We have known for more than a decade that erectile dysfunction (ED) is closely correlated with a number of chronic conditions involving compromised vascular function, such as coronary artery disease, hypertension, diabetes, and hypercholesterolemia.[1] It is only recently, however, with our improved understanding of the mechanism of erection and the pathophysiology of ED, that we are getting a clearer picture of the nature of these associations and interrelated etiologies. Advances in this area present clinicians with an opportunity to save lives and improve the quality of life of their patients.
A number of recent high-profile reports have alerted healthcare providers to one aspect of this ED-cardiovascular disease (CVD) connection -- that men with ED are likely to have or to develop cardiovascular risk factors -- so that ED can serve as a useful warning signal of potential heart disease down the road. The other side of this equation, however -- that men with heart disease are likely to have ED -- has received less attention. Even when they are aware of this association, practitioners treating a patient with a life-threatening condition such as heart disease may not be inclined to treat ED out of misplaced safety concerns. Other clinicians may downplay the importance of treating ED, considering it merely a nuisance condition. Patients, however, may think otherwise. One of the lessons we have learned of late is the importance of quality of life in overall health. ED can cause or exacerbate depression, which is known to be an independent risk factor in other conditions.
The purpose of this Clinical Update is to review the evidence demonstrating the association between ED and cardiovascular risk factors, and to discuss how clinicians may make use of recent advances in our understanding of these associations to improve the treatment of their patients.
ED, defined by the National Institutes of Health as the inability of a man to achieve and maintain a penile erection sufficient for sexual activity, has been estimated to affect up to 30 million men in the United States.[2] Results from the landmark Massachusetts Male Aging Study suggested that approximately 52% of men aged 40-70 years experienced ED to a greater or lesser degree.[1] Ten percent of the men in the Massachusetts study complained of complete ED (total inability to achieve an erection with sexual activity), 25% had moderate ED, and 17% minimal ED. Foremost among the risk factors for ED identified by this study was age. The prevalence of ED ranged from 40% at age 40 to 67% at age 70. Complete ED was found in 5% of men at age 40 and increased to 15% of men at age 70.
Among the modifiable risk factors examined in the Massachusetts study, ED was associated most strongly with heart disease and cardiovascular risk factors such as hypertension, diabetes, smoking, and lipid abnormalities, specifically a low HDL level. After adjusting for age, the probability of complete ED was found to be 39% in those with treated heart disease, 28% in those with treated diabetes, and 15% in those with treated hypertension, as compared with 10% in the study population as a whole. These associations of ED with cardiovascular risk factors have since been confirmed by a number of other studies.[3-6] A follow-up study to the Massachusetts Male Aging study[7] showed that other risk factors for CVD -- smoking and elevated body mass index (BMI) -- were also strongly associated with ED. Cigarette smoking almost doubled the likelihood of moderate or complete ED, which is not entirely surprising, but cigar smoking and even passive exposure to cigarette smoke also significantly predicted ED. There are, of course, nonvascular causes of ED, including neurologic and hormonal disorders, trauma, and structural abnormalities. In addition, ED may occur as a side effect of certain medicines. But in men over the age of 40, vascular disorders are the most likely cause of ED. The vascular etiology may occur even before well-delineated atherosclerotic plaques are observed in the arteries that supply the penis. One reason for this is that a very early step in the continuum of atherosclerosis is endothelial dysfunction. Endothelial dysfunction prevents normal vasodilation of the arteries, a process that can occur well before flow-limiting plaques develop. Smooth-muscle cell abnormalities may also contribute to the vascular component of ED.
