Urologists need to consider the increased cardiovascular morbidity in men with erectile dysfunction
By Natan Bar-Chama, MD,
and Stan Honig, MD
ERECTILE dysfuction (ED), defined as the inability to reach or maintain an erection sufficient for satisfactory sexual performance, is age-related and an extremely prevalent medical condition. It is esti-mated to affect more than half of all men over the age of 60, and in the United States alone, ED will develop in more than 600,000 men aged 40-69 annually.1
Recent epidemiologic studies have solidified the relationship between ED, endothelial dysfunction, and cardiovascular disease (CVD). Although it is well accepted that these entities have common risk factors such as diabetes, obesity, hypertension, dyslipidemia, smoking, and metabolic syndrome, the role of ED as an early indicator of future cardiovascular morbidity is emerging. The urologic community stands at the forefront in promoting to medical colleagues the concept that ED is the “canary in the coal mine” for cardiovascular health.
Vital message for patients
Moreover, it is vital that we convey this message to ED patients. If they understand the link between ED and endothelial dysfunction and CAD, patients may be more willing to seek medical attention for ED, initiate proactive strategies to improve overall cardiovascular health, and ad-here to chronic phosphodiesterase-5 (PDE-5) therapy if its beneficial effects on endothelial dysfunction and CAD is further established.
There are two mechanisms by which CVD and ED are interrelated. In one model, the uniform vascular obstruction occurring secondary to atherosclerosis has a demonstrable clinical effect on the smaller penile arteries prior to the larger-diameter coronary arteries. In the second model, diffuse endothelial dysfunction defined as impaired nitric oxide (NO)-mediated smooth muscle relaxation occurs throughout the body and one of its early clinical manifestations is ED.
Pritzker et al2 were the first to demonstrate that a substantial number of “healthy” men with ED when further examined were discovered to have silent CAD. Fifty-six percent of his study population of 50 men with ED and no prior diagnosis of CAD had a positive cardiac stress test. In a pooled analysis of similar subsequent publications 22% of men with ED and no prior CVD had a positive stress test; of greater concern is the fact that 94% of these men had significant coronary stenosis at angiography.
Substantive epidemiologic data recently have further established ED as an independent and significant risk factor for future cardiac events such as MI and stroke. In men with symptomatic CAD and ED, Montorsi et al3 observed that the symptoms of ED were present on average three years prior to MI. Furthermore, long-standing ED (more than 30 months) was more significantly associated with multiple vessel disease at the time of the initial MI. In a large retrospective analysis of 25,000 men, Blumentals et al4 demonstrated that after adjusting for confounding variables (age at ED diagnosis, smoking, obesity, and medication usage), men with ED had
twice the risk of a heart attack as those without ED. On further analysis, men older than 40 years with ED had a three to four times greater risk of a heart attack compared with a younger cohort of men (age 30-39) without ED.
Gazzaruso et al5 recently defined the relationship between ED, silent significant myocardial ischemia, and type 2 diabetes. ED was present in 33.8% of diabetics with silent significant CAD compared to only 4.7% in men with no significant CAD. Af-ter adjusting for confounding variables, ED was found to be the most accurate predictor of silent CAD in this population.
In a study published in the Journal of the American Medical Association (2005;294:2996-3002), Ian M. Thompson, MD, and his colleagues illuminated the fact that ED is an independent and significant risk factor for future cardiovascular events. The researchers analyzed data on 4,247 men who participated in the Prostate Cancer Prevention Trial, which compared finasteride and placebo. The men were older than 55 years with no ED at study entry. After five years, 2,420 men (57%) reported ED. After adjusting for all covariates, men with incident ED had a significantly increased risk of angina, MI, and stroke compared to those without ED. The study also highlighted that the longer the duration of ED, the higher the likelihood that these men will experience a cardiovascular event. In their conclusion, ED was cited as an independent risk factor for subsequent cardiovascular events at the same or greater magnitude than a family history of premature CAD, smoking, or hypercholesterolemia.
Role of endothelial dysfunction
Endothelial dysfunction is an integral component of the pathogenesis of CVD and ED, and has been shown to be an independent predictor of future cardiovascular events. Kaiser et al6 was the first to demonstrate abnormal endothelial function in men with ED and no documented CAD. To date, all four published studies on the subject have demonstrated that men with ED and no clinical manifestations of CAD demonstrate abnormal endothelial function compared with controls who did not have ED. Detecting endothelial dysfunction in “healthy” men with ED further strengthens the concept that ED is an early marker of CVD that is independent of the more traditional risk factors.
In light of these compelling epidemiologic and scientific data link-ing ED, endothelial dysfunction and CAD, there is a need to define and use tests that will further stratify and identify ED patients at high risk for previously undetected CAD. The Princeton consensus panel reviewed the safety and drug interaction data for all three PDE-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant CVD. The Princeton II consensus guidelines highlighted that ED is an early symptom or harbinger of CVD, due to the common risk factors and pathophysiology mediated through endothelial dysfunction.7 They recommended that all men with ED should undergo a full medical assessment and concluded that any asymptomatic man who presents with ED that does not have an obvious cause should be treated as a cardiac (or vascular) patient until proven otherwise. As such, these men should be screened for vascular disease and undergo blood glucose, lipid, and BP measurements. Their recommendations also include that ideally, all patients at risk, but asymptomatic, for coronary disease should undergo an elective stress test to facilitate risk stratification. The Minority Health Institute (MHI) convened an expert advisory panel of cardiologists and urologists to design a new practice model algorithm that uses ED as a clinical tool for early identification of men with systemic vascular disease.8 The MHI algorithm stipulates that all men aged 25 years and older, regardless of sexual dysfunction complaints, should be asked about ED. The presence of ED should prompt an aggressive assessment for cardiovascular risk and occult systemic vascular disease.
