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Keywords:

  • Beta-blockade;
  • Erectile dysfunction;
  • High-risk hypertension

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

Background: Erectile dysfunction (ED) is a multifactorial disease related to age, vascular disease, psychological disorders, or medical treatments. Beta-blockade agents are the recommended treatment for hypertensive patients with some specific organ damage but have been outlined as one of leading causes of drug-related ED, although differences between beta-blockade agents have not been assessed. Methods: Cross-sectional and observational study of hypertensive male subjects treated with any beta-blockade agent for at least 6 months. ED dysfunction was assessed by the International Index of Erectile Dysfunction (IIEF). Results: 1.007 patients, mean age 57.9 (10.59) years, were included. The prevalence of any category of ED was 71.0% (38.1% mild ED; 16.8% moderate ED; 16.1% severe ED). Patients with ED had longer time since the diagnosis of hypertension and higher prevalence of risk factors and comorbidities. The prevalence of ED increased linearly with age. ED patients received more medications and were more frequently treated with carvedilol and less frequently with nebivolol. Patients treated with nebivolol obtained higher scores in every parameter of the IIEF questionnaire. The multivariate analysis identified independent associations between ED and coronary heart disease (OR: 1.57), depression (OR: 2.25), diabetes (OR: 2.27), atrial fibrillation (OR: 2.59), and dyhidopiridines calcium channel blockers (OR: 1.76); treatment with nebivolol was associated to lower prevalence of ED (OR: 0.27). Conclusion: ED is highly prevalent in hypertensive patients treated with beta-blockade agents. The presence of ED is associated with more extended organ damage and not to cardiovascular treatments, except for the lower prevalence in nebivolol-treated patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse [1,2]. The prevalence of ED seems to be very high but registries and clinical trials have yielded many divergent results concerning is real prevalence, that ranges from 12% in Italy [3] to 18%[4] or 52%[5] in the United States. The accurate diagnosis of ED should be based on precise tools from which the International Index for Erectile Dysfunction (IIEF) has been outlined as one the most precise methods for the evaluation of male sexual function [6,7].

Incidence of ED has been related to chronic diseases [2,8,9] but also to hypertension [4,5,8] and especially to antihypertensive treatments [2,4,5]. Beta-blockade agents are an efficient therapy for hypertension and are especially recommended for patients with coronary heart disease, heart failure, or permanent atrial fibrillation [10]; nevertheless, these patients are at the highest risk for ED and beta-blockade agents have been related to higher incidence of ED [2,11]. Different beta-blockade agents have differential metabolic [12] and vascular effects [13–15] and therefore the incidence of ED could differ according to each agent. With this antecedents the Section of Hypertension from the Spanish Society of Cardiology designed the DELTHA (Disfunción ErectiL en pacientes con HTA/Erectile Dysfunction in Hypertensive patients) registry with the aim of describing the prevalence of ED in hypertensive patients treated with beta-blockade agents and identify clinical features and medical treatments associated to ED.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

Study Design

Descriptive, cross-sectional, multicentre registry performed in outpatient clinics. The inclusion criteria were: male gender, age > 18 years old, active treatment with beta-blockade agents for at least 6 months, active sexual live, agree to participate and sign the informed consent and the capability to answer a self-applied questionnaire. Exclusion criteria were: secondary hypertension, prostate disease with our without previous surgical treatment or any limitation that impairs patients' capability to understand the informed consent. The study design, protocol, and informed consent were approved by the ethics committee of the University Hospital of San Juan, Alicante (Spain).

Inclusion period lasted four months (January to April, 2007) and 128 investigators involved in treatment of patients with hypertension, namely cardiologist, internal medicine and nephrology specialists, participated in patients’ collection. Each investigator included 10 consecutive patients from which he personally obtained the informed consent, clinical antecedents and medical treatments in a written protocol. Information from physical examination and biochemical determinations (last available within 6 months) were obtained. The IIEF questionnaire was self-fulfilled by each patient. A sample size >1.000 was estimated to achieve statistically significant differences (α error = 5%) between different beta-blockade agents.