Once it was firmly established by the Massachusetts study that ED and CVD shared the same risk factors, the question naturally arose as to whether ED could be a marker or sentinel for the development of cardiac events. Although this hypothesis has been put forth a number of times in recent years, solid evidence to back it up was lacking until the publication of a report by Thompson and colleagues[8] in 2005. This landmark study used data from the 9457 men in the placebo group of the Prostate Cancer Prevention Trial to determine whether ED was an associated subsequent development of CVD. The men were evaluated every 3 months for the development of ED and CVD over a 9-year period starting in 1994. Of the 4247 men who did not have ED at study entry, 2420 (57%) reported the development of ED (incident ED) in the subsequent 5 years. Only 15% of the men (1394 of 9457) had CVD at study entry. Following adjustment for other covariates (age, BMI, blood pressure, lipids, diabetes, family history, race, smoking, level of physical activity, and quality of life) incident ED was associated with a hazard ratio of 1.25 (95% confidence interval [CI] = 1.02-1.53; P = .04) for the development of new cardiovascular events during the study. For men who either had ED at the start of the study or developed it during the course of the study, the hazard ratio for developing CVD during the course of the study was 1.45 (95% CI = 1.25-1.69; P < .001). The cardiovascular events associated with ED included myocardial infarction, stroke, angina, transient ischemic attack, and others. In men presenting with incident ED and no prior cardiovascular event, the 7-year estimate of cardiovascular events approached 15%. The association between subsequent cardiovascular event and incident ED (0.015 per person-year) or ED at study onset (0.024 per person-year) was within the range associated with other well-known cardiovascular risk factors, such as current smoking or family history. The authors concluded that ED may be a predictor of cardiovascular events in some men and that ED should prompt a work-up of cardiovascular risk factors.
Other studies have lent further support to the possible use of ED as an early warning signal for CVD. Blumentals and coworkers[9] carried out a retrospective analysis of data from a large managed-care database in the United States. They identified 12,825 men with ED and an equal number without. The men with ED had a 2-fold increased risk for acute myocardial infarction (odds ratio = 1.99; 95% CI = 1.17-3.38) after adjusting for age, smoking, obesity, and the use of cardiovascular medicines. There was a trend for an increase in the risk between ED and myocardial infarction with age.
In another case-control study, Montorsi and colleagues[10] examined data from 300 consecutive patients who presented with acute chest pain and angiographically documented coronary disease using structured interviews and the validated International Index of Erectile Function questionnaire. The prevalence of ED among these men was 49% (14% mild, 21% mild to moderate, 14% moderate, and 51% severe). In 67% of these patients, ED symptoms were clinically evident before those of coronary artery disease. The mean time between development of ED symptoms followed by coronary artery disease symptoms was 38.8 months. All patients with diabetes (type 1) and ED developed ED before coronary artery disease symptoms. In an accompanying commentary, Montorsi proposed the "artery size hypothesis" to help explain the findings.[11] Given that atherosclerosis is a systemic disease, one would expect it to affect all vascular beds simultaneously. In actuality, however, symptoms rarely occur in all beds at the same time. Montorsi hypothesized that symptoms occur first in smaller blood vessels because they cannot allow passage of the same amount of plaques as the larger blood vessels. Because penile arteries are smaller in diameter than coronary arteries or carotid arteries, symptoms of ED should appear before symptoms of coronary artery disease or cerebrovascular disease. While this intriguing hypothesis is supported by some of the clinical reports described above, it has yet to be fully validated.
Montorsi's studies showed a relatively high prevalence of ED (49%) among men presenting with acute chest pain due to coronary artery disease, but there remained unanswered the question of how common ED is in men with stable chronic coronary artery disease. In order to study this issue, our research group[12] administered the validated Sexual Health Inventory for Men (SHIM) questionnaires to 76 men with chronic stable coronary artery disease during a routine outpatient visit to an urban cardiology practice. The mean patient age was 64 years; most of these men had not previously discussed ED with their cardiologist. The SHIM score, which takes into account the ability of a man to both achieve and maintain erection through successful sexual intercourse, was low, at 21 or less in 53 of the men (70%), results which are consistent with ED. Four of the men who completed the questionnaire had had a history of ED but were now being treated with sildenafil. The SHIM scores of these 4 men were nearly normal. With these 4 included among those with ED, 57 of 76 (75%) of the men with chronic coronary artery disease either had ED or had a recent history of ED. About a quarter of these men had severe ED. In contrast, the proportion of men with severe ED in the general population of men ages 40-70 is approximately 10%. Our report concluded that "ED is extremely common in men with chronic coronary artery disease (affecting approximately 75%) yet most cardiologists do not ask about it. The SHIM is a useful, quick, and inexpensive tool for discussion and diagnosis of ED in this population."
