity. Caution is required in extrapolating these
values measured in younger persons to an older patient
population. The resting heart rate value was about
70 beats per minute (bpm) and peaked at 125 bpm at
orgasm in the coitus man-on-top position. In the other
3 types of sexual activity, the heart rates were similar.
Thus, arousal appears responsible for most of the
increase in heart rate from baseline to the peak observed
value, with perhaps some additional contribution ascribed
to exertion in the man-on-top that position. A very
similar pattern was seen for the METs, with a resting
value of 1 and a peak value of about 3 with coitus
man-on-top. The METs values were similar for the other
3 types of sexual activity; arousal was responsible
for most of the increase in METs.
A very large functional reserve was demonstrated
in the Bohlen study population: a treadmill capacity
of 10 METs with a peak heart rate of 165 bpm compared
to sexual activity capacity of 4 METs and peak heart
rate of 125 bpm. In an older group of healthy men
65 years of age, the treadmill capacity can be expected
to be about 10 METs with a peak heart rate of 165
bpmstill a very substantial functional reserve.
These persons clearly would be able to carry out sexual
activity without concern for their metabolic capacity.
Moreover, in older persons it is likely that peak
heart rate and the MET capacity during sexual activity
is less than in younger persons.
A treadmill exercise test will provide an idea of
what is the capacity of the patient and what is their
functional reserve, and this is often very helpful
in prescribing sexual activity for patients with CAD.
Table
1. Clinical Trials of Sildenafil |
Acute
MI |
Rate/100
patient years |
Placebo
|
0.95 |
Sildenafil,
DB |
0.85 |
Sildenafil,
OL |
0.53 |
Sildenafil,
total |
0.58 |
All-Cause
Mortality |
Rate/100
patient years |
Placebo |
0.53 |
Sildenafil,
DB |
0.55 |
Sildenafil,
OL |
0.34 |
Sildenafil,
total |
0.37 |
The Prescription Event Monitoring (PEM) study conducted
in England in 6501 men (mean age 57 years, follow-up
4.9 months) evaluated the risk of cardiac events in
patients who had recently begun sildenafil treatment.
Primary care physicians surveyed adverse events reported
by men who had begun sildenafil treatment for ED.
Morbidity and mortality rates in this study were comparable
with age-standards norms. The incidence of MI and
ischemic heart disease mortality was virtually identical
in the treated men compared to a reference population,
and this was also true for MI, death from MI or death
from IHD. There was no evidence of increased risk
of MI or death from MI in men receiving sildenafil
compared to the general English population.
Table
2. Events in the Prescription Event Monitoring
Study |
Incidence
of MI and IHD mortality
0.31100 patient-years in treated men vs
0.31100 patient-years in general population.
Incidence of MI, death from MI, or death from
IHD
0.71100 patient-years in treated men vs
0.61100 patient-years in general population. |
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Sexual activity is a less potent trigger of an acute
coronary event than are smoking, hyperlipidemia, exercise,
and anger. In both an MI and death, the rupture of
a vulnerable coronary plaque is the mechanism. It
is characterized by a thin cap and is nonobstructive.
Notably, patients are generally asymptomatic.
Thus, a patient may be completely asymptomatic and
have no treadmill-inducible ischemia, and yet have
some narrowing of the coronary lumen and a thin-walled
plaque overlying a lipid-containing material. If the
plaque should rupture, generally near the margins
and the lipid material enters the lumen, thrombosis
of various degrees can result and the acute coronary
syndromes are then recognized, including AMI. In the
US, some 100 million persons have 1 or more major
risk factors and 50 million have 2 or more major risk
factors.
Patients with known CAD often have inducible ischemia
or angina, and generally have an occlusive, thick-walled
plaque insulating the lipid material. This type of
lesions is not usually associated with acute coronary
syndromes (ACS), but is associated with the clinical
manifestations of angina. In the US, about 18 million
patients have established CAD, and about 9 million
persons with some combination of the major risk factors.
How do we identify the patients susceptible to ACS
(50 million at high risk, 9 million with established
CAD), whether or not sexual activity is the trigger
for those syndromes?
An ischemic response to exercise might be expected
in about 1/3 of the clinical CAD population. However,
the problem is the 2/3 of persons who do not have
an ischemic responsea substantial proportion
will have evident vulnerable plaque. About 40% of
patients with clinical CAD will demonstrate vulnerable
plaque, and they represent a very substantial challenge
for management.
