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Special Lecture
Cardiovascular Implications of Treatment for Erectile Dysfunction
Robert F. DeBusk
Stanford University School of Medicine, Palo Alto, CA
 
  • AMI and sexual activity
  • Identifying persons at risk for AMI
  • ED: An indicator of endothelial dysfunction
  • Evaluation of patients with erectile dysfunction
  • Safety of PDE-5 inhibitors in cardiac patients
  • PDE-5 inhibitors: onset and duration of activity
  • Novel uses of PDE-5 inhibitors
  • Clinical practice and PDE-5 inhibitors
  • Closing


  • 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 bpm—still 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.

     





    AMI and sexual activity


    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 response—a 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 patient’s 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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    Closing


    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 patient’s disclosure of erectile dysfunction presents the clinician with the opportunity to evaluate the patient’s broader health, including endothelial dysfunction, which may lead to the development of CAD in the future.

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