These studies certainly suggest that men presenting with ED ought to be questioned and worked up for cardiovascular risk factors (hypertension, dyslipidemia, diabetes, smoking, obesity, lack of physical activity). Identifying and treating these risk factors may reduce cardiovascular morbidity and mortality. Looked at it in one light, the clinician who examines a man presenting with ED has a wonderful opportunity to practice preventative cardiology. Conversely, if a patient presents with known heart disease or risk factors for CVD, he should be questioned regarding sexual health and ED. Many of these patients can benefit by receiving medical therapy for ED.
In June 2004, a conference on sexual dysfunction and cardiac risk was held in Princeton, New Jersey. The purpose of the conference was to update guidelines for the safe management of cardiac patients with ED that had been formulated at the first such meeting in 1999. The updated guidelines from the Second Princeton Consensus Conference[13] addressed in detail the treatment of sexual dysfunction in patients with risk factors for CVD or frank heart disease. According to the guidelines, patients are to be divided into low-, intermediate-, and high-cardiovascular-risk groups (Table). Patients in the low-risk category generally can initiate or resume sexual activity or receive therapy for ED, including the phosphodiesterase inhibitors. Patients in the high-risk group have unstable cardiac conditions which need to be addressed and corrected before initiation of therapy for sexual dysfunction. Patients in the intermediate group (eg, patients with moderate angina) require additional cardiovascular work-up (such as an exercise stress test or echocardiogram) before they can be reclassified into the high-risk or low-risk group. The panel recommended that all patients have cardiovascular risk factor evaluation and management. Lifestyle intervention in ED, such as weight loss and increased physical activity, were recommended.
Table. Cardiovascular Risk in Patients Presenting With ED: Second Princeton Consensus Conference| Risk Group | Clinical Features | Notes |
| Low-Risk Patients | Asymptomatic, < 3 cardiovascular risk factors | Risk factors include: age, male sex, hypertension, diabetes mellitus, smoking, dyslipidemia, sedentary lifestyle, and family history of premature coronary artery disease. |
| Controlled hypertension | With 1 or more antihypertensive medication. Beta-blockers and thiazide diuretics may predispose men to ED. | |
| Mild, stable angina pectoris | Antianginal drug treatment may have to be modified to accommodate ED drug. | |
| Post-revascularization | Stress testing may help in evaluating residual ischemia. Patients without significant residual ischemia are considered low-risk. | |
| History of myocardial infarction (> 6-8 weeks) | Asymptomatic patients who have had MI more than 6 weeks previously, those who show no ischemia upon stress testing, or those who have undergone revascularization are at low risk for coitus-induced myocardial infarction. | |
| Mild valvular disease | Patients with mild mitral valve disease or with mild aortic stenosis are not at significantly increased risk. | |
| Left ventricular dysfunction | New York Heart Association (NYHA) class I | |
| Other cardiovascular conditions | Patients with pericarditis, mitral valve prolapse, or atrial fibrillation with controlled ventricular response are not at high risk. | |
| Intermediate- or Indeterminate-Risk Patients | Asymptomatic, ≥ 3 risk factors (excluding male sex) | Risk factors include: age, hypertension, diabetes mellitus, smoking, dyslipidemia, sedentary lifestyle, and family history of premature coronary artery disease. Patients who are asymptomatic during moderately intense exertion do not require stress test. |
| Moderate, stable angina pectoris | Stress testing may help determine patient's risk profile. | |
