Introduction. BWV Schouten 1, AM Bohnen 1, JLHR Bosch 2, RMD Bernsen 1, JW Deckers 3, GR Dohle 4 and S Thomas 1

Transcription

1 (2008) 20, & 2008 Nature Publishing Group All rights reserved /08 $ ORIGINAL ARTICLE Erectile dysfunction prospectively associated with cardiovascular disease in the Dutch general population: results from the Krimpen Study BWV Schouten 1, AM Bohnen 1, JLHR Bosch 2, RMD Bernsen 1, JW Deckers 3, GR Dohle 4 and S Thomas 1 1 Department of General Practice, Erasmus MC, Rotterdam, The Netherlands; 2 Department of Urology, University Medical Centre Utrecht, Utrecht, The Netherlands; 3 Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands and 4 Department of Urology, Erasmus MC, Rotterdam, The Netherlands The possible relationship between erectile dysfunction and the later occurrence of cardiovascular disease while biologically plausible has been evaluated in only a few studies. Our objective is to determine the relation between ED as defined by a single question on erectile rigidity and the later occurrence of myocardial infarction, stroke and sudden death in a population-based cohort study. In Krimpen aan den IJssel, a municipality near Rotterdam, all men aged years, without cancer of the prostate or the bladder, without a history of radical prostectomy, neurogenic bladder disease, were invited to participate for a response rate of 50%. The answer to a single question on erectile rigidity included in the International Continence Society male sex questionnaire was used to define the severity of erectile dysfunction at baseline. Data on cardiovascular risk factors at baseline (age smoking, blood pressure, total- and high-density lipoprotein cholesterol, diabetes) were used to calculate Framingham risk scores. During an average of 6.3 years of follow-up, cardiovascular end points including acute myocardial infarction, stroke and sudden death were determined. Of the 1248 men free of CVD at baseline, 258 (22.8%) had reduced erectile rigidity and 108 (8.7%) had severely reduced erectile rigidity. In 7945 person-years of follow-up, 58 cardiovascular events occurred. In multiple variable Cox proportional hazards model adjusting for age and CVD risk score, hazard ratio was 1.6 (95% confidence interval (CI): ) for reduced erectile rigidity and 2.6 (95% CI: ) for severely reduced erectile rigidity. The population attributable risk fraction for reduced and severely reduced erectile rigidity was 11.7%. In this population-based study, a single question on erectile rigidity proved to be a predictor for the combined outcome of acute myocardial infarction, stroke and sudden death, independent of the risk factors used in the Framingham risk profile. (2008) 20, 92 99; doi: /sj.ijir ; published online 30 August 2007 Keywords: cardiovascular disease; erectile dysfunction; epidemiology; risk factor Introduction Erectile dysfunction is a common condition in middle-aged and older men with prevalences, depending on definition and age, ranging from 2% Correspondence: Dr BWV Schouten, Department of General Practice, Erasmus MC, PO Box 2040, Rotterdam 3000 CA, The Netherlands. b.schouten@erasmusmc.nl Take Home Message: Negative answers on the question Do you get erections? increase the risk of cardiovascular disease by a factor between one and a half and two and a half. This appears to be of the same magnitude as the classical risk factors diabetes and smoking. Received 25 April 2007; revised 7 July 2007; accepted 20 July 2007; published online 30 August 2007 (40 years) to 86%, (older than 80 years). 1 3 The finding that the new oral therapies act on the vascular component of erectile dysfunction has increased interest in the relation between vascular and erectile problems. 4 9 Because erectile dysfunction shares the same risk factors as cardiovascular disease (CVD), for example age, smoking, diabetes mellitus, hypertension and hyperlipidaemia, it has been suggested that erectile dysfunction might be a prospective marker for CVD. 2,6 11 Several cross-sectional studies have emphasized the similarity of cardiovascular risk factors and the risk factor for erectile dysfunction. 6 8 A recent longitudinal study in the placebo group of a randomised-controlled trial also suggested the relation Before this premise that erectile

