http://informahealthcare.com/tam ISSN: 1368-5538 (print), 1473-0790 (electronic) Aging Male, 2014; 17(2): 81–86 ! 2014 Informa UK Ltd. DOI: 10.3109/13685538.2013.873782
ORIGINAL ARTICLE
Should men with mild erectile dysfunction be closely evaluated for cardiovascular diseases in the Korean population? Sung Yong Cho1, Hwancheol Son1, Soo Woong Kim2, and Jae-Seung Paick2 1
Department of Urology, Seoul National University Boramae Medical Center, Seoul, Republic of Korea and 2Department of Urology, Seoul National University Hospital, Seoul, Korea Abstract
Keywords
This study compared demographic characteristics and prevalence of cardiovascular comorbidities between men with mild erectile dysfunction (ED) and men with more severe ED. Men with 6-month history of ED and in monogamous heterosexual relationships were included. Non-responders to type 5 phosphodiesterase inhibitors or patients receiving regular treatment with nitrate, anticoagulants, androgens, and anti-androgens were excluded. ED was defined according to the International Index of Erectile Function questionnaire score: no ED (26), mild ED (22–25), and others (522). The review identified 70 patients with mild ED (6.0%, group A) and 1098 patients with more severe ED (94.0%, group B) were included. Of the patients in group B, 365 had mild-to-moderate ED (30.5%), 505 had moderate ED (43.2%), and 233 had severe ED (20.0%). Mean ages and body mass indices showed no differences between groups A and B. Group A had shorter mean duration of ED (p ¼ 0.025). Although patients in group A had milder ED with shorter duration than group B patients, cardiovascular risk factors such as diabetes, hypertension and lipid disorder were still common for group A. The most common comorbidity was diabetes, which was twice as likely for patients in group B. Except for diabetes the prevalence of all diseases was comparable between the two groups. In conclusion, patients with mild ED should be closely evaluated for cardiovascular comorbidities.
Diabetes mellitus, erectile dysfunction, impotence, prevalence
Introduction The association between erectile dysfunction (ED) and cardiovascular diseases has been investigated in various studies, which have shown that there is an increased risk of cardiovascular diseases in patients with ED [1–5]. Endothelial dysfunction seems to have an important role in the pathophysiology of ED, and most patients with ED have been found to have more than one cardiovascular risk factor among common factors, such as old age, hypertension, diabetes, dyslipidemia, smoking, and physical inactivity [1–3,5]. The presence and severity of ED are usually evaluated by the simplified International Index of Erectile Function (IIEF) questionnaires, which classifies patients as having no ED, mild, mild to moderate, moderate or severe [6,7]. The prevalence of mild ED in elderly patients has been reported to be more than 20% [8,9]. Controversial findings have been reported regarding to the association between mild ED and cardiovascular diseases.
Address for correspondence: Jae-Seung Paick, Department of Urology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Tel: +82 2 2072 2422. Fax: +82 2 742 4665. E-mail: [email protected]
History Received 6 February 2013 Revised 5 October 2013 Accepted 20 November 2013 Published online 7 January 2014
Some studies have demonstrated a positive correlation between the severity of ED and the prevalence of cardiovascular comorbidities in elderly men [9,10]. One study reported that only moderate-to-severe ED, but not mild ED, was associated with increased risk for coronary heart diseases or cerebrovascular stroke within 10 years [3]. In contrast, some studies have demonstrated that the prevalence of cardiovascular comorbidities in men with mild ED was comparable to that in men with more severe ED [8,9,11]. Despite the potential relationships between ED and cardiovascular diseases, men with mild ED do not appear to seek or receive appropriate medical care because of attitudes, beliefs, or other psychological factors [11,12]. More importantly, investigations have been scarce for the association between mild ED and cardiovascular diseases [11]. Furthermore, the prevalence of cardiovascular comorbidities had not been compared among patients with mild ED and patients with more severe ED in Asian populations. Therefore, the aims of the present study were to investigate the demographic characteristics and underlying diseases among men who were included in a randomized, doubleblinded, placebo-controlled, parallel-group studies of udenafil (ZYDENA; Dong-A pharm., Seoul, Korea) [13–15] including an unpublished phase II study of udenafil and to compare the
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prevalence of cardiovascular comorbidities between patients with mild ED and patients with more severe ED.
Materials and methods Patients A retrospective review was performed for male subjects aged between 19 and 70 years with a 6-month history of ED and who have been in a monogamous heterosexual relationship from the manufacturer’s database for udenafil [13–15], although one of them was not published. Subjects were excluded for ED secondary to penile anatomical defects, spinal cord injury, radical pelvic or prostate surgery, prior diagnosis of other sexual disorders, hyperprolactinemia, lowered level of testosterone, poorly-controlled diabetes or psychiatric disorder, history of active peptic ulcer disease, major hematological, renal or hepatic abnormalities. Additionally, subjects were excluded either for significant cardiovascular diseases such as stroke, myocardial infarct, and severe arrhythmia, or for history of alcoholism or substance abuse. Patients who received regular treatment with nitrate, anticoagulants except aspirin, androgens, and anti-androgens were excluded as well. Non-responders to other type 5 phosphodiesterase inhibitors (PDE5Is) and responders to other PDE5Is exposed within 2 weeks were also excluded. The review identified a total of 70 patients with mild ED (6.0%) and 1098 patients with higher severity of ED (94.0%). The study was approved by the institutional review board (IRB) of our institution. Clinical parameters Demographic characteristics such as age, body weight, height, smoking history, causes of ED and history of PDE5Is use were collected. Additionally, patients were evaluated for prior medical history of cardiovascular disease, prostate disease, lipid disorder, gastrointestinal disorder, and psychological disorder. Demographic characteristics, prevalence of comorbidities, and prior medications were compared between patients with mild ED (group A) and patients with higher severity of ED (group B). ED was defined according to the IIEF- EF score: no ED (26), mild ED (22–25), mildto-moderate ED (17–21), moderate ED (11–16), and severe ED (511). A patient was considered to have psychogenic ED when psychological factors were identified as the predominant or exclusive cause of ED [12]. Statistical analysis All variables were presented as mean ± SD (range) or N (%). Demographic characteristics, prevalence of comorbidities, and prior medications were compared by the Chi-square test or Fisher’s exact test. Because of a large discrepancy in sample sizes between the two groups, mean values and standard deviations of the baseline demographic data were matched for the analysis. Furthermore, one-to-one propensity score-matching was performed to reduce treatment-related bias in estimating the association between ED and comorbidities [16]. Each patient in group A was matched to another in group B, based on the calculated propensity scores using multiple logistic-regression analysis. Continuous and
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categorical parameters were combined to yield a propensity score for each patient in groups A and B. The means and standard deviations related to matching covariates were equivalent between both groups. Subsequently, the prevalence of comorbidities was investigated between the matched groups. All statistical analyses were performed using commercially available software (SPSS 14.0, Inc., Chicago, IL. and SAS 9.2, SAS institute, Cary, NC). All comparisons were performed at a two-sided a level of 0.05.
