ORIGINAL ARTICLE Is erectile dysfunction a predictor of cardiovascular events or stroke? A prospective study using a validated questionnaire

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1 (2010) 22, & 2010 Nature Publishing Group All rights reserved /10 $ ORIGINAL ARTICLE Is erectile dysfunction a predictor of cardiovascular events or stroke? A prospective study using a validated questionnaire A Ponholzer 1, G Gutjahr 2, C Temml 3 and S Madersbacher 1 1 Department of Urology and Andrology, Danube Hospital, Vienna, Austria; 2 Department of Medical Statistics, Medical University, Vienna, Austria and 3 Department of Preventive Health, City of Vienna, Vienna, Austria Erectile dysfunction (ED) is linked to various cardiovascular risk factors and may therefore serve as a predictor of cardiovascular events. To gain further insight into this relationship, we reviewed all data regarding hospital admission for cardial or cerebral vascular disease that occurred until 2008 in a cohort of men who underwent a health investigation in Erectile function was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. In total, 2506 men with a negative history of cardial or cerebral vascular disease were analysed. During the 6.5-year followup, 58 cardiovascular events (2.3%) occurred. Men without ED (IIEF-5 422; n ¼ 1636) at baseline developed a cardiovascular event in 1.9% (n ¼ 32) as compared with 2.9% ( þ 52%; n ¼ 26) in those with ED (IIEF-5 p22; n ¼ 670). In contrast to age (hazard ratio (HR): 1.6; for every decade), hypertension (HR: 1.88; ) and diabetes (HR: 2.6; ), ED was not an independent risk factor for a cardiovascular event. Although men with ED were at increased risk for future cardiovascular events, ED was not an age-independent predictor of cardiovascular events in our cohort. (2010) 22, 25 29; doi: /ijir ; published online 24 September 2009 Keywords: myocardial infarction; stroke; coronary heart disease; erection Introduction Vascular component is considered to have the most important role in the pathogenesis of erectile dysfunction (ED). 1 This paradigm is mainly supported by the fact that ED shares almost all risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and smoking, with arteriosclerosis. 2 6 Therefore, ED has been investigated in patients with vascular disorders, such as coronary heart disease (CHD), peripheral vascular and cerebrovascular disease. 7 9 Owing to the increasing evidence indicating a significant correlation between ED and vascular disorders, it has been hypothesized that ED may be representative of vascular integrity in general. 10 ED could therefore serve as a predictive symptom for potentially life-threatening CHD or stroke, both of which are leading causes of mortality in industrialized societies. 11 Two recent studies have suggested that ED represents an independent risk factor for future cardiovascular events, even independent of classic risk factors, such as diabetes and hypertension. 12,13 In 2005, we calculated the 10-year risk for CHD or stroke in a cohort of men with known International Index of Erectile Function (IIEF-5) score using the Framingham risk profile. This study showed that moderate-to-severe ED was associated with a considerably (calculated) increased risk for CHD and stroke. 14 Using the above-mentioned cohort, we report in this study on the association between ED and cardiovascular events that occurred during a 6.5-year follow-up. It is the first prospective trial on this issue that used a validated ED questionnaire (IIEF-15). Correspondence: Professor A Ponholzer, Department of Urology and Andrology, Danube Hospital, SMZ-Ost, Langobardenstrasse 122, Vienna 1220, Austria. antonponholzer@hotmail.com Received 23 June 2009; revised 22 July 2009; accepted 25 July 2009; published online 24 September 2009 Materials and methods Study cohort Between 2001 and 2003, two cohorts of men aged years who participated in a voluntary health examination in the area of Vienna were assessed