| History of myocardial infarction (> 2 weeks, < 6 weeks) | These patients may be at heightened risk for sex-induced ischemia, reinfarction, and malignant arrhythmia. | |
| Left ventricular dysfunction or congestive heart failure | Patients in NYHA class II may be at risk for exacerbation of symptoms if they engage in sexual activity. | |
| Noncardiac sequelae of atherosclerotic disease | Patients with peripheral arterial disease, history of stroke or transient ischemic attacks have higher risk for myocardial infarction. | |
| High-Risk Patients | Unstable or refractory angina pectoris | Patients with unstable angina are at heightened risk for myocardial infarction during sex or exercise. |
| Uncontrolled hypertension | Patients with untreated, poorly controlled, accelerated, or malignant hypertension are at increased risk for cardiac and vascular events. | |
| Congestive heart failure | Patients with NYHA class III or IV congestive heart failure may be at heightened risk for cardiac decompensation. | |
| Recent myocardial infarction (<2 weeks) | Sexual activity may put these patients at increased risk for reinfarction, cardiac rupture, or arrhythmia. | |
| High-risk arrhythmia | Patients most at risk for malignant arrhythmias during sex seem to be those with left ventricular dysfunction. | |
| Obstructive hypertrophic cardiomyopathy | Risks of sexual activity for patients with this condition are not well defined. Further evaluation may help determine management. | |
| Moderate-to-severe valve disease | Risks of sexual activity for patients with this condition are not well defined. |
While the Princeton Guidelines are just that -- guidelines -- they do provide a reasonable approach to the patient who seeks therapy for sexual dysfunction but who also may have risk factors for CVD or heart disease. One analysis suggested that exercise stress testing was useful in the intermediate group. Solomon and colleagues[14] reported data on men with ED referred to a cardiologist for additional work-up. Patients who exercised more than 4 minutes (4.5-6.0 metabolic equivalents of the task - METS) on a Bruce protocol with normal blood pressure response and without ischemic symptoms or electrocardiogram changes were then reclassified as low-risk and offered ED treatment. Of 85 men who underwent an exercise treadmill test, 68 achieved the low-risk category and were offered immediate therapy for ED. Fourteen men reached an endpoint prior to 4 minutes of exercise and underwent further evaluation such as cardiac catheterization. An additional 3 men who reached an endpoint within 4 minutes had already had recent coronary angiography showing minimal disease and were restratified as low-risk patients. Treatment of ED among men who eventually were deemed low-risk was not associated with any subsequent cardiac events.
Mechanism of Action
The phosphodiesterase-5 (PDE-5) inhibitors -- sildenafil (Viagra, Pfizer), vardenafil (Levitra, Bayer HealthCare), and tadalafil (Cialis, Lilly) -- are the mainstay of therapy for ED. These agents have been shown to be highly effective in treating patients with ED associated with vascular disease. Their mechanism of action is via the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway -- the natural pathway by which an erection is known to develop. During sexual stimulation, NO is released by nonadrenergic-noncholinergic nerves as well as by the endothelial cells of the vasculature of the corpus cavernosum. The NO then enters the adjacent smooth muscle cells of the blood vessel where it stimulates guanylate cyclase to catalyze the formation of cGMP, which ultimately causes vascular smooth muscle relaxation with subsequent increased flow of blood into the sinusoids of the corpus cavernosum, leading to an erection. cGMP is then broken down by PDE-5 with resultant detumescence. The PDE-5 inhibitors prevent the breakdown of cGMP, relaxing the corpus cavernosum smooth muscle cell, thereby improving blood flow into the sinusoids and penile erection.