Results Of the total of 1168 patients, there were 70 cases of mild ED (6.0%), 360 cases of mild-to-moderate ED (30.8%), 505 cases of moderate ED (43.2%), and 233 cases of severe ED (20.0%). The mean ages were not significantly different between groups A and B. In addition, no differences in body mass index were found (25 ± 2 kg/m2 versus 25 ± 3 kg/m2), and the proportion of men with BMI greater than 25 was similar between the two groups (44.3% versus 42.8%). The mean duration of ED was shorter in group A than in group B (p ¼ 0.025), and the range of ED duration was much broader for group B than for group A (4.3 ± 3.6 years versus 3.8 ± 3.3 years). The occurrence of organic diseases was higher for group B than for group A (57.3% versus 48.6%), though not statistically significant. Although patients in group A had mild ED, 88.6% of cases were due to organic causes (Table 1). Group A had a greater percentage of patients whose ED was due to mainly psychogenic causes (11.4%) than group B (6.2%), though statistically insignificant. The most common comorbidity in groups A and B was diabetes mellitus, as shown in Table 2 (37.1% versus 57.1%, p ¼ 0.001), and patients in group B were twice as likely to have diabetes as those in group A. Except for diabetes, the prevalence of comorbid diseases was comparable between the two groups. Although group A patients only had a mild degree of ED with a shorter duration, cardiovascular risk factors such as diabetes, hypertension, and lipid disorder were common. The propensity score matched groups showed similar results between groups A and B. The prevalence of all diseases except diabetes was comparable between the two matched groups. Matched patients in group B were twice as likely to have diabetes as those in group A (odds ratio 2.45, 95% CI 1.5–3.8, p50.001). The use of concomitant medications was also common (Table 3). A larger portion of group B patients used medications related to diabetes (p ¼ 0.001) and renin-angiotensin system (p ¼ 0.046) than did group A patients, although the use of other medications was comparable between the groups. However, comparison of the use of anti-hypertensive medications was not assessed because medications related to hypertension can be combined in a multitude of ways. Although 11.4% of patients in group A were found to have mainly psychogenic causes of ED, no anti-anxiety medication had been prescribed.
Discussion Several previous investigations have shown that ED is an agedependent condition and that patients with risk factors for cardiovascular diseases such as diabetes, hypertension,
Relationship between mild erectile dysfunction and cardiovascular diseases
DOI: 10.3109/13685538.2013.873782
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Table 1. Demographics, history of ED, and history of smoking. Udenafil mild ED N Demographics Age (years) Weight (kg) Height (cm) BMI (kg/m2) Obesity Underweight (BMI518.5) Normal weight (BMI 18.5–24.9) Overweight (BMI 25–29.9) Obese (BMI 30) Erectile dysfunction Duration (year) Etiology Mainly organic Mainly psychogenic Mixed Smoking Never smoked Smoker Ex-smoker Prior user of other PDE-5 inhibitors
Udenafil except for mild ED
Udenafil database
1098 (94.0%)
1168 (100%)
70 (6.0%) 53 ± 8 71 ± 9 169 ± 5 25 ± 2 0 39 29 2
(28–71) (53–99) (158–180) (19–32)
55 ± 8 71 ± 9 169 ± 5 25 ± 3
(0) (55.7%) (41.4%) (2.9%)
5 623 432 38
3.8 ± 3.3 (0–19)
(27–80) (47–109) (130–186) (17–37) (0.5%) (56.7%) (39.3%) (3.5%)
4.3 ± 3.6 (0–25)
55 ± 8 71 ± 9 169 ± 5 25 ± 3 5 662 461 40
(27–80) (47–109) (130–186) (17–37) (0.4%) (56.7%) (39.5%) (3.4%)
4.2 ± 3.6 (0–25)
34 (48.6%) 8 (11.4%) 28 (40.0%)
629 (57.3%) 68 (6.2%) 401 (36.5%)
663 (56.8%) 76 (6.5%) 429 (36.8%)
20 19 31 56
339 347 412 787
367 358 443 843
(28.6%) (27.1%) (44.3%) (80.0%)
(30.9%) (31.6%) (37.5%) (71.7%)
p
(31.4%) (30.7%) (37.9%) (72.2%)
NS NS NS NS NS – NS NS NS 0.025* NS 0.040* NS NS NS NS NS NS NS
BMI, body mass index; PDE, phosphodiesterase; ED, erectile dysfunction; NS, not significant. All variables were reported as mean ± standard deviation (range) or N (%). *p50.05. Table 2. Prevalence of comorbidities.