2 dysfunction is an independent, prospective marker of CVD can be used clinically, it requires confirmation in prospective, population-based studies. A broad range of aspects of erectile dysfunction can be measured by a questionnaire such as the international index of erectile function. However, in large epidemiological studies and eventually in daily medical practice it is more convenient to have a single question, which is related to the vascular aspects of erectile dysfunction and the risk of future cardiovascular events. In this longitudinal population-based cohort study, we assess a single question on the severity of erectile dysfunction as a risk indicator for CVD (in this study defined as acute myocardial infarction, sudden death or stroke). We also explore the value of this question as a possible addition to a standard Framingham risk profile. Methods Patients and data collection In 1995, a large community-based study on male urogenital tract problems and general health status was started (the Krimpen Study); the design of this study has been described previously. 14,15 All men in Krimpen aan den IJssel who were years old in June 1995 were eligible for the study. Excluded were men with a history of radical prostatectomy, prostate or bladder cancer, neurogenic bladder disease, or men who were not able to complete questionnaires or visit the health centre (n ¼ 235). Enrolment took place between August 1995 and January 1998, for a response rate of 50%. Figure 1 presents details of the selection process. All men entering the cohort study provided written informed consent, including permission to retrieve data from their medical record and their pharmacist. The Medical Ethics Committee of Erasmus MC Rotterdam approved the study. At baseline, 1688 participants completed a 113- item self-administered questionnaire that as a compilation of validated questionnaires included questions about medical history, general health, socio-economic status, as well as urologic questions including the International Continence Society (ICS) male sex questionnaire. Internal consistency revealed Cronbach s a values of 0.63 and 0.75 for symptoms and bother, respectively. 16 The questionnaires of 27 men were lost before entering their data in the database. 17 All men visited at baseline the local health centre for blood pressure, height and bodyweight measurement and to give information on current drug use. Participants who had at baseline no record of acute myocardial infarction, stroke, transient ischaemic attack or abdominal aortic aneurysm, were not consulting a cardiologist, and did not use chronic platelet antiaggregation medication, nitrates, or heart glycosides, based on GP records, questionnaire answers and/or pharmacist data, were designated as CVD-free men and were included in the present analysis (n ¼ 1248). In the Netherlands, all inhabitants are registered with a general practitioner (GP) who is informed whenever their patient visits an emergency room, a specialist, or a (substitute) physician. 18 In the community of Krimpen, all GPs store their patient data in a computerized system, and code their medical records using the International Classification of Primary health Care (ICPC). 19 Complete GP records were obtained in 1622 participants (98%), data (myocardial infarction, stroke, transient ischaemic attack, sudden death, total cholesterol and the high-density lipoprotein) were extracted according to a predefined protocol. Participants who moved out of the area after baseline were excluded from further follow-up. The local pharmacists provided data on drug dispenses from January 1994 to July Medication data were analysed using the Anatomical Therapeutical Chemical classification. 20 Definitions Erectile dysfunction was assessed by the ICS male sex questionnaire. 3,21 The answers on the question: Do you get erections? were categorized into: (a) no erectile dysfunction: a self-reported normal erection; (b) moderate erectile dysfunction: a report of erections with reduced rigidity ; and (c) severe erectile dysfunction: a report of erections with severely reduced rigidity or no erections. Risk score for cardiovascular disease: the risk of a myocardial infarction, sudden death and stroke based on the equations from the Framingham heart study was added up and transformed by arcsinus of the square root. 22 Cardiovascular event: as used by the Antithrombotic Trialists Collaboration, 23 a documented acute myocardial infarction, sudden death or stroke, registered in the medical records of the GPs during follow-up, as judged by an expert panel consisting of a cardiologist (JD), a general practitioner (AB) and a researcher (BS). Of all identified cases, the medical files and hospital discharge letters were blinded and examined by two members of the expert panel (the cardiologist was always a member). An acute myocardial infarction was defined as an event when relevant biomarkers were positive, or acute electrocardiography ST-segment elevations were followed by administration of fibrinolytics, or a positive myocardial scintigraphy with related documented clinical symptoms within 6 months of scintigraphy. Stroke was defined as central neurological deficits documented by a neurologist or GP with a duration longer than 24h, and/or a positive cerebral CT scan for stroke. 93

