Erectile Dysfunction and Subsequent Cardiovascular Disease
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Synopsis: Erectile dysfunction should prompt investigation and intervention for cardiovascular risk factors.
Source: Thompson IM, et al. Erectile Dysfunction and Subsequent Cardiovascular Disease. JAMA. 2005;294:2996-3002.
The use of therapeutic agents for erectile dysfunction (ED) or impotence has been an enormous story since the advent of sildenafil (Viagra) some years ago. Recent data suggests that more than 10 million men in the United States have some degree of ED; approximately 30,000 men die yearly from prostate cancer. Some have suggested that ED may be a clue to occult vascular disease, given the fact that nitric oxide (NO) modulates erectile function; thus, the common sense hypothesis that vascular disease in one organ may increase the likelihood of endothelial dysfunction in other areas of the body, particularly the coronary arteries.
The Prostate Cancer Prevention Trial was a 7-year prospective RCT evaluating the drug finasteride on the prevalence of prostate cancer. Finasteride, the primary result of this trial, blocks conversion of testosterone to dihydrotestosterone (N Engl J Med. 2003;349:215-224) demonstrated a reduction in prostate cancer. A sub-study sought to evaluate the incidence and prevalence of ED over the duration of the trial. Thus, in addition to yearly PSA levels and digital rectal examinations, a standardized yearly survey addressing sexual function was included to examine the issues of ED, decreased libido, and decreased ejaculation volume. Cardiovascular events were also evaluated as part of safety monitoring, and included myocardial infarction, revascularization, stroke, TIA, or congestive heart failure. The sexual function component of the Prostate Cancer Prevention Trial was carried out in the placebo group. Men who had a history of cardiovascular disease at entry were excluded from the primary analysis, but were carefully followed; a proportional hazards regression model was used to evaluate the association of ED with cardiovascular disease, with a separate analysis of each of the major cardiovascular events. Men with and without ED at baseline were followed for changes in sexual function. Two models were used to address cardiovascular events, including an unadjusted and co-variant-adjusted approach. The interval from the onset of ED to the first cardiovascular event was assessed in men with no prior history of a cardiovascular event.
Results: Eight thousand sixty-three men had no cardiovascular disease at study entry, representing 85% of the entire placebo cohort; however, 47% of these individuals reported some degree of ED at study entry. Of the 4247 men who reported no ED at study entry, 57% noted the development of incident ED by 5 years, increasing to 65% at 7 years. Seventy-six percent of all enrollees completed the 7-years protocol. Incident ED was associated with the development of angina, myocardial infarction, and stroke, (P-value of 0.04 for angina and 0.06 for stroke). Men with ED "had a significantly increased risk of myocardial infarction or angina, relative to men without a report of ED, after adjusting for potential confounders" (hazard ratio of 1.37, P = 0.02). When men with ED at study entry were added to the total population, the results were similar. The highest hazard was for TIA (HR of 1.9, P = 0.02) and 1.45 for any cardiovascular event (P < 0.01). Men who reported a reduction in libido and had no ED were excluded from the analysis but evaluated for the first report of cardiovascular disease. These individuals were defined as grade 3-4 (moderate to severe) sexual dysfunction, but represented only 1% of the entire cohort. Hazard ratios were comparable in men with a decrease in libido prior to developing overt ED. After the first year of the study, 2% of all men with ED developed a cardiovascular event, and 11% at 5 years. An evaluation of cardiovascular risk factors indicated that ED "had an equal or greater effect on subsequent cardiovascular event of the same magnitude as a family history of myocardial infarction, cigarette smoking, or measures of hyperlipidemia."
Thompson and colleagues comment that up to half of all deaths from CAD occur in men without a history of vascular disease. They note that patients with cardiovascular disease frequently report preexisting ED, as also demonstrated in other studies. Risk factors for ED and cardiovascular disease are well known, and include obesity, cigarette smoking, physical inactivity, diabetes, hypertension, and hyperlipidemia. Some patients have ED without cardiovascular disease or cardiovascular risk factors, and presumably have a defect in the peripheral penile vasculature "independent of other systemic vascular disease." Reports in literature have suggested that ED "is a harbinger of cardiovascular disease" peripheral vascular disease has also been found to be markedly increased in patients with preexisting ED.
This study of asymptomatic healthy men utilizing a yearly questionnaire for ED indicates that half (47%) had some degree of ED at the time of study entry; 57% of those who had no ED at entry developed sexual symptoms after 5 years. Thompson et al point out that the use of the Sexual Problems Scale may be somewhat outdated methodology for evaluating ED, and also recognize they do not have adequate data on medications that could be related to ED. Thompson et al cite the Massachusetts Male Aging Study estimate that more than 600,000 American men develop ED annually; men over 70 with ED have a 2-fold greater risk of cardiovascular disease than men without ED.
Thus, "this analysis suggests that the initial presentation of a man with ED should prompt the evaluating physician to screen for standard cardiovascular risk factors." Nevertheless, there is no evidence that lifestyle or behavioral interventions, including PDE-5 agents, can "reduce or delay the onset on ED." Thompson et al conclude that this study provides the first evidence "of a strong association between ED and subsequent development of clinical cardiovascular events." They suggest that symptoms of ED "should prompt an assessment of cardiovascular risk factors and vigorous interventions as appropriate."
The remarkable success of the PDE-5 inhibitors attests to the widespread prevalence of some degree of abnormal sexual function in males. One wonders if a decline in sexual function is truly abnormal, in that at least 50% ultimately develop ED. Several years ago at one of the national heart meetings, a poster was presented regarding a small cohort of men that had ED and a substantial burden of cardiovascular risk factors; Thompson et al suggested enhanced clinical observation of such individuals and vigorous treatment of risk factors. This makes common sense. It would appear reasonable that sexual dysfunction or ED be included in the routine cardiovascular risk assessment of middle-aged or older men, with a report of ED stimulating aggressive risk factor identification as well as treatment. Thus, it is appropriate to initiate a search for cardiovascular risk factors, as well as behavioral and pharmacologic therapies for ED, in those men who might otherwise slip through the cracks of prevention.