The Cardiovascular Safety of PDE-5 Inhibitors
The issue of the safety of the PDE-5 inhibitors, especially in the cardiac patient, has received considerable attention. Because PDE-5 is found not only in the arteries supplying the genitals but also in systemic arteries and veins, PDE-5 inhibitors are mild vasodilators and may be associated with small reductions in blood pressure. In general, falls in arterial blood pressure are less than 10 mm Hg and are usually not associated with a reflex tachycardia. Certainly, many of the common side effects of the PDE-5 inhibitors, such as headache, flushing, and dizziness, can be attributed to vasodilator side effects. Nevertheless, discontinuation due to these side effects, which are often considered nuisance side effects, is very low. Concern that PDE-5 inhibitors might induce severe hypotension or induce a coronary steal phenomenon (robbing blood flow from an already ischemic area of the heart and diverting it to an area of normal flow), and hence precipitate a myocardial infarction, has been shown to be groundless upon examination of data from large, placebo-controlled studies.[15,16] In these trials there was no evidence of an increase in the rate of myocardial infarction or cardiac death in men taking PDE-5 inhibitors vs placebo vs age-standardized male populations. Moreover, the PDE-5 inhibitors have not been shown to exacerbate ischemia during exercise stress testing of patients with known coronary artery disease. [17]
PDE-5 Inhibitors in Men With Coronary Artery Disease
The PDE-5 inhibitors have been shown to be effective in men with known coronary artery disease. Conti and colleagues[18] showed that sildenafil improved erections in 70% of men with known coronary artery disease compared with 20% in patients who received placebo. A recent analysis[19] confirmed and extended these results. Patients with ED and clinically stable coronary artery disease were randomized to sildenafil or placebo for 12 weeks. By 12 weeks, patients receiving sildenafil had significantly better improvements on questions 3 and 4 of the International Index of Erectile Function than did patients receiving placebo (n = 72; P < .01). Patients taking sildenafil were more likely to report improved erections (64%) and improved intercourse (65%) vs patients receiving placebo (21% and 19%). Of note, there were no serious drug-related adverse cardiovascular events.
PDE-5 Inhibitors in Men With Hypertension
Sildenafil was also shown to be effective in patients with hypertension, including those on multiple antihypertensive medicines.[20] In our study, the efficacy of sildenafil in patients with hypertension was about 70%. Of note, the incidences of treatment-related adverse events, adverse events potentially related to hypotension, and cardiovascular adverse events were similar to those observed in patients not taking antihypertensive medicines. Pickering and colleagues[21] studied men over the age of 18 years with a documented history of ED and hypertension who were receiving a stable dose of 2 or more antihypertensive medications. Patients then received either placebo (n = 283) or sildenafil (n = 279). While 71% reported improved erections in the sildenafil group, only 17.6% reported improved erections in the placebo group. Although 62.4% of the men reported successful intercourse attempts in the sildenafil group, only 26.1% reported successful intercourse in the placebo group. Adverse effects of the sildenafil were similar to what had been reported in patients not on antihypertensive medicines.