3 94 Figure 1 Selection process of men free of CVD at baseline (n ¼ 1248). CVD, cardiovascular disease. Sudden death was defined as a death that occurred suddenly and unexpectedly for which there was no other plausible explanation than vascular disease. We assumed that all such cases are due to cardio- or vascular disease. In case of disagreement, both members of the panel would re-examine the information about the event. In case of continuing disagreement, the third member of the panel made the decision; this was however never necessary. Diabetes mellitus status was a compilation of the answer on the questionnaire (under treatment for diabetes mellitus in the past 3 months) and/or the use of antidiabetics (according to pharmacist) during the 3 months before baseline. Smoking status was part of the questionnaire (never smoked, stopped more than 5 years ago, active smoker). Statistical analysis For each person, the duration of follow-up, expressed as person-years, was defined as the time period between baseline measurement and the occurrence of a first cardiovascular event or, in case of no event, the date of retrieval of the GP data (between August 2002 and January 2003). Because we did not have the total cholesterol and the highdensity lipoprotein values of the participants exactly at baseline, we used available serum levels, recorded as near as possible before baseline. To deal with missing data on total cholesterol and highdensity lipoprotein cholesterol, we used a multiple imputation strategy, assuming that the cholesterol levels were missing at random For the imputation of total cholesterol and high-density lipoprotein cholesterol levels, we used a model with all baseline data and cardiovascular, cerebrovascular

4 and diabetes diagnoses before and after baseline in the medical records of the GPs. We calculated a risk score at baseline (based on the Framingham equations using age, smoking status diabetes mellitus status, systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol) as a measure of the pre-existing risk for CVD to reduce the degrees of freedom. Age, smoking status diabetes mellitus status, and systolic blood pressure had no missing values. To test the assumption that the risk score is appropriately calibrated to our cohort we used a c-statistic. The area under the curve was 0.725, which was assumed sufficient for the cause. Cumulative incidences per quartile of the risk score (n ¼ 312 per quartile) were presented to check for linearity. Incidence rates of cardiovascular events per 1000 person-years were calculated assuming a dispersed Poisson distribution. Hazard ratios were calculated using the Cox proportional hazard model with the occurrence of a cardiovascular event as the outcome variable. In the first set of Bivariate Cox regression models we included erectile dysfunction, and one of the following variables as possible confounders: bother with erectile dysfunction (see appendix); sexual activity (sexually active/not sexually active see appendix); alcohol use (0, 1 2, 42 U/day); age (years); body mass index (kg/m 2 ); family history of CVD before the age of 60 years; marital status (single/partner); level of education (primary school only/higher); use of b-blocking agents; use of benzodiazepines; use of diuretics; use of lipid-lowering drugs; the risk score; and the use of antidepressants. All the variables were measured at baseline measurements. These variables were added to a multivariable model if inclusion in the first model changed the estimate of the log of the hazard ratio (b) of erectile dysfunction with more than 5%. Final analyses were performed using variables with a P-value o0.05 in the multivariable model. Where applicable 95% confidence intervals (CIs) are given. As an alternative to multiple imputations, we reanalysed with the mean value of the known cholesterol levels applied to the missing values. Moreover, we reanalysed our data with other risk scores such as the SCORE risk profile, and different Framingham risk profiles All analyses were done using SAS Graphs were made in SPSS version To calculate a population attributable fraction (PAF), we used the formula