Even more challenging is the 50 million patients
at higher risk for CAD. In this population, perhaps
10% would show ischemia, some of whom would not show
a vulnerable plaque. But the great majority of patients
in this population will show vulnerable plaque in
the absence of any ischemia. This is a continuing
challenge.
The rate of AMI and death may approximate 3% per
year in the clinical CAD population, accounting for
120,000 acute events annually. But the 20 million
patients at high-risk for CAD account for 200,000
acute events annually, despite the lower annual rate.
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Identifying
persons at risk for AMI |
The clinical spectrum of CAD can be likened to an
iceberg, with the clinical manifestation of angina
representing just the visible tip of the iceberg,
preclinical silent ischemia and endothelial dysfunction
representing the major core of unseen iceberg, and
normal patients the shallow base of the iceberg.
The presence of coronary endothelial dysfunction
is prognostic. One study showed that most of the patients
with anatomically normal coronary arteries had vasoconstriction
in response to acetylcholine injection and had a less
favorable prognosis, compared to the smaller number
of patients who had vasodilation and a more favorable
prognosis. Clearly, the endothelium may be dysfunctional,
even in normal coronary arteries.
Erectile dysfunction is often an early sign of CAD.
Any lumen narrowing or endothelial dysfunction will
be seen in the penile arteries before the coronary
arteries, because the penile arteries are smaller
in diameter (1-2 mm) than coronary arteries (3-4 mm).
Erectile dysfunction and endothelial dysfunction
share common precursors and similar outcomes. Diabetes,
hypertension, dyslipidemia, and smoking contribute
to oxidative stress that results in endothelial cell
injury. The clinical manifestations can include vasoconstriction,
thrombosis, acute coronary events, chronic CAD due
to atherosclerosis, and, importantly, erectile dysfunction.
The similarity between these two phenomena must be
recognized.
Erectile dysfunction, in most cases, is a consequence
of endothelial dysfunction. But many patients with
endothelial dysfunction may not manifest erectile
dysfunction at a particular point in time, but over
time they are likely to do so. In fact, the erectile
dysfunction may be an early indicator of subclinical
CAD or at least of endothelial dysfunction involving
the coronary arteries.
Management of the two EDs is a big challenge.
Risk factor modification is required in patients with
clinical CAD and those at risk. An important therapeutic
approach to erectile dysfunction is smoking cessation,
in conjunction with exercise, diet, and the treatment
of chronic conditions, such as hyperlipidemia, hypertension,
and diabetes. Combination pharamacotherapy to prevent
recurrent ACS has included beta-blockers, ACE inhibitors,
statins, and antiplatelet agents.
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ED: An indicator
of endothelial dysfunction |
The clinical spectrum of CAD can be likened to an
iceberg, with the clinical manifestation of angina
representing just the visible tip of the iceberg,
preclinical silent ischemia and endothelial dysfunction
representing the major core of unseen iceberg, and
normal patients the shallow base of the iceberg.
The presence of coronary endothelial dysfunction
is prognostic. One study showed that most of the patients
with anatomically normal coronary arteries had vasoconstriction
in response to acetylcholine injection and had a less
favorable prognosis, compared to the smaller number
of patients who had vasodilation and a more favorable
prognosis. Clearly, the endothelium may be dysfunctional,
even in normal coronary arteries.
Erectile dysfunction is often an early sign of CAD.
Any lumen narrowing or endothelial dysfunction will
be seen in the penile arteries before the coronary
arteries, because the penile arteries are smaller
in diameter (1-2 mm) than coronary arteries (3-4 mm).
Erectile dysfunction and endothelial dysfunction
share common precursors and similar outcomes. Diabetes,
hypertension, dyslipidemia, and smoking contribute
to oxidative stress that results in endothelial cell
injury. The clinical manifestations can include vasoconstriction,
thrombosis, acute coronary events, chronic CAD due
to atherosclerosis, and, importantly, erectile dysfunction.
The similarity between these two phenomena must be
recognized.