Initially, there was a concern that some patients with high blood pressure might become hypotensive if the vasodilator activity of the PDE-5 inhibitor was added to the effect of an antihypertensive medicine. Clinical trials showed that when PDE-5 inhibitors were administered to patients already on most major antihypertensive medicines, there were either very minimal or no additive reductions in blood pressure similar to those observed with the PDE-5 inhibitor alone. This observation has held true for all 3 of the PDE-5 inhibitors currently on the market. In addition, there were no increases in vasodilator side effects of the PDE-5 inhibitors with or without concomitant antihypertensives.[22-24]
Thiazide diuretics. Thiazide diuretics, such as hydrochlorothiazide, have been recommended as first-line treatment for hypertension by the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.[25] However, thiazide diuretics by themselves can induce ED (as can other antihypertensive agents, such as beta-blockers). Recently we tested whether the long-acting PDE-5 inhibitor tadalafil could improve ED in hypertensive patients receiving thiazide diuretics for hypertension. From placebo-controlled trials, 163 patients were identified who had been taking thiazides. Patients receiving tadalafil in this subgroup had an improvement in their International Index of Erectile Function from 14.0 at baseline to 23.4 after therapy. The proportion of patients who reported improved erection on the global assessment question was 87.4% in the tadalafil groups vs 32.6% of those receiving placebo; P < .001. Of note, in patients not receiving thiazides, the positive response to tadalafil was similar, at 85.2% (P < .001 vs placebo). In addition, vardenafil was also shown to be an effective PDE-5 inhibitor in men with ED who had hypertension and were taking antihypertensive medicines.[26]
Alpha-blockers. The labeling for all 3 PDE-5 inhibitors includes a precaution regarding potential hypotension with alpha-blocker use. Of course, alpha-blockers can cause orthostatic hypotension on their own, but some clinical studies suggested a potentiation of hypotension when PDE-5 inhibitor was given with an alpha-blocker. In general, it is best to start a PDE-5 inhibitor after the patient has been on a stable dose of an alpha-blocker for a period of time, and to begin with the lowest doses of each agent. For sildenafil, it has been suggested that doses of 50-100 mg not be given within a 4-hour window of an alpha-blocker; for the smallest available dose of sildenafil, 25 mg, no time restriction in regard to the alpha-blocker is necessary. As a general rule, patients should be educated about the potential risk of the PDE-5 inhibitor plus alpha-blocker combination and be monitored for signs and symptoms of orthostatic hypotension.[27]
Nitrates. All 3 PDE-5 inhibitors can potentiate the hypotensive effects of organic nitrates, and therefore use of these agents (including both short-acting and long-acting preparations of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate) is contraindicated in patients taking PDE-5 inhibitors. Organic nitrates are NO donors and hence increase the production of cGMP, which affects the NO-cGMP pathway. PDE-5 inhibitors prevent the breakdown of cGMP. Thus, when organic nitrates are administered at the same time as a PDE-5 inhibitor, there is both an increase in cGMP production as well as a decrease in breakdown of cGMP, which can then lead to an increase in cGMP with vasodilation and hypotension in some individuals. This phenomenon has been seen with all 3 of the currently available PDE-5 inhibitors.[28-30]
If a patient has taken sildenafil or vardenafil (which has a half-life of about 4 hours) and then develops angina, the recommendation of an American College of Cardiology/American Heart Association Consensus Committee is to withhold nitrates for 24 hours.[31] However, if a patient takes tadalafil (which has a half-life of about 17.5 hours) and then has angina, nitrates should be withheld for about 48 hours.[32] During the period of time in which nitrates should not be administered, other antianginal and anti-ischemic agents are reasonable choices -- beta-blockers, calcium blockers, aspirin, morphine, statins, and others.[33] Although nitrates are antianginal agents, they have not been shown to reduce adverse cardiovascular events or reduce cardiac death in the setting of an acute coronary syndrome.
PDE-5 Inhibitors in Men With Ventricular Tachycardia
Vardenafil does carry a precaution regarding the QT interval: "Patients with congenital QT prolongation and those taking Class 1A (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmics should avoid using Levitra,"[30] on the basis of studies showing small increases in QTc with this agent. Neither sildenafil nor tadalafil carries this warning.
Thus, studies to date suggest that PDE-5 inhibitors are effective in patients with known vascular disease, including coronary artery disease and hypertension.
While the PDE-5 inhibitor, sildenafil, started out as an agent being investigated for angina, it was only serendipity that led to the discovery that it improved erections during these trials. Recently there has been increased interest in the application of PDE-5 inhibitors for other cardiovascular applications. Because PDE-5 is rich in the pulmonary vasculature, sildenafil was shown to effectively treat pulmonary hypertension and recently was FDA-approved for this indication (as Revatio). The PDE-5 inhibitors also appear to improve endothelial function and are now being investigated for possible use in congestive heart failure and ischemic heart disease.
Supported by an independent educational grant from Pfizer.
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