prevalenceðHR 1Þ PAF ¼ 100 þ prevalenceðhr 1Þ Using estimates of age-adjusted population prevalence s for reduced rigidity and severely reduced rigidity calculated out of the Krimpen prevalence data. 32 We used the adjusted hazard ratios of erectile dysfunction. Results There were 1248 CVD-free men with a total followup time of 7945 person-years. During follow-up 58 (4.6%) participants had a cardiovascular event: that is, 39 had a myocardial infarction, 14 participants had a stroke and 5 participants died suddenly. The mean follow-up was 6.33 years (range years). At baseline out of 1248 CVD-free men, 258 (22.8%) had reduced erectile rigidity and 108 (8.7%) had severely reduced erectile rigidity. Of 1661 men with baseline data, 39 (2%) had no data available on their cardiovascular events status: of which 33% had abnormal erections compared to 31% in the 1248 CVD-free men (n.s.). A survey of non-responders (n ¼ 500) found that participants were slightly younger than non-responders (mean age 61.2 years, s.d. 6.7 years, compared with 62.3 years, s.d. 7.6 years; Po0.001), but did not differ significantly in treatment for CVD (6.2% compared to 8.8%, P ¼ 0.11). 15 The baseline characteristics for the erectile rigidity status groups show an increasing risk for cardiovascular events by the risk score with increasing severity of the erectile rigidity status (Table 1), increasing from a risk of 0.12 with normal erections to 0.18 with erections with severely reduced rigidity (Po0.05). The risk score ranged from 0.00 to 0.83 in increasing risk representation. An increasing risk score was associated with an increasing proportion of cardiovascular events. In all quartiles (n ¼ 312 each) of the baseline risk score, a more reduced erectile rigidity showed an increasing proportion of cardiovascular events in that quartile. (Figure 2). The incidence rates of cardiovascular events increased with age from 4.1/1000 person-years in the group aged years to 15.8/1,000 personyears in those aged years (Po0.05). This agedependent increase was also present in the reduced erectile rigidity group: incidence rates ranged from 10.1/1000 person-years in the group aged years to 28.3/1000 person-years in those aged years (Po0.05). In the group with severely reduced erectile rigidity, the incidence rate was almost constant across the two youngest age groups. For the age group years, because of the low number of events, no reliable incidence rate could be estimated (Table 2). Incidence rates of cardiovascular events increased statistically significant from 5.1/1000 person-years in men with normal erections to 10.1/1000 person-years in men with reduced erectile rigidity to 19.0/1000 person-years in men with severely reduced erectile rigidity (Po0.05). The univariate hazard ratio of reduced erectile rigidity for cardiovascular events (compared to normal erections) was 2.0 (95% CI: ), whereas for severely reduced erectile rigidity this hazard ratio was 3.8 (95% CI: ). To determine the added value of erectile rigidity in predicting the occurrence of cardiovascular 95

5 96 Table 1 Baseline characteristics, mean values or number of cases per erectile dysfunction status for men free of CVD at baseline All (n ¼ 1248, 100%) Normal erections (n ¼ 856, 68.6%) Reduced erectile rigidity (n ¼ 284, 22.8%) Severely reduced erectile rigidity (n ¼ 108, 8.7%) Age on invitation date (years) Total cholesterol (mmol/l) a High-density lipoprotein (mmol/l) a Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Body mass index (kg/m 2 ) Diabetes mellitus 40 (3.2%) 25 (3.2%) 5 (1.8%) 10 (9.3%) Family history b 14 (1.1%) 8 (0.9%) 5 (1.8%) 1 (0.9%) Current smoker 312 (25.0%) 207 (24.2%) 70 (24.6%) 35 (32.4%) Use of b-blocking agents (C07) c 97 (7.8%) 64 (7.5%) 25 (8.8%) 8 (7.4%) Use of benzopdiazepines (N05BA 25 (2.0%) 15 (1.8%) 7 (2.5%) 3 (2.8%) and N05CD) Use of diuretics (C03) 23 (1.8%) 14 (1.6%) 6 (2.1%) 3 (2.8%) Use of antidepressants (N06A) 16 (1.3%) 10 (1.2%) 5 (1.8%) 1 (0.9%) Risk score for CVD d Abbreviation: CVD, cardiovascular disease. a Based on imputed information. b First-degree relative with a first cardiovascular event before their 60th birthday. c Medication use (Anatomical Therapeutical Chemical Classification coding). d Risk score as calculated by the 1991 Framingham equations. 