2 26 A prospective study on ED regarding the presence and severity of ED (see below). The provider of this health project was the Department of Preventive Health of the City of Vienna. Every citizen is allowed to undergo this health evaluation free of charge once a year. For the current analysis, men with a known history of CHD, myocardial infarction or stroke at baseline were excluded. In 2008, all information regarding hospital admissions for cardial or cerebral disease of these participants that occurred between 2001 and 2008 were retrieved (International Classification of Diseases codes I20 25 and I60 69). Institutional review board approval was obtained, and all study participants provided informed consent. Health investigation During health examination, the following parameters were assessed routinely: (1) detailed medical history, (2) assessment of concurrent medical drugs and therapies, (3) physical examination including blood pressure, electrocardiogram and spirometry, (4) sociodemographic parameters including marital status, cigarette smoking and alcohol consumption and (5) blood laboratory study including kidney and liver function, red and white cell counts, low- and high-density lipoprotein counts, total cholesterol, triglycerides and fasting glucose. Cardiovascular risk factors Total cholesterol, triglycerides and high-density lipoprotein were quantified using Hitachi 717 by Roche (Basel, Switzerland) (BM) with serum obtained from fasting patients between 0800 and 1000 hours. Lowdensity lipoprotein was calculated according to Friedwald s formula. For systolic and diastolic blood pressure determination, three measurements were obtained for each individual (1) by the study nurse before medical examination, (2) by the general practitioner (GP) during the medical examination and (3) by the study nurse after the medical examination each time after the patient had been sitting for 5 min. Mean values of these three measurements were used for all analyses. Diabetes mellitus was classified as yes when the patient was under treatment with insulin or any oral antidiabetic drug or if the fasting blood glucose level was 46.9 mmol l 1. Smoking status was classified as yes when the patient had smoked regularly during the previous 12 months; antihypertensive therapy was classified as yes when present at the time of investigation. Each parameter was diagnosed and confirmed by a GP. Erectile dysfunction The IIEF-5 questionnaire was used to assess the prevalence and severity of ED according to a classification system developed by Rosen et al., 15 which was slightly modified by combining the mild-to-moderate and moderate groups into one group to facilitate statistical evaluation into three categories, such as no ED (IIEF-5 score ¼ 22 25), mild ED (IIEF-5 score ¼ 17 21) and moderate-to-severe ED (IIEF-5 score ¼ 5 16). Statistical analysis Quantitative variables were summarized by minimum, maximum, mean and s.d.; qualitative variables were summarized by frequencies. The difference in censored survival times was tested by log-rank test. Cox regression was used to adjust for age confounding and subsequently to adjust for a pre-selected list of established cardiovascular risk factors. The ageadjusted Cox model was also separately fitted in relevant age subgroups. Results Study cohort Of a total of 2869 men who underwent the standardized health examination in the years between 2001 and 2003 and those who completed the IIEF-5 (see below), 2506 men without a history of CHD or cerebral vascular disease at baseline entered the current database for re-evaluation in The mean age was 45 years with the majority of men aged years (n ¼ 1680) and 826 men aged between 50 and 90 years (Table 1). The principal characteristics of the study population are presented in Table 1. The mean IIEF-5 score was 21 (range: 5 25), with 1636 men (65.3%) without ED, 634 (25.3%) with mild ED and 236 (9.4%) with moderate-to-severe ED at baseline (Table 2). Men with ED were on average 6 years older (49 versus 43 years) and had an identical body mass index (26 versus 26)comparedwiththosewithoutED. ED versus events During the observation period with a total of person-years for analysis, 58 cerebrovascular events, 44 cardiac (1.7%) and 16 cerebral events were Table 1 General population characteristics N ¼ 2506 Min Max Mean s.d. Age (years) Body mass index IIEF-5 score Total cholesterol (mg per 100 ml) HDL (mg per 100 ml) 8, LDL (mg per 100 ml) Fasting glucose (mg per 100 ml) RR systolic (mm Hg) RR diastolic (mm Hg) Abbreviations: IIEF, International Index of Erectile Function; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

3 A prospective study on ED Table 2 ED, events and vascular risk factors 27 Total ED No ED n Percentage (%) n Percentage (%) n Percentage (%) No ED (IIEF-5 421) Mild ED (IIEF 16 21) Mod-sev ED (IIEFo16) Events: total Events: heart Events: stroke Diabetes mellitus Hypertension Nicotine abuse Abbreviations: ED, erectile dysfunction; IIEF, International Index of Erectile Function; Mod-sev, moderate-to-severe. 100 Table 3 Age-adjusted hazard ratio (HR) according to ED (IIEFo22) 99 Age (years) n ED (%) Events (%) HR (95% CI) Events (%) ED present ED absent n ¼ 20 (0.1) 0.65 ( ) 50 þ n ¼ 38 (4.3) 1.2 ( ) Abbreviations: CI, confidence interval; ED, erectile dysfunction; IIEF, International Index of Erectile Function. 95 Age-adjusted HR: % CI: ; P=0.78 Table 4 Hazard ratio (HR) for event; (CI) in men aged 50 þ years 94 HR 95% CI P-value Time (years) Figure 1 Events total; erectile dysfunction (ED) versus no ED (International Index of Erectile Function, IIEFo22) (HR ¼ hazard ratio; CI ¼ confidence interval). recorded (Table 2). Men without ED (IIEF-5 422; n ¼ 1636) at baseline developed a cardiovascular event in 1.9% (n ¼ 32) as compared with 2.9% ( þ 52%; n ¼ 26) in those with ED (IIEF-5 p22; n ¼ 670) (P ¼ 0.04) (Table 2, Figure 1). However, ED could not be identified as an ageindependent predictor of the occurrence of any cardiovascular or cerebrovascular event with a hazard ratio (HR) of 0.92 (95% ; P ¼ 0.78) (IIEF versus p21) (Figure 1). When stratifying our data according to age, HRs ranging from 0.07 (20 29 years) to 1.5 (80 þ ) were obtained when ED was defined by an IIEFo22. When defining ED by an IIEF-5o16 (moderate-to-severe ED) and when comparing the rate of events with those without ED (IIEF-5: 22 25) non-significant HRs were observed (data not shown). In a subgroup analysis of men aged 450 years (n ¼ 826), a HR of 1.2 was observed in those with an IIEF-5o22), this difference, however, was again not statistically significant (Table 3). ED Yes/no Age 10 years Hypertension Yes/no Diabetes Yes/no BMI 1 Unit Cholesterol 10 mg per 100 ml Abbreviations: BMI, body mass index; CI, confidence interval; ED, erectile dysfunction. Risk factors for events In addition, age (HR: 1.6; 95% confidence interval ; P ¼ 0.01) for every 10 years, hypertension (HR: 1.88; ; P ¼ 0.01) and diabetes (HR: 2.66; ; P ¼ 0.01) were significant predictors of any event (Table 4). ED (P ¼ 0.48), body mass index (n ¼ 0.65) and cholesterol (n ¼ 0.26) were all non-significant predictors of a cardiovascular event (Table 4). Discussion In 2005, our group published data on the basis of the Framingham risk profile to evaluate the role of ED as a predictor of cardiovascular and cerebrovascular events. In a cohort of men undergoing a health investigation in Vienna, we calculated the future