Udenafil mild ED N Diabetes mellitus Hypertension BPH/prostatitis Benign prostatic hyperplasia Prostatitis Lipid disorder Hypercholesterolemia Hypertriglyceridemia Gatrointestinal disorder Gastritis Gastrooesophageal reflux disease Duodenitis Irritable bowel syndrome Liver disorder Viral hepatitis Hepatic steatosis Hepatic cirrhosis Hepatitis, others Depression Anxiety disorder
Udenafil except for mild ED (matched)
Udenafil except for mild ED
p
Odds ratio (95% CI)
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1098 627 (57.1%) 358 (32.6%) 334 (30.4%) 304 (27.7%) 30 (2.7%) 173 (15.8%) 172 (15.7%) 1 (0.1) 137 (12.5%) 95 (8.7%) 38 (3.5%) 2 (0.2%) 2 (0.2%) 158 (14.4%) 64 (5.8%) 47 (4.3%) 3 (0.3) 16 (0.5) 4 (0.4) 3 (0.3)
0.001* NS – NS – NS NS – NS NS NS – – NS NS NS – – – –
2.3 (1.4–3.7)
70 26 (37.1%) 18 (25.7%) 24 (34.3%) 24 (34.3%) 9 (12.9%) 9 (12.9%) 10 (14.3%) 6 (8.6%) 4 (5.7%)
5 (7.1%) 3 (4.3%) 2 (2.9%)
BPH, benign prostatic hyperplasia; GI, gastrointestinal; ED, erectile dysfunction; NS, not significant. All variables were reported as N (%). *p50.05.
dyslipidemia, smoking, and physical inactivity are at a higher risk for ED [5–7,9,14,15]. In addition, some studies have found that patients with mild ED experienced less cardiovascular comorbidity than those with moderate or severe ED. Ponholzer et al. reported that patients with moderate or severe ED, but not those with mild ED, were at greater risks for coronary heart disease or stroke, when compared to those without ED for over a decade [3]. Patients with mild ED only showed a minimally increased risk for coronary heart
disease or stroke, which was statistically insignificant [3]. In another study, Chew et al. compared the prevalence of cardiovascular risk factors and diseases in various age groups and reported that the prevalence of these conditions significantly increased with the severity of ED [8]. In the Krimpen study, risk scores were used to show that there is an increasing risk for cardiovascular accidents with increasing severity of ED [2]. In the study, the prevalence of diabetes and current smoking status were significantly higher in patients with
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Table 3. Concomitant medications used in patients with ED.
N Drugs used in diabetes Agents acting on the renin-angiotensin system Calcium channel blockers Beta blocking agents Diuretics Antithrombotic agents Drugs used in benign prostatic hyperplasia Lipid modifying agents Anti-acid medications Drugs for functional gastrointestinal disorders
Udenafil mild ED
Udenafil except for mild ED
Udenafil database
p
70 26 (37.1%) 12 (17.1%) 16 (22.9%) 8 (11.4%) 7 (10.0%) 12 (17.1%) 20 (28.6%) 9 (12.9%) 33 (47.1%) 9 (12.9%)
1098 627 (57.1%) 309 (28.1%) 285 (26.0%) 104 (9.5%) 63 (5.7%) 285 (26.0%) 264 (24.0%) 162 (14.8%) 255 (23.2%) 119 (10.8%)
1168 653 (55.9%) 321 (27.5%) 301 (25.8%) 112 (9.6%) 69 (5.9%) 297 (25.4%) 284 (24.3%) 171 (14.6%) 288 (24.7%) 128 (11.0%)
0.001* 0.046* NS NS NS NS NS NS 50.001* NS
Odds ratio (95% CI) 2.3 (1.4–3.7) 1.9 (1.1–3.6)
0.4 (0.2–0.6)
ED, erectile dysfunction; NS, not significant. All variables were reported as N (%). *p50.05.