18 the risk score for cardiovascular disease changed the b of erectile rigidity status by more than 5%, making these three variables eligible for selection in the multivariable model. Bother was not a confounder on erectile dysfunction. For the multivariable model, sexual activity and age were not statistically significant (P-value 0.15 and 0.25, respectively) leaving a model with only risk score for CVD and erectile rigidity. In the model, risk score for cardiovascular disease and erectile rigidity status were both significant (P-value o0.001 and 0.005, respectively). The hazard ratio of reduced erectile rigidity for cardiovascular events (compared to normal erections) was 1.6 (95% CI: ), whereas for severely reduced erectile rigidity (compared to normal erections) this hazard ratio was 2.6 (95% CI: ) (Figure 3). With the alternative computations (using a mean value of the cholesterol levels for the missing values, the SCORE risk profile, and different Framingham risk profile), the hazard ratios ranged from 1.5 to 1.9 for reduced erectile rigidity and from 2.3 to 2.8 for severely reduced erectile rigidity (all within the calculated CIs). The PAF for reduced rigidity was 4.4% (95% CI: %) and 7.2% (95% CI: %) for severely reduced rigidity. Combined is this a PAF of 11.7%. Figure 2 Distribution of cardiovascular occurrence according cardiovascular risk score quartiles and erectile dysfunction status. disease, we corrected for the classical risk factors (by means of the risk score for CVD) in a Cox proportional hazard model. Only sexual activity, age and Discussion Our study represents half of the male population in Krimpen aan den IJssel who were aged years in This is the first study that confirms longitudinally and in a non-selected population

6 Table 2 Incidence rate: cardiovascular events/1000 person-years (95% CI) 97 Normal erections (n ¼ 856) Reduced erectile rigidity (n ¼ 284) Severely reduced erectile rigidity (n ¼ 108) P-values for trend All men (n ¼ 1248) years 5.1 (4.2; 6.1) 10.1 (7.4; 13.8) 19.7 (6.9; 56.4) o (3.3; 5.2) years 6.4 (4.7; 8.7) 12.6 (8.0; 19.9) 22.9 (11.7; 44.8) o (7.7; 12.4) years 12.2 (6.4; 23.4) 28.3 (13.2; 61.0) NA a o (10.0; 24.8) P-values for o o o o trend All 5.1 (4.2; 6.1) 10.1 (7.4; 13.8) 19.0 (11.5; 31.5) o (6.3; 8.5) Abbreviation: CI, confidence interval. a Due to the small number of participants, no stable incidence rate could be calculated. Figure 3 Cumulative incidence of cardiovascular events according to erectile function status. that men with erectile dysfunction are at a higher risk for CVD defined as the combination of myocardial infarction, stroke or sudden death. This risk is highest among men with severe erectile dysfunction and decreases in men with moderate or no erectile dysfunction. The risk for the severe erectile dysfunction group was increased irrespective of advancing age being taken into account; this suggests a dose response relation. We do not have information about the duration of erectile dysfunction before the baseline evaluation of the men. Nevertheless, the divergent hazard functions of erectile dysfunction that were found during the whole follow-up period (Figure 3), suggest that erectile dysfunction is an early prospective indicator for myocardial infarction, stroke and sudden death. The risk brought about by the presence of erectile dysfunction is significant and relevant, even when adjusted for the factors age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, diabetes and smoking as expressed in the risk score for CVD. The PAF, which in this study measures the proportion of CVD that can be attributed to abnormal erectile function, is 11.7%. This means that potentially 11.7% of the cardiovascular events could be avoided, for example by primary or secondary prevention measures after finding a reduced erectile rigidity. So far, cross-sectional and basic science studies strongly suggested that erectile dysfunction is an indicator for CVD. Consensus panels, reviews and CME programs have elaborated on this relationship. 11,33 A longitudinal study, based on soft end points (unconfirmed reports of participants) in a population of volunteers selected to participate in a randomised-controlled cancer prevention trial, suggested a hazard ratio for erectile dysfunction of 1.45 for the occurrence of any cardiovascular event (congestive heart failure, transient ischaemic attack, angina and arrhythmia besides myocardial infarction, stroke and sudden death). 12,13 Congestive heart failure, transient ischaemic attack and arrhythmia were not significantly related with previous erectile dysfunction when analysed separately. Another longitudinal study identified erectile dysfunction as an independent risk factor for silent myocardial ischaemia in diabetics. 9 A cross-sectional study in patients with erectile dysfunction also emphasized the association with risk factors for CVD.