Erectile dysfunction, in most cases, is a consequence
of endothelial dysfunction. But many patients with
endothelial dysfunction may not manifest erectile
dysfunction at a particular point in time, but over
time they are likely to do so. In fact, the erectile
dysfunction may be an early indicator of subclinical
CAD or at least of endothelial dysfunction involving
the coronary arteries.
Management of the two EDs is a big challenge.
Risk factor modification is required in patients with
clinical CAD and those at risk. An important therapeutic
approach to erectile dysfunction is smoking cessation,
in conjunction with exercise, diet, and the treatment
of chronic conditions, such as hyperlipidemia, hypertension,
and diabetes. Combination pharamacotherapy to prevent
recurrent ACS has
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Evaluation
of patients with erectile dysfunction |
Stepwise risk stratification and patient management
was developed as a clinical framework for the evaluation
of patients with erectile dysfunction, by the Princeton
Conference in 1999.
Based on this risk stratification, the 50%-70% of
patients who do not have evidence of severe myocardial
ischemia or LV dysfunction can be encouraged to initiate
or resume sexual activity and be treated for sexual
dysfunction, including the use of sildenafil or the
other PDE-5 inhibitors. High-risk patients who report
severe ischemia or LV dysfunction should be advised
to defer sexual activity until the cardiac condition
is stabilized. Patients in the indeterminate risk
group should undergo cardiovascular assessment and
re-stratification into either the low risk or high
risk category.
Low
Risk Features |
Asymptomatic, < 3 major risk factors for CAD
Controlled hypertension
Mild, stable angina
S/P coronary revascularization, MI
Mild valvular disease
Mild heart disease |
High
Risk Features |
Unstable or refractory angina
Moderate/severe heart failure
High-risk arrhythmias
Moderate/severe valvular disease
Cardiomyopathies |
Intermediate
Risk Features |
3 or more coronary risk factors
Moderate, stable angina
Moderate heart failure
Cerebrovascular or peripheral vascular disease
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Safety of
PDE-5 inhibitors in cardiac patients |
In a few patients sexual activity may be inadvisable
due to underlying cardiac conditions, although that
tends to be infrequent. PDE-5 inhibitors interact
with nitrates. Because PDE-5 inhibitors potentiate
the hypotensive effects of organic nitrates, even
in non-cardiac persons, they are contraindicated in
patients receiving organic nitrates. The AHA/ACC
recommendations regarding PDE-5 inhibitors state that
patients who use PDE-5 inhibitors should not use organic
nitrates.
DeBusk and colleagues reported there are 2 reasons
for post-coital angina. One is dynamic and transient
and results simply from a transiently increased myocardial
oxygen demand due to an increase in heart rate, blood
pressure and the effects of arousal. However, often
in the setting of post-coital angina the patient is
experiencing more than just transient angina, but
the early phases of what may be a progressive syndrome
that would be classified as an ACS.
Patients who are prescribed PDE-5 inhibitors should
be told to go to the emergency department at the hospital
if they develop post-coital angina. Many of these
patients will be having an ACS and can be appropriate
diagnosed and treated.
Patients who are not encouraged to seek emergency
services and to tell the emergency staff they have
taken a PDE-5 inhibitor are often reluctant to seek
urgent care. Particularly if the patient has taken
a nitrate, even though they have been told not to
be the physician prescribing the PDE-5 inhibitor.
In the US, many patients will still take a nitrate,
despite the warning from the physician, because they
think it will help with the angina. Therefore, patients
must be told clearly that they may experience post-coital
angina, and if they do so, do not take nitrates and
to go the emergency room. This would avoid a lot of
the reluctance of patients to seek urgent care and
would also alleviate a lot of the concern of physicians,
including cardiologists, to prescribe PDE-5 inhibitors,
especially for patients with known CAD. If a patient
experiences post-coital angina and has not taken a
PDE-5 inhibitor, he can take nitroglycerine and if
the angina persists seek emergency care.