‘‘severely reduced erectile rigidity’’ than in those with ‘‘reduced erectile rigidity’’ [2]. However, this study used the ICS male sex questionnaire [17], which is different from the IIEF-5 or IIEF-EF, so direct comparison is difficult between the Krimpen and the present study which used IIEF-EF. Some investigators have also studied the association between prevalence of ED and cardiovascular risk factors [1,5] and reported that cardiovascular risk factors are significantly dependent on severity of ED, as patients with ED seemed to show increased cardiovascular risk factors compared to patients without ED. Despite the abundance of investigations comparing patients with ED to those without ED, there has been a lack of comparative analyses of patients with mild ED to patients with more severe grades of ED. Men with mild ED are usually overlooked in the outpatient setting because they generally experience less cardiovascular comorbidity than those with moderate or severe ED, but also because mild ED has been thought to be caused by temporary psychological factors such as anxiety or depression [12]. However, recent studies have suggested that mild ED can be an early sign of cardiovascular pathology [18–20], and certain investigations have shown that men with mild ED experience substantial benefit from PDE5Is [21,22]. Recently, Lee et al. had investigated whether men with mild ED have the same risk factors for cardiovascular diseases compared to those for the general ED clinical trial population [11]. The study concluded that risk factors and prevalence of underlying cardiovascular comorbidities were similar between men with mild ED and the general ED clinical trial population and that mild ED should be regarded as an important indicator of underlying cardiovascular diseases. Finally, they suggested that men who present with mild ED should be actively evaluated for underlying cardiovascular diseases. Likewise, the present study found that group A patients had similar risk factors and prevalence of underlying cardiovascular comorbidities as those in group B. The prevalence of diabetes, however, was significantly higher in group B than in group A, which, in turn, is higher than that of the general population in the same age group in the East Asian population [23,24]. All of these findings emphasize the importance of adequate evaluation and management of patients mild ED in order to screen and treat any underlying cardiovascular
comorbidity. Physicians should recommend changes in lifestyle to reduce risk factors for heart diseases in patients with mild ED [25,26]. The present study intended to demonstrate no significant differences in the prevalence of cardiovascular comorbidities between the groups A and B and to show the clinical significance of group A compared to group B. No significant differences in prevalence of cardiovascular diseases were demonstrated except that of diabetes, when the baseline demographic data showed no differences between the two groups. The results were similar between the propensity score matched groups. Interestingly, we found that men with mild ED have cardiovascular risk factors similar to patients with higher grades of ED in the Korean population, and this study reflects the findings by Lee et al. in the other population [11]. Although these results do not provide direct evidence of an association between ED and cardiovascular risk factors, deeper understanding of underlying risks for cardiovascular disease in men with mild ED will highlight the importance of early and adequate management. Therefore, as European Association of Urology recommended [27] cardiovascular risks should be also evaluated first in patients with mild ED, which can be used as for treatment algorithm for resuming sexual function. The clinically validated questionnaire, IIEF, should be administered; physical examination and routine laboratory tests including glucose-lipid profile and testosterone level are usually required. Reversible risk factors and hazardous lifestyle pattern would be important for the recovery of sexual activity. Specific diagnostic tests of nocturnal penile tumescence and rigidity test, intracavernouls injection test, penile ultrasonography, and arteriography should be performed when indicated. Lifestyle management, treatment of reversible risk factors, and appropriate choice of treatment method including oral pharmacotherapy or secondline intracavernous injection therapy should be also actively monitored in patients with mild ED during follow-up period. Limitations of the study A limitation of the present study was that patients were divided according to IIEF-EF severity categories. As a result,
DOI: 10.3109/13685538.2013.873782
Relationship between mild erectile dysfunction and cardiovascular diseases
patients in the mild-to-moderate ED category were distinguished from those with mild ED, although actual symptoms were not so different. A clearer boundary between the two categories would have been ideal for the comparative analysis. Such a limitation was inevitable, however, because patients were divided according to IIEF-EF severity categories. Another limitation was missing data on therapies by which subgroup analyses on patients using hypertension or diabetes medications could not be performed. Furthermore, because there are many types and combinations of hypertension medications, it was difficult to simply group such medications together into one category of concomitant medications. Therefore, we described each concomitant medication used in hypertension in groups A and B. Although we performed the analysis with propensity score matching, the number of patients included in the analysis was small. However, this would be derived the small portion of patients with mild ED among the total number of patients with ED who wished to receive medical therapy. Despite the limitations, however, our findings will be valuable for managing cardiovascular diseases in patients with mild ED in the early stage. In particular, further prospective studies that analyze erectile responses should clarify some important unanswered questions on the appropriate management of men with mild ED.
Conclusion Patients with mild ED had cardiovascular risk factors such as diabetes, hypertension, and lipid disorder, which were similar to patients with more severe ED. Thus, patients who present with mild ED should be closely evaluated to determine the presence of cardiovascular risk factors. Treatment of reversible risk factors would be important for the recovery of sexual activity.
Acknowledgements The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis and also the database support of Dong-A. Pharm.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
References 1. Chang ST, Chu CM, Hsu JT, et al. Surveillance of cardiovascular risk factors for outpatients in different erectile dysfunction severity. Int J Impot Res 2009;21:116–21. 2. Schouten BW, Bohnen AM, Bosch JL, et al. Erectile dysfunction prospectively associated with cardiovascular disease in the Dutch general population: results from the Krimpen Study. Int J Impot Res 2008;20:92–9. 3. Ponholzer A, Temml C, Obermayr R, et al. Is erectile dysfunction an indicator for increased risk of coronary heart disease and stroke? Eur Urol 2005;48:512–8; discussion 517–8.