7 98 Now, our study shows this relationship for unselected patients in the open population and even after correction for other risk factors. Our study used a definition of erectile dysfunction based on the ICS male sex questionnaire. At the starting point of this study, this was the only validated erectile dysfunction question. The single question asks about the rigidity of the erection, later on the international index of erectile function was developed to assess all domains of erectile dysfunction. Derby showed that a single question is closely correlated with the international index of erectile function erection domain. 34 Since measurement error of exposure or outcomes, would bias towards the null, and we found clear dose response relationship of statistical significance. The possibility of biased measures of exposure and outcomes makes the study stronger, instead of weaker. In our study with a mean follow-up of 6.3 years resulting in 7945 person-years, we identified 58 cardiovascular events. Since this limits the number of variables in multivariable analysis, we used the Framingham risk score to combine six variables into one. Moreover, we selected the remaining variables as possible confounders one by one to make the model as sparse as possible. This approach assumes that, in our study population, the relative risks for CVD are similar to those in the Framingham population. Because we were not sure that this assumption was justified, we also applied other risk scores (such as SCORE, and different varieties of the Framingham risk profile) All these resulted in hazard ratios and models similar to our first approach. Overall, erectile dysfunction status showed different cumulative incidences for CVD in each stratum of the Framingham score (Figure 2). Therefore, erectile rigidity status is a harbinger of CVD, independent of other risk factors. As in all observational longitudinal studies, residual confounding due to single measurements may influence the results. However, since our measurements reflect clinical practice, erectile rigidity can be used as an important indicator of imminent CVD in practice. We think that the finding of a reduced erectile rigidity should lower the threshold for primary or secondary prevention measures, since they are proven effective. Our study does not elucidate the issue of causality or sequential aetiological events; it remains unknown whether erectile dysfunction by itself is a pure risk factor for CVD or just the first sign of otherwise unrecognized CVD. Depending on the exact nature of this relationship, more or less stringent preventive measures (secondary or primary preventive intervention) might be indicated. As severe erectile dysfunction increases the risk of CVD compared with moderate erectile dysfunction, we would advise to include a single question on erectile rigidity and its severity in the assessment of cardiac risk in men. Conclusions This is the first longitudinal population-based study to present data on a single question on erectile rigidity as an independent indicator for upcoming cardiovascular events. The question Do you get erections? with consequent answer categories is a strong risk indicator for cardiovascular events independent of the classical risk factors. Within 6.3 years, compared to normal erections, severely reduced erectile rigidity has a hazard ratio of 3.8 on CVD and reduced erectile rigidity a hazard ratio of 2.0. Adjusted for the classical risk factors severely reduced erectile rigidity has a hazard ratio of 2.6 and reduced erectile rigidity 1.6. Our findings confirm the results of previous crosssectional and longitudinal studies. Therefore, we suggest that a single question on erectile function should be incorporated in cardiovascular risk assessment in men. Furthermore, we suggest that a cardiovascular risk profile assessment should be considered in men presenting with an erectile dysfunction. Acknowledgments Baseline was funded by an unconditional grant from SUWO (Foundation for urologic scientific research). Follow up was partly funded by an unconditional grant of Pfizer Inc. References 1 Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men years old: longitudinal results from the Massachusetts male aging study. J Urol 2000; 163: Prins J, Blanker MH, Bohnen AM, Thomas S, Bosch JL. Prevalence of erectile dysfunction: a systematic review of population-based studies. Int J Impot Res 2002; 14: Schouten BW, Bosch JL, Bernsen RM, Blanker MH, Thomas S, Bohnen AM. Incidence rates of erectile dysfunction in the Dutch general population. Effects of definition, clinical relevance and duration of follow-up in the Krimpen Study. Int J Impot Res 2005; 17: Kirby M, Jackson G, Betteridge J, Friedli K. Is erectile dysfunction a marker for cardiovascular disease? Int J Clin Pract 2001; 55: Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins A, Thomas S et al. Correlates for erectile and ejaculatory dysfunction in older Dutch men: a community-based study. J Am Geriatr Soc 2001; 49: Ponholzer A, Temml C, Obermayr R, Wehrberger C, Madersbacher S. Is erectile dysfunction an indicator for increased risk of coronary heart disease and stroke? Eur Urol 2005; 48: , discussion Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: results of the health professionals follow-up study. Ann Intern Med 2003; 139: Eaton CB, Liu YL, Mittleman MA, Miner M, Glasser DB, Rimm EB. A retrospective study of the relationship of biomarkers for