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PDE-5 inhibitors:
onset and duration of activity |
Tadalafil has a longer half-life than sildenafil
or vardenafil. Clinicians, including cardiologists,
have questioned whether the additional hours of active
half-life in which an interaction can be demonstrated
between nitrates and tadalafil constitutes an increased
clinical risk. If it does constitute an increased
risk, post-coital angina probably occurs infrequently
and DeBusk is not persuaded there is any additional
risk to patients who have used tadalafil. If post-coital
angina does not occur, the question often is whether
angina will occur later during, unrelated to sexual
activity, but the patient cannot take a nitrate because
he has taken tadalafil. Patients who have had
post-coital angina will usually report they have had
angina previously, so tadalafil was not a unique precipitant
of angina. The patient taking tadalafil or any other
PDE-5 inhibitor who has angina after sexual activity
will have angina under other circumstances, with one
exception: some patients are so sedentary that virtually
the most strenuous activity is sexual activity and
that represents a somewhat different category of patient
and represent an indication for an exercise test in
these persons.
Table
4. Characteristics of PDE-5 inhibitors |
PDE-5
Inhibitor |
Onset
median (min) |
Onset
range (min) |
Duration
(h) |
Half-life
(h) |
Sildenafil |
27 |
30-60 |
4 |
3-5 |
STadalafil |
45 |
30-45 |
36 |
17.5 |
Vardenafil |
26 |
20-40 |
4 |
4 |
Alpha-1 blockers are another consideration in conjunction
with PDE-5 inhibitors. With sildenafil, the precaution
is for 25 mg alpha-1 blocker no sooner than 4 hours
after taking sildenafil. For tadalafil, all apha-1
blockers except tamsulosin 0.4 mg are contraindicated.
For vardenafil, all alpha-1 blockers are contraindicated.
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Novel uses
of PDE-5 inhibitors |
Clearly, there will be standard applications for
PDE-5 inhibitors in erectile dysfunction, with the
main concerns of drug interactions with nitrates and
alpha-1 blockers. Emerging applications include the
use of PDE-5 inhibitors to mitigate the effects of
endothelial dysfunction in at least the pre-clinical
phases of CAD to benefit the endothelium of patients
destined to develop CAD. Once angina appears, there
is clearly the complication of using nitrates in these
patients. This is an exciting area of research and
some studies demonstrate a beneficial effect of PDE-5
inhibitor on the coronary endothelial function. This
class of drugs is already in use for primary pulmonary
hypertension and in other cases of heart failure.
The treatment practice for hyperlipidemia provides
a framework for understanding the broader use of PDE-5
inhibitors. Considering the initial approach to hyperlipidemia,
the clinical approach was to treat elevated lipoprotein
values to target levels. The emphasis for management
was largely anatomic and measured in terms of the
degree to which the burden of coronary atherosclerosis
might be diminished. The focus was on disease. In
recent years, there has been a shift in emphasis,
with the current approach being to screen patients
for an increased coronary risk of MI and death and
to use the statins as a component of combination pharmacotherapy
to reduce risk. The emphasis is functional, to prevent
ACS, and ultimately the focus is on health. Higher
and higher doses of statins are being used in broader
populations to prevent ACS. The same will be
true of PDE-5 inhibitors. They will be used in conjunction
with other medications to enhance the health of patients
with underlying ischemic heart disease.
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Clinical
practice and PDE-5 inhibitors |
There are patient-partner related considerations
in clinical practice, including failure to seek care
and premature discontinuation of effective therapy.
Not all patients with erectile dysfunction will seek
treatment.
There are also professional considerations, including
reimbursement for treatment of erectile dysfunction.
Importantly patient attitudes towards erectile dysfunction
often reflect the attitude and practices of health
care professionals. It has been true in the past that
patients often do not tell physicians about erectile
dysfunction, because they may feel shame, reluctance
to raise the issue, and often perceive that physicians
are not knowledgeable about its management. If clinicians
do not make it possible for the patient to disclose
that he has erectile dysfunction, he simply will not
do so. This means not only a lost opportunity to manage
the erectile dysfunction, but also to evaluate the
patients broader health, including the likelihood
of developing CAD. The benefits of the pharmacotherapy
can only extend as far as the clinical setting will
permit.
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Erectile dysfunction and CAD frequently co-exist.
Effective cardiovascular care of patients with erectile
dysfunction requires an emphasis on coronary risk
factors and combination pharmacotherapy. A comprehensive
approach will enable the great majority of patients
with erectile dysfunction and CAD to continue or resume
sexual activity. The patients disclosure of
erectile dysfunction presents the clinician with the
opportunity to evaluate the patients broader
health, including endothelial dysfunction, which may
lead to the development of CAD in the future.
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