Data Collection

Paper protocols were typed in an electronic database through SAS statistical software by an external and independent company. Data typing was made by duplicates to assure accuracy in this procedure. When all data were introduced several filters were applied to detect noncoherent parameters. Once the data management was finished, the database was blocked to avoid external changes through statistical analysis.

ED was assessed by the IEEF questionnaire. This questionnaire has 15 questions that measure different aspects concerning sexual function, concretely erectile function (6 questions: 1 to 15 and 15), satisfaction with the intercourses (questions 6 to 8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12) and global satisfaction (questions 13 and 14). The sum of every question allows the classification of ED in four categories: no ED (26–30 points), mild ED (17–25 points), moderate DE (11–16 points), and severe DE (6–10 points).

Blood pressure control was considered when two consecutive measurements were <140/90 mmHg or <130/85 mmHg diabetic patients [10,16]. Dyslipidemia was recorded when this diagnosis was present in previous medical reports, total cholesterol was >220 mg/dL or LDL >160 mg/dL [17]. Glomerular filtration rate (GFR) was estimated from serum creatinine values by the Modification of Diet in Renal Disease[18] equation.

Statistical Analysis

Final data were processed by SPSS 15.0 (SPSS Inc, Chicago, IL) statistical package. Chi-square and Fisher test analysis were used to assess differences between groups. Analysis of variance was made for continuous variables with normal distribution; for non-normally distributed variables Kruskal–Wallis was used. The assessment of differences between each medical treatment in the IIEF results covariance analysis were carried out; a stepwise logistic regression was made to assess associations of clinical variables and the presence of ED. Statistical significance was accepted at P value < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

A total of 1242 patients were collected from which 50 (4.0%) were excluded for not being treated with any beta-blockade agent and 185 (14.9%) for not having all the IIEF questionnaire fulfilled; so the final sample were 1007 patients, with mean age 57.9 (10.59) years. The prevalence of any category of ED was 71.0% from which 38.1% were mild-ED, 16.8% moderate-ED, and 16.1% severe-ED. As depicted in Table 1, patients with ED had longer time since the diagnosis of hypertension, worst blood pressure control, and higher prevalence of risk factors, target organ damage and noncardiac comorbidities. Regarding physical examination, ED patients had higher prevalence of obesity and systolic blood pressure; serum glucose was the only parameter significantly different between both groups. The prevalence of ED increased linearly in each decade of age (Figure 1).

Table 1.  Clinical features of patients according to the presence or abscence of ED
 TotalNo erectile dysfunctionErectile dysfunctionP
  1. BMI, body mass index; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; HDL, high-density lipoproteins; LDL, low-density lipoproteins.

Patients (%)1007 (100%)292 (29.0%)715 (61.0%) 
Age57.9 (10.4)53.2 (10.1)59.9 (9.9)<0.01
BMI (Kg/m2)28.3 (3.8)27.5 (3.4)28.6 (3.9)<0.01
Waist circumference (cm)100.3 (12.7)97.2 (12.8)101.6 (12.4)<0.01
Systolic BP (mmHg)142.0 (17.5)140.4 (17.2)142.6 (17.6)0.08
Diastolic BP (mmHg)83.3 (11.5)81.6 (11.0)84.0 (11.6)<0.01
Heart rate68.1 (11.9)68.3 (10.8)68.0 (12.3)0.70
Years since hypertension onset6.0 (5.6)4.8 (5.1)6.5 (5.8)<0.01
Hypertension control35.4%42.6%32.5%<0.01
Diabetes28.3%14.3%33.8%<0.01
Dyslipidemia63.3%54.2%67.0%<0.01
Current smokers25.9%34.0%22.6%<0.01
Previous coronary heart disease57.0%27.6%65.1%<0.01
Coronary revascularization72.9%75.7%71.7%0.20
Heart failure9.8%5.2%11.7%<0.01
Atrial fibrillation14.6%8.0%17.3%<0.01
Peripheral artery disease11.9%4.7%14.7%<0.01
GFR < 60 mL/min/173 m210.8%5.1%13.1%<0.01
COPD12.6%11.5%13.0%0.71
Previous stroke4.7%2.8%5.5%0.07
Depression9.7%5.4%11.4%<0.01
GFR (mL/min/1.73 m2)83.7 (72.3)87.6 (27.0)82.2 (83.7)0.35
Glycemia (mg/dL)112.3 (33.3)102.5 (21.8)116.1 (36.2)<0.01
Total cholesterol (mg/dL)200.5 (41.3)201.7 (35.8)200.0 (43.3)0.59
HDL (mg/dL)46.7 (11.8)47.8 (12.1)46.2 (11.6)0.10
LDL (mg/dL)123.0 (33.0)122.8 (28.5)123.0 (34.7)0.94
Triglycerides (mg/dL)150.0 (64.8)147.1 (57.4)151.2 (67.5)0.41
Creatinine (mg/dL)1.3 (1.5)1.1 (1.3)1.3 (1.5)0.12
Glycated hemoglobin*7.3 (1.3)7.6 (1.7)7.2 (1.3)0.15
image