8 atherosclerosis and erectile dysfunction in 988 men. Int J Impot Res 2007; 19: Gazzaruso C, Giordanetti S, De Amici E, Bertone G, Falcone C, Geroldi D et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004; 110: Kirby M, Jackson G, Simonsen U. Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract 2005; 59: Roumeguere T, Wespes E, Carpentier Y, Hoffmann P, Schulman CC. Erectile dysfunction is associated with a high prevalence of hyperlipidemia and coronary heart disease risk. Eur Urol 2003; 44: Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005; 294: Schouten B, Bohnen AM, Thomas S. Erectile dysfunction and incidence of cardiovascular disease. JAMA 2006; 295: Blanker MH, Prins J, Bosch JL, Schouten BW, Bernsen RM, Groeneveld FP et al. Loss to follow-up in a longitudinal study on urogenital tract symptoms in Dutch older men. Urol Int 2005; 75: Blanker MH, Groeneveld FP, Prins A, Bernsen RM, Bohnen AM, Bosch JL. Strong effects of definition and nonresponse bias on prevalence rates of clinical benign prostatic hyperplasia: the Krimpen study of male urogenital tract problems and general health status. BJU Int 2000; 85: Tubaro A, Polito M, Giambroni L, Famulari C, Gange E, Ostardo E. Sexual function in patients with LUTS suggestive of BPH. Eur Urol 2001; 40(Suppl 1): Stijnen T, Arends LR. [Roaming through methodology. XVI. What to do about missing data] Dwalingen in de methodologie. XVI. Wat te doen met ontbrekende waarnemingen? Ned Tijdschr Geneeskd 1999; 143: Eijkelenburg-Waterreus van Y, Schellevis F, Bakker de D, Tiersma W, Westert G. Gegevens in het elektronisch medisch dossier: bruikbaar voor het optimaliseren van de probleemlijst? Huisarts en Wetenschap 2001; 44: Lamberts H, Wood M. ICPC: International Classification of Primary Care. Oxford University Press: Oxford, Miller GC, Britt H. A new drug classification for computer systems: the ATC extension code. Int J Biomed Comput 1995; 40: Donovan JL, Abrams P, Peters TJ, Kay HE, Reynard J, Chapple C et al. The ICS- BPH Study: the psychometric validity and reliability of the ICSmale questionnaire. Br J Urol 1996; 77: Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991; 121: Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: Rubin D. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Inc: New York, Faris PD, Ghali WA, Brant R, Norris CM, Galbraith PD, Knudtson ML et al. Multiple imputation versus data enhancement for dealing with missing data in observational health care outcome analyses. J Clin Epidemiol 2002; 55: Landrum MB, Becker MP. A multiple imputation strategy for incomplete longitudinal data. Stat Med 2001; 20: Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular events. J Clin Epidemiol 1994; 47: Wilson PW, D Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: SAS/BASEs and SAS/STATs software version 9.1 TS Level 03M0 of the SAS system for Windows. [the SAS System for Windows program] 9.1 service pack 3 version. Copyrightr 2003 SAS Institute Inc. Cary, NC, USA. 31 Woodward M, Bassetti WHC (eds). Epidemiology Study Design and data analysis, Texts in Staitistical Science 2nd edn. Chapman and Hall CRC Press: Boca Raton, Blanker MH, Bosch JL, Groeneveld FP, Bohnen AM, Prins A, Thomas S et al. Erectile and ejaculatory dysfunction in a community-based sample of men 50 to 78 years old: prevalence, concern, and relation to sexual activity. Urology 2001; 57: Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Billups K, Burnett AL et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005; 96: 85M 93M. 34 Derby CA, Araujo AB, Johannes CB, Feldman HA, McKinlay JB. Measurement of erectile dysfunction in population-based studies: the use of a single question self-assessment in the Massachusetts Male Aging Study. Int J Impot Res 2000; 12: Appendix International Continence Society: Male sex question on erectile dysfunction Do you get erections? How much of a problem is this for you? Yes, with normal rigidity Yes, with reduced rigidity Yes, with severely reduced rigidity No, erection not possible Not a problem A bit of a problem Quite a problem A serious problem Question about sexual activity If you are not sexually active anymore. how long ago did this stop? ymonths yyears