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4. El-Sakka AI, Morsy AM, Fagih BI, Nassar AH. Coronary artery risk factors in patients with erectile dysfunction. J Urol 2004;172: 251–4. 5. Montorsi F, Briganti A, Salonia A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003;44:360–4; discussion 364–5. 6. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319–26. 7. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999;54:346–51. 8. Chew KK, Bremner A, Jamrozik K, et al. Male erectile dysfunction and cardiovascular disease: is there an intimate nexus? J Sex Med 2008;5:928–34. 9. Ponholzer A, Temml C, Mock K, et al. Prevalence and risk factors for erectile dysfunction in 2869 men using a validated questionnaire. Eur Urol 2005;47:80–5; discussion 85–6. 10. Khoo EM, Tan HM, Low WY. Erectile dysfunction and comorbidities in aging men: an urban cross-sectional study in Malaysia. J Sex Med 2008;5:2925–34. 11. Lee JC, Benard F, Carrier S, et al. Do men with mild erectile dysfunction have the same risk factors as the general erectile dysfunction clinical trial population? BJU Int 2011;107: 956–60. 12. Fisher WA, Rosen RC, Eardley I, et al. The multinational Men’s Attitudes to Life Events and Sexuality (MALES) Study Phase II: understanding PDE5 inhibitor treatment seeking patterns, among men with erectile dysfunction. J Sex Med 2004;1:150–60. 13. Zhao C, Kim SW, Yang DY, et al. Efficacy and safety of once-daily dosing of udenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2011;60:380–7. 14. Paick JS, Kim SW, Yang DY, et al. The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J Sex Med 2008;5:946–53. 15. Park HJ, Park JK, Park K, et al. Efficacy of udenafil for the treatment of erectile dysfunction up to 12 hours after dosing: a randomized placebo-controlled trial. J Sex Med 2010;7:2209–16. 16. Austin PC, Grootendorst P, Anderson GM. A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 2007;26:734–53. 17. Donovan JL, Abrams P, Peters TJ, et al. The ICS-’BPH’ Study: the psychometric validity and reliability of the ICSmale questionnaire. Br J Urol 1996;77:554–62. 18. Solomon H, Man JW, Wierzbicki AS, Jackson G. Relation of erectile dysfunction to angiographic coronary artery disease. Am J Cardiol 2003;91:230–1. 19. Ma RC, So WY, Yang X, et al. Erectile dysfunction predicts coronary heart disease in type 2 diabetes. J Am Coll Cardiol 2008; 51:2045–50. 20. Blumentals WA, Gomez-Caminero A, Joo S, Vannappagari V. Should erectile dysfunction be considered as a marker for acute myocardial infarction? Results from a retrospective cohort study. Int J Impot Res 2004;16:350–3. 21. Benard F, Carrier S, Lee JC, et al. Men with mild erectile dysfunction benefit from sildenafil treatment. J Sex Med 2010;7: 3725–35. 22. Sommer F, Klotz T, Engelmann U. Improved spontaneous erectile function in men with mild-to-moderate arteriogenic erectile dysfunction treated with a nightly dose of sildenafil for one year: a randomized trial. Asian J Androl 2007;9:134–41. 23. Jee SH, Appel LJ, Suh I, et al. Prevalence of cardiovascular risk factors in South Korean adults: results from the Korea Medical Insurance Corporation (KMIC) Study. Ann Epidemiol 1998;8: 14–21. 24. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090–101. 25. Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol 2004;43:1405–11.
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26. Jackson G, Boon N, Eardley I, et al. Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus. Int J Clin Pract 2010;64:848–57.
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27. Nehra A, Jackson G, Miner M, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2012;87:766–78.
Notice of Correction The version of this article published online ahead of print on 07 Jan 2014 contained an error in the acknowledgments. The sentence ‘‘The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis’’ should have read ‘‘The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis and also the database support of Dong-A. Pharm.’’ The error has been corrected for this version.
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ORIGINAL ARTICLE
Should men with mild erectile dysfunction be closely evaluated for cardiovascular diseases in the Korean population? Sung Yong Cho1, Hwancheol Son1, Soo Woong Kim2, and Jae-Seung Paick2 1
Department of Urology, Seoul National University Boramae Medical Center, Seoul, Republic of Korea and 2Department of Urology, Seoul National University Hospital, Seoul, Korea Abstract
Keywords
This study compared demographic characteristics and prevalence of cardiovascular comorbidities between men with mild erectile dysfunction (ED) and men with more severe ED. Men with 6-month history of ED and in monogamous heterosexual relationships were included. Non-responders to type 5 phosphodiesterase inhibitors or patients receiving regular treatment with nitrate, anticoagulants, androgens, and anti-androgens were excluded. ED was defined according to the International Index of Erectile Function questionnaire score: no ED (26), mild ED (22–25), and others (522). The review identified 70 patients with mild ED (6.0%, group A) and 1098 patients with more severe ED (94.0%, group B) were included. Of the patients in group B, 365 had mild-to-moderate ED (30.5%), 505 had moderate ED (43.2%), and 233 had severe ED (20.0%). Mean ages and body mass indices showed no differences between groups A and B. Group A had shorter mean duration of ED (p ¼ 0.025). Although patients in group A had milder ED with shorter duration than group B patients, cardiovascular risk factors such as diabetes, hypertension and lipid disorder were still common for group A. The most common comorbidity was diabetes, which was twice as likely for patients in group B. Except for diabetes the prevalence of all diseases was comparable between the two groups. In conclusion, patients with mild ED should be closely evaluated for cardiovascular comorbidities.
Diabetes mellitus, erectile dysfunction, impotence, prevalence
Introduction The association between erectile dysfunction (ED) and cardiovascular diseases has been investigated in various studies, which have shown that there is an increased risk of cardiovascular diseases in patients with ED [1–5]. Endothelial dysfunction seems to have an important role in the pathophysiology of ED, and most patients with ED have been found to have more than one cardiovascular risk factor among common factors, such as old age, hypertension, diabetes, dyslipidemia, smoking, and physical inactivity [1–3,5]. The presence and severity of ED are usually evaluated by the simplified International Index of Erectile Function (IIEF) questionnaires, which classifies patients as having no ED, mild, mild to moderate, moderate or severe [6,7]. The prevalence of mild ED in elderly patients has been reported to be more than 20% [8,9]. Controversial findings have been reported regarding to the association between mild ED and cardiovascular diseases.
Address for correspondence: Jae-Seung Paick, Department of Urology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Tel: +82 2 2072 2422. Fax: +82 2 742 4665. E-mail: [email protected]
History Received 6 February 2013 Revised 5 October 2013 Accepted 20 November 2013 Published online 7 January 2014
Some studies have demonstrated a positive correlation between the severity of ED and the prevalence of cardiovascular comorbidities in elderly men [9,10]. One study reported that only moderate-to-severe ED, but not mild ED, was associated with increased risk for coronary heart diseases or cerebrovascular stroke within 10 years [3]. In contrast, some studies have demonstrated that the prevalence of cardiovascular comorbidities in men with mild ED was comparable to that in men with more severe ED [8,9,11]. Despite the potential relationships between ED and cardiovascular diseases, men with mild ED do not appear to seek or receive appropriate medical care because of attitudes, beliefs, or other psychological factors [11,12]. More importantly, investigations have been scarce for the association between mild ED and cardiovascular diseases [11]. Furthermore, the prevalence of cardiovascular comorbidities had not been compared among patients with mild ED and patients with more severe ED in Asian populations. Therefore, the aims of the present study were to investigate the demographic characteristics and underlying diseases among men who were included in a randomized, doubleblinded, placebo-controlled, parallel-group studies of udenafil (ZYDENA; Dong-A pharm., Seoul, Korea) [13–15] including an unpublished phase II study of udenafil and to compare the
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prevalence of cardiovascular comorbidities between patients with mild ED and patients with more severe ED.