Figure 1. Prevalence of erectile dysfunction according to age.

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Table 2 shows medical treatments of patients; patients with ED received higher number of active medications, more frequently antiplatelets, loop diuretics, statins, diabetes-related medication, and antihypertensive treatments. With regard to beta-blockade agents, patients with ED were more frequently treated with carvedilol and less frequently with nebivolol. No differences were found in age, gender, or risk factors when comparing patients treated with each betablockade agent. The analysis of patients with established cardiovascular disease showed that atenolol and bisoprolol were the most frequently used agents in the presence of coronary heart disease or heart failure (Figure 2); nevibolol was the less frequently used agent in patients with coronary heart disease and its prescription was higher than carvedilol in the context of heart failure. According to each IIEF parameter, patients treated with nebivolol obtained higher scores in every section (Table 3). When the prevalence of each ED category was assessed according to each beta-blockade agents it was observed that almost 50% of ED cases of patients treated with atenolol, bisoprolol or nebivolol were mild-ED (Figure 3); patients treated with carvedilol or metoprolol obtained the highest percentage of moderate or severe ED.

Table 2.  Medical treatments of patients according to the presence or absence of erectile dysfunction
 TotalNo Disfunción eréctilDisfunción eréctilP
  1. ACEI, angiotensin-convertor enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blockers.

Median number of drugs2.0 (2.0–3.0)2.0 (2.0–3.0)3.0 (2.0–3.0)<0.01
Loop diuretics13.1%9.6%14.5%0.03
Thiazide diuretics15.8%15.4%15.9%0.83
Espironolactone3.8%2.4%4.3%0.14
Antiplatelet agents52.2%36.6%58.6%<0.01
Insulin7.1%1.7%9.2%<0.01
Oral antidiabetics19.5%9.9%23.4%<0.01
Fibrate2.1%1.4%2.4%0.34
Statins63.7%53.4%68.1%<0.01
Dihydropyridines CCB19.1%14.4%21.0%0.02
Nondihydropyridines CCB2.7%1.7%3.1%0.22
ACEI33.6%28.1%35.8%0.02
ARB35.0%28.1%37.8%<0.01
Beta-blockade agents
 Atenolol27.9%25.7%28.8%0.32
 Bisoprolol25.9%25.0%26.3%0.67
 Carvedilol15.3%10.3%17.3%<0.01
 Nebivolol23.6%34.9%19.0%<0.01
 Metoprolol3.0%2.1%3.4%0.27
 Others0.5%0.0%0.7%0.17
image

Figure 2. Percentage of patients treated with each betablockade agent in patients with established cardiovascular disease.

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Table 3.  IIEF parameters according to each beta-blockade agent
 TotalAtenololBisoprololCarvedilolNebivololMetoprololP
  1. Data presented as median (intercuartilic range).