Montorsi et al3 recommended additional noninvasive tests for those men with intermediate cardiac risk. This intermediate risk group, which is estimated to represent almost 40% of the U.S. population, is defined utilizing the standardized Framingham risk score as having a 10% to 20% risk of developing a heart attack or die from coronary disease in the next 10 years. Additional testing aimed to better define CAD risk should be considered in this population and include tests to assess both obstructive and non-obstructive CVD. Tests to assess obstructive CAD include: coronary calcium score by electron-beam computed tomography, electrocardiographic stress test, nuclear imaging, and coronary angiography. To ascertain non-obstructive diffuse cardiovascular risk, assessment of endothelial function, carotid intima-media thickness, ankle brachial index, and penile duplex Doppler were discussed by the authors.
It is apparent that urologists need to implement cardiovascular risk stratification to identify ED patients at high risk for previously undetected CAD. To broaden the urologist's role in identification of occult CVD, several diagnostic techniques can be incorporated including standardized CVD risk questionnaires such as the Framingham risk score, BP, glucose, and lipid measurements, and an initial physical examination focusing on detecting peripheral
vascular disease. For some men with ED, consideration of in-office, non-invasive assessment of endothelial function and or penile duplex Doppler ultrasound can be considered.
Doppler evaluation
In the ED population, the penile duplex Doppler evaluation has been considered a screening tool for previously undetected CAD. In a pooled analysis of all published studies, the results of this evaluation have a negative predictive value of 84% and a positive predictive value of 32%. In other words, the finding of a normal Doppler response defined as a PSV greater than 35 cm/s in a patient with ED makes obstructive CAD unlikely. Conversely, an abnormal Doppler response indicates previously undiagnosed obstructive CAD in approximately 30% of cases, which may statistically reflect a poor predictive value but arguably may be clinically significant. Use of this diagnostic modality has been in decline, however, because it requires an intracavernosal injection and it is not recommended prior to initiating first line oral therapy for ED.
Assessment of endothelial dysfunction has been used to replace penile Doppler and help determine ED etiology. Recently, Mazo et al9 and Ucar et al10 have demonstrated that the severity of the endothelial dysfunction correlated with ED etiology. Endothelial function was significantly lower in patients with arteriogenic ED as demonstrated by penile Doppler than in patients with other forms of ED (psychogenic, venous occlusive dysfunction). Recently, numerous urol-ogy and men's health centers in the United States and Europe have incorporated endothelial function assessment of their ED population using the FDA-approved, noninvasive, com-puter based EndoPAT-2000 unit (Itamar Medical Ltd., Caesarea, Israel). At the recent annual meeting of the Sexual Medicine Society of North America, Khera et al11 reported that in the ED population screening with the EndoPAT-2000 unit is useful in establishing cardiovascular risk in the urology office setting and it holds promise for differentiating arteriogenic ED from venous occlusive dysfunction. Prospective scientific as well as epidemiological studies using this technology are ongoing at numerous medical facilities.
PDE-5 inhibitors are first line therapy for ED. They have revolutionized the perception of this disease entity and are the mainstay of the global treatment of ED. The medications are being used in other therapeutic areas, such as pulmonary hypertension and lower urinary tract symptoms (LUTS). In addition, all three PDE-5 inhibitors have demonstrated improvement in endothelial function. Furthermore, it appears that the benefit of the drugs on endothelial function persists even after patients discontinue use of the medications, suggesting a sustained physiological impact. Rosano et al12 demonstrated that the improvement on endothelial function following chronic tadalafil use persisted for up to two weeks following cessation of therapy.
Familiarity by the urological community for chronic PDE-5 inhibitor therapy has been established primarily for penile rehabilitation following prostate cancer treatments, LUTS, and salvage treatment for non-responders to on-demand PDE-5 inhibitor use. Chronic dosing for tadalafil is currently approved in Europe and was recently approved by the FDA. It appears that chronic PDE-5 inhibitor therapy is required to achieve improvement in endothelial function. In a prospective crossover study, Aversa et al13 demonstrated that improvement in endothelial function was noted only in men on chronic tadalafil therapy and not in those only using the drug on demand for sexual function. One can foresee the possibility of a new algorithm whereby an ED patient with endothelial dysfunction will not only be referred for a more aggressive cardiologic evaluation but the treating urologist will consider initiating chronic PDE-5 therapy to treat ED as well as achieve overall improvement in endothelial function.
Conclusions
Our practice of medicine will benefit by continuing to focus on as well as advance our understanding of the relationship between ED, endothelial dysfunction, and CVD. Furthermore, the urological community has a responsibility to consider the increased cardiovascular morbidity and mortality in our ED patients more seriously and together with our medical colleagues need to further refine the clinical algorithms for the screening of the ED patient for latent CVD.
An associate clinical professor of urology at the University of Connecticut Health Center in Farmington, Conn., Dr. Honig practices at the Urology Center in New Haven, Conn. and is a member of the Renal & Urology News editorial advisory board. Dr. Bar-Chama is an associate professor in both the Department of Urology and the Department of Obstetrics, Gynecology, and Reproductive Science at The Mount Sinai School of Medicine in New York.
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