Materials and methods Patients A retrospective review was performed for male subjects aged between 19 and 70 years with a 6-month history of ED and who have been in a monogamous heterosexual relationship from the manufacturer’s database for udenafil [13–15], although one of them was not published. Subjects were excluded for ED secondary to penile anatomical defects, spinal cord injury, radical pelvic or prostate surgery, prior diagnosis of other sexual disorders, hyperprolactinemia, lowered level of testosterone, poorly-controlled diabetes or psychiatric disorder, history of active peptic ulcer disease, major hematological, renal or hepatic abnormalities. Additionally, subjects were excluded either for significant cardiovascular diseases such as stroke, myocardial infarct, and severe arrhythmia, or for history of alcoholism or substance abuse. Patients who received regular treatment with nitrate, anticoagulants except aspirin, androgens, and anti-androgens were excluded as well. Non-responders to other type 5 phosphodiesterase inhibitors (PDE5Is) and responders to other PDE5Is exposed within 2 weeks were also excluded. The review identified a total of 70 patients with mild ED (6.0%) and 1098 patients with higher severity of ED (94.0%). The study was approved by the institutional review board (IRB) of our institution. Clinical parameters Demographic characteristics such as age, body weight, height, smoking history, causes of ED and history of PDE5Is use were collected. Additionally, patients were evaluated for prior medical history of cardiovascular disease, prostate disease, lipid disorder, gastrointestinal disorder, and psychological disorder. Demographic characteristics, prevalence of comorbidities, and prior medications were compared between patients with mild ED (group A) and patients with higher severity of ED (group B). ED was defined according to the IIEF- EF score: no ED (26), mild ED (22–25), mildto-moderate ED (17–21), moderate ED (11–16), and severe ED (511). A patient was considered to have psychogenic ED when psychological factors were identified as the predominant or exclusive cause of ED [12]. Statistical analysis All variables were presented as mean ± SD (range) or N (%). Demographic characteristics, prevalence of comorbidities, and prior medications were compared by the Chi-square test or Fisher’s exact test. Because of a large discrepancy in sample sizes between the two groups, mean values and standard deviations of the baseline demographic data were matched for the analysis. Furthermore, one-to-one propensity score-matching was performed to reduce treatment-related bias in estimating the association between ED and comorbidities [16]. Each patient in group A was matched to another in group B, based on the calculated propensity scores using multiple logistic-regression analysis. Continuous and
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categorical parameters were combined to yield a propensity score for each patient in groups A and B. The means and standard deviations related to matching covariates were equivalent between both groups. Subsequently, the prevalence of comorbidities was investigated between the matched groups. All statistical analyses were performed using commercially available software (SPSS 14.0, Inc., Chicago, IL. and SAS 9.2, SAS institute, Cary, NC). All comparisons were performed at a two-sided a level of 0.05.
Results Of the total of 1168 patients, there were 70 cases of mild ED (6.0%), 360 cases of mild-to-moderate ED (30.8%), 505 cases of moderate ED (43.2%), and 233 cases of severe ED (20.0%). The mean ages were not significantly different between groups A and B. In addition, no differences in body mass index were found (25 ± 2 kg/m2 versus 25 ± 3 kg/m2), and the proportion of men with BMI greater than 25 was similar between the two groups (44.3% versus 42.8%). The mean duration of ED was shorter in group A than in group B (p ¼ 0.025), and the range of ED duration was much broader for group B than for group A (4.3 ± 3.6 years versus 3.8 ± 3.3 years). The occurrence of organic diseases was higher for group B than for group A (57.3% versus 48.6%), though not statistically significant. Although patients in group A had mild ED, 88.6% of cases were due to organic causes (Table 1). Group A had a greater percentage of patients whose ED was due to mainly psychogenic causes (11.4%) than group B (6.2%), though statistically insignificant. The most common comorbidity in groups A and B was diabetes mellitus, as shown in Table 2 (37.1% versus 57.1%, p ¼ 0.001), and patients in group B were twice as likely to have diabetes as those in group A. Except for diabetes, the prevalence of comorbid diseases was comparable between the two groups. Although group A patients only had a mild degree of ED with a shorter duration, cardiovascular risk factors such as diabetes, hypertension, and lipid disorder were common. The propensity score matched groups showed similar results between groups A and B. The prevalence of all diseases except diabetes was comparable between the two matched groups. Matched patients in group B were twice as likely to have diabetes as those in group A (odds ratio 2.45, 95% CI 1.5–3.8, p50.001). The use of concomitant medications was also common (Table 3). A larger portion of group B patients used medications related to diabetes (p ¼ 0.001) and renin-angiotensin system (p ¼ 0.046) than did group A patients, although the use of other medications was comparable between the groups. However, comparison of the use of anti-hypertensive medications was not assessed because medications related to hypertension can be combined in a multitude of ways. Although 11.4% of patients in group A were found to have mainly psychogenic causes of ED, no anti-anxiety medication had been prescribed.