4 28 A prospective study on ED risk of CHD or stroke (10 years) and correlated this risk with ED according to the IIEF-5 score. This analysis suggested that men with moderate-tosevere ED (IIEF-5o16) were at a 65% increased relative risk of developing CHD and a 43% increased risk of having a stroke within 10 years compared with those without ED. 14 Although retrospective, cross-sectional and calculated prospective designed studies indicate that ED may serve as a predictor of future cardiovascular events, well-described, large, prospective data on this association in a general population are scant The first large, prospective study reporting on incidence data of CHD in men with ED was within the framework of the PCPT (Prostate Cancer Prevention Trial). 12 In the placebo arm (n ¼ 9.457), ED was assessed by a structured interview and CHD was analysed according to the adverse events study protocol at study entry and every 3 months for the entire study period (7 years). Baseline or incident ED that developed during follow-up was found to significantly predict any cardiac event with a HR of 1.45 (95% confidence interval: ; Po0.001). 12 This study is hampered by the use of a non-validated questionnaire for ED (at the time of the initiation of PCPT in 1992, a validated ED questionnaire was not available) and soft end points (unconfirmed reports of cardiovascular events by the patients). Furthermore, this analysis was based on an unusually high incidence of ED: among 4247 men with no ED at study entry, 2420 (57%) reported incident ED after 5 years, and this figure increased to 65% at 7 years. Similar findings were recently reported in the population-based Krimpen study. A single question on erectile rigidity was identified as a predictor of acute myocardial infarction, stroke and sudden death independently of the Framingham risk factor profile. 13 Cardiovascular events were carefully recorded according to the Antithrombotic Trialists Collaboration. A documented acute myocardial infarction, sudden death or stroke, registered in the medical records of the GPs during follow-up was judged by an expert panel consisting of a cardiologist, GP and a researcher. In this cohort of 1248 men aged between 50 and 75 years were followed up for a mean time period of 6.3 years ( years), the HR for (n ¼ 58) men with reduced and severely reduced rigidity was 1.6 (95% confidence interval: ) and 2.6 (95% confidence interval: ), respectively. The authors, however, did not provide an explanation as to why ED increased cardiovascular risk independently of the vascular risk factors. Prompted by our above-mentioned results and the two publications by Thompson and Schouten, we prospectively assessed the incidence of CHD or stroke in a fairly large cohort of men (n ¼ 2.506) who underwent a health investigation. During a 6.5-year follow-up, a total of 58 events occurred. Although men with ED (IIEF-5p22) had a 52% increased risk for a cardiovascular event, ED (in contrast to age, hypertension and diabetes) was not an independent risk factor in a multivariate analysis. The most important strengths of our study are (1) the use of a validated questionnaire to assess ED (for the first time in a prospective study on the association between ED and cardiovascular events), (2) the detailed knowledge of comorbidities due to a standardized health investigation guided by a GP and (3) the hard end points (hospital admission for cardiovascular events). In contrast to the above-mentioned two studies, ED was not an independent risk factor for cardiovascular events. This discrepancy is most likely because of the lower absolute number of events, in our series. We therefore might not have had adequate power (despite similar HRs) in the 50 þ (n ¼ 826) sub-population, which represents the most relevant population for investigating the association between ED and future cardiovascular events. Interestingly, the relative number of events in 50 þ men in our series (4.3%) was almost identical to the Krimpen study (4.6%, mean age: 61 years). The substantially higher rate of events in the PCPT trial (10%) is most likely because of the soft cardiovascular end points in this trial. Despite several methodological differences (such as cohorts, assessment of ED, definition and assessment of cardiovascular events) and the fact that ED was not an independent predictor of cardiovascular events in our series, the majority of studies and expert opinions 19,20 point in the same direction, that is, that men with ED are at higher risk for future cardiovascular events. These observations have two important clinical implications: first a cardiovascular risk profile should be obtained in men with ED and second, erectile function should be assessed in cardiovascular risk assessment. Conflict of interest The authors declare no conflict of interest. Acknowledgments This study was supported by unrestricted educational grants provided by Lilly Austria and Bayer Health Care Austria. References 1 Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: Feldman HA, Goldstein I, Hatzichristou D, Krane RJ, McKinlay JB. Impotence and its medical and psychological correlates: results of the Massachussets Male Aging study. J Urol 1994; 151:

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