Discussion Several previous investigations have shown that ED is an agedependent condition and that patients with risk factors for cardiovascular diseases such as diabetes, hypertension,
Relationship between mild erectile dysfunction and cardiovascular diseases
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Table 1. Demographics, history of ED, and history of smoking. Udenafil mild ED N Demographics Age (years) Weight (kg) Height (cm) BMI (kg/m2) Obesity Underweight (BMI518.5) Normal weight (BMI 18.5–24.9) Overweight (BMI 25–29.9) Obese (BMI 30) Erectile dysfunction Duration (year) Etiology Mainly organic Mainly psychogenic Mixed Smoking Never smoked Smoker Ex-smoker Prior user of other PDE-5 inhibitors
Udenafil except for mild ED
Udenafil database
1098 (94.0%)
1168 (100%)
70 (6.0%) 53 ± 8 71 ± 9 169 ± 5 25 ± 2 0 39 29 2
(28–71) (53–99) (158–180) (19–32)
55 ± 8 71 ± 9 169 ± 5 25 ± 3
(0) (55.7%) (41.4%) (2.9%)
5 623 432 38
3.8 ± 3.3 (0–19)
(27–80) (47–109) (130–186) (17–37) (0.5%) (56.7%) (39.3%) (3.5%)
4.3 ± 3.6 (0–25)
55 ± 8 71 ± 9 169 ± 5 25 ± 3 5 662 461 40
(27–80) (47–109) (130–186) (17–37) (0.4%) (56.7%) (39.5%) (3.4%)
4.2 ± 3.6 (0–25)
34 (48.6%) 8 (11.4%) 28 (40.0%)
629 (57.3%) 68 (6.2%) 401 (36.5%)
663 (56.8%) 76 (6.5%) 429 (36.8%)
20 19 31 56
339 347 412 787
367 358 443 843
(28.6%) (27.1%) (44.3%) (80.0%)
(30.9%) (31.6%) (37.5%) (71.7%)
p
(31.4%) (30.7%) (37.9%) (72.2%)
NS NS NS NS NS – NS NS NS 0.025* NS 0.040* NS NS NS NS NS NS NS
BMI, body mass index; PDE, phosphodiesterase; ED, erectile dysfunction; NS, not significant. All variables were reported as mean ± standard deviation (range) or N (%). *p50.05. Table 2. Prevalence of comorbidities.
Udenafil mild ED N Diabetes mellitus Hypertension BPH/prostatitis Benign prostatic hyperplasia Prostatitis Lipid disorder Hypercholesterolemia Hypertriglyceridemia Gatrointestinal disorder Gastritis Gastrooesophageal reflux disease Duodenitis Irritable bowel syndrome Liver disorder Viral hepatitis Hepatic steatosis Hepatic cirrhosis Hepatitis, others Depression Anxiety disorder
Udenafil except for mild ED (matched)
Udenafil except for mild ED
p
Odds ratio (95% CI)
70
1098 627 (57.1%) 358 (32.6%) 334 (30.4%) 304 (27.7%) 30 (2.7%) 173 (15.8%) 172 (15.7%) 1 (0.1) 137 (12.5%) 95 (8.7%) 38 (3.5%) 2 (0.2%) 2 (0.2%) 158 (14.4%) 64 (5.8%) 47 (4.3%) 3 (0.3) 16 (0.5) 4 (0.4) 3 (0.3)
0.001* NS – NS – NS NS – NS NS NS – – NS NS NS – – – –
2.3 (1.4–3.7)
70 26 (37.1%) 18 (25.7%) 24 (34.3%) 24 (34.3%) 9 (12.9%) 9 (12.9%) 10 (14.3%) 6 (8.6%) 4 (5.7%)
5 (7.1%) 3 (4.3%) 2 (2.9%)
BPH, benign prostatic hyperplasia; GI, gastrointestinal; ED, erectile dysfunction; NS, not significant. All variables were reported as N (%). *p50.05.
dyslipidemia, smoking, and physical inactivity are at a higher risk for ED [5–7,9,14,15]. In addition, some studies have found that patients with mild ED experienced less cardiovascular comorbidity than those with moderate or severe ED. Ponholzer et al. reported that patients with moderate or severe ED, but not those with mild ED, were at greater risks for coronary heart disease or stroke, when compared to those without ED for over a decade [3]. Patients with mild ED only showed a minimally increased risk for coronary heart
disease or stroke, which was statistically insignificant [3]. In another study, Chew et al. compared the prevalence of cardiovascular risk factors and diseases in various age groups and reported that the prevalence of these conditions significantly increased with the severity of ED [8]. In the Krimpen study, risk scores were used to show that there is an increasing risk for cardiovascular accidents with increasing severity of ED [2]. In the study, the prevalence of diabetes and current smoking status were significantly higher in patients with
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Table 3. Concomitant medications used in patients with ED.
N Drugs used in diabetes Agents acting on the renin-angiotensin system Calcium channel blockers Beta blocking agents Diuretics Antithrombotic agents Drugs used in benign prostatic hyperplasia Lipid modifying agents Anti-acid medications Drugs for functional gastrointestinal disorders
Udenafil mild ED
Udenafil except for mild ED
Udenafil database
p
70 26 (37.1%) 12 (17.1%) 16 (22.9%) 8 (11.4%) 7 (10.0%) 12 (17.1%) 20 (28.6%) 9 (12.9%) 33 (47.1%) 9 (12.9%)
1098 627 (57.1%) 309 (28.1%) 285 (26.0%) 104 (9.5%) 63 (5.7%) 285 (26.0%) 264 (24.0%) 162 (14.8%) 255 (23.2%) 119 (10.8%)
1168 653 (55.9%) 321 (27.5%) 301 (25.8%) 112 (9.6%) 69 (5.9%) 297 (25.4%) 284 (24.3%) 171 (14.6%) 288 (24.7%) 128 (11.0%)
0.001* 0.046* NS NS NS NS NS NS 50.001* NS
Odds ratio (95% CI) 2.3 (1.4–3.7) 1.9 (1.1–3.6)
0.4 (0.2–0.6)
ED, erectile dysfunction; NS, not significant. All variables were reported as N (%). *p50.05.
‘‘severely reduced erectile rigidity’’ than in those with ‘‘reduced erectile rigidity’’ [2]. However, this study used the ICS male sex questionnaire [17], which is different from the IIEF-5 or IIEF-EF, so direct comparison is difficult between the Krimpen and the present study which used IIEF-EF. Some investigators have also studied the association between prevalence of ED and cardiovascular risk factors [1,5] and reported that cardiovascular risk factors are significantly dependent on severity of ED, as patients with ED seemed to show increased cardiovascular risk factors compared to patients without ED. Despite the abundance of investigations comparing patients with ED to those without ED, there has been a lack of comparative analyses of patients with mild ED to patients with more severe grades of ED. Men with mild ED are usually overlooked in the outpatient setting because they generally experience less cardiovascular comorbidity than those with moderate or severe ED, but also because mild ED has been thought to be caused by temporary psychological factors such as anxiety or depression [12]. However, recent studies have suggested that mild ED can be an early sign of cardiovascular pathology [18–20], and certain investigations have shown that men with mild ED experience substantial benefit from PDE5Is [21,22]. Recently, Lee et al. had investigated whether men with mild ED have the same risk factors for cardiovascular diseases compared to those for the general ED clinical trial population [11]. The study concluded that risk factors and prevalence of underlying cardiovascular comorbidities were similar between men with mild ED and the general ED clinical trial population and that mild ED should be regarded as an important indicator of underlying cardiovascular diseases. Finally, they suggested that men who present with mild ED should be actively evaluated for underlying cardiovascular diseases. Likewise, the present study found that group A patients had similar risk factors and prevalence of underlying cardiovascular comorbidities as those in group B. The prevalence of diabetes, however, was significantly higher in group B than in group A, which, in turn, is higher than that of the general population in the same age group in the East Asian population [23,24]. All of these findings emphasize the importance of adequate evaluation and management of patients mild ED in order to screen and treat any underlying cardiovascular
comorbidity. Physicians should recommend changes in lifestyle to reduce risk factors for heart diseases in patients with mild ED [25,26]. The present study intended to demonstrate no significant differences in the prevalence of cardiovascular comorbidities between the groups A and B and to show the clinical significance of group A compared to group B. No significant differences in prevalence of cardiovascular diseases were demonstrated except that of diabetes, when the baseline demographic data showed no differences between the two groups. The results were similar between the propensity score matched groups. Interestingly, we found that men with mild ED have cardiovascular risk factors similar to patients with higher grades of ED in the Korean population, and this study reflects the findings by Lee et al. in the other population [11]. Although these results do not provide direct evidence of an association between ED and cardiovascular risk factors, deeper understanding of underlying risks for cardiovascular disease in men with mild ED will highlight the importance of early and adequate management. Therefore, as European Association of Urology recommended [27] cardiovascular risks should be also evaluated first in patients with mild ED, which can be used as for treatment algorithm for resuming sexual function. The clinically validated questionnaire, IIEF, should be administered; physical examination and routine laboratory tests including glucose-lipid profile and testosterone level are usually required. Reversible risk factors and hazardous lifestyle pattern would be important for the recovery of sexual activity. Specific diagnostic tests of nocturnal penile tumescence and rigidity test, intracavernouls injection test, penile ultrasonography, and arteriography should be performed when indicated. Lifestyle management, treatment of reversible risk factors, and appropriate choice of treatment method including oral pharmacotherapy or secondline intracavernous injection therapy should be also actively monitored in patients with mild ED during follow-up period. Limitations of the study A limitation of the present study was that patients were divided according to IIEF-EF severity categories. As a result,
DOI: 10.3109/13685538.2013.873782
Relationship between mild erectile dysfunction and cardiovascular diseases
patients in the mild-to-moderate ED category were distinguished from those with mild ED, although actual symptoms were not so different. A clearer boundary between the two categories would have been ideal for the comparative analysis. Such a limitation was inevitable, however, because patients were divided according to IIEF-EF severity categories. Another limitation was missing data on therapies by which subgroup analyses on patients using hypertension or diabetes medications could not be performed. Furthermore, because there are many types and combinations of hypertension medications, it was difficult to simply group such medications together into one category of concomitant medications. Therefore, we described each concomitant medication used in hypertension in groups A and B. Although we performed the analysis with propensity score matching, the number of patients included in the analysis was small. However, this would be derived the small portion of patients with mild ED among the total number of patients with ED who wished to receive medical therapy. Despite the limitations, however, our findings will be valuable for managing cardiovascular diseases in patients with mild ED in the early stage. In particular, further prospective studies that analyze erectile responses should clarify some important unanswered questions on the appropriate management of men with mild ED.
Conclusion Patients with mild ED had cardiovascular risk factors such as diabetes, hypertension, and lipid disorder, which were similar to patients with more severe ED. Thus, patients who present with mild ED should be closely evaluated to determine the presence of cardiovascular risk factors. Treatment of reversible risk factors would be important for the recovery of sexual activity.
Acknowledgements The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis and also the database support of Dong-A. Pharm.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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Notice of Correction The version of this article published online ahead of print on 07 Jan 2014 contained an error in the acknowledgments. The sentence ‘‘The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis’’ should have read ‘‘The authors acknowledge the contribution of Sohee Oh, PhD (Department of Medical Statistics, SMG-SNU Boramae MC) to the interpretation of statistical analysis and also the database support of Dong-A. Pharm.’’ The error has been corrected for this version.
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