  2. P values for the comparison between groups.

n (%)1007 (100%)281 (27.9%)261 (25.9%)154 (15.3%)238 (23.6%)30 (3.0%) 
Erectil function21.0 (14.0–26.0)21.0 (15.0–26.0)22.0 (14.0–26.0)16.0 (9.0–23.0)25.0 (18.0–28.0)15.5 (5.25–23.25)<0.01
Orgasmic function9.0 (5.0–10.0)8.0 (5.0–10.0)9.0 (6.0–10.0)7.0 (3.0–10.0)10.0 (7.0–10.0)9.0 (2.0–10.0)<0.01
Sexual desire6.0 (5.0–8.0)6.0 (5.0–8.0)6.0 (5.0–8.0)5.0 (4.0–7.0)7.0 (6.0–8.0)5.5 (4.0–8.0)<0.01
Satisfaction with intercourses10.0 (7.0–12.0)10.0 (7.0–11.0)10.0 (7.0–12.0)8.0 (3.0–10.0)11.0 (9.0–13.0)10.0 (3.25–11.0)<0.01
Global satisfaction7.0 (5.0–8.0)6.0 (4.0–8.0)7.0 (5.0–8.0)6.0 (4.0–8.0)8.0 (6.0–8.0)6.0 (6.0–8.0)<0.01
image

Figure 3. Prevalence of erectile dysfunction categories according to each beta-blockade agent.

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Finally, a multivariate analysis adjusted by time since hypertension diagnosis, identified independent associations between ED and coronary heart disease, depression, diabetes, atrial fibrillation and dyhidopiridines calcium channel blockers (Table 4); according to medical treatments, treatment with nebivolol was associated to lower prevalence of ED and dihydropyridines CCB to higher prevalence of ED (Figure 4).

Table 4.  Multivariate analysis of clinical variables associated to any degree of erectile dysfunction
VariableORIC 95%P
  1. COPD, chronic obstructive pulmonary disease.

Age (for 1 year increase)1.051.03–1.10<0.01
Blood pressure control1.801.24–0.850.26
Current smoking0.800.54–1.150.22
Coronary heart disease1.571.04–2.380.03
COPD1.100.59–2.020.77
Peripheral artery disease2.010.98–4.150.06
Depression2.251.13–4.500.02
Diabetes2.271.41–3.64<0.01
Hypercholesterolemia1.280.81–2.010.30
Heart failure0.840.40–1.790.65
Atrial fibrillation2.591.34–5.00<0.01
Renal dysfunction3.101.58–0.800.20
Previous stroke0.620.24–1.580.32
image

Figure 4. Multivariate analysis of cardiovascular treatments associated to ED. ACEI, angiotensin-convertor enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blockers.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

The DELTHA study demonstrates that the prevalence of ED in high-risk hypertensive patients treated with beta-blockade agents is very high, is associated to more extended target organ damage and is only associated with a scarce number of cardiovascular treatments. The standardized diagnosis of ED by the IIEF questionnaire in a large sample of hypertensive patients is one of the virtues of the study and allowed the identification of such high prevalence of ED and recognition of independent associations with several clinical features.

The prevalence of ED observed in this study was higher than previous reports that assessed its prevalence in general population [3–5] or hypertensive patients [8,19] and is closer to the prevalence reported in patients with cardiovascular disease [9,20,21]. The high prevalence of ED found in our sample could be explained by the inclusion criteria (diagnosis of hypertension and active treatment with beta-blockade agents) what resulted in the collection of high-risk patients [10] with a high prevalence of diabetes, coronary heart disease and coronary revascularization. Moreover, the accurate diagnosis of ED by a validated and self-applied questionnaire yielded the detection of more cases than would have been obtained by clinical interview; in fact, more that one-third of cases were mild-ED.

Current hypertension guidelines [10,16] do not include ED as a target organ damage and it has been traditionally considered a side-effect of medication [2]. Nevertheless, the results of our study demonstrate that clinical features explain the association of medical treatments with ED because the univariate association of ED with several active treatments was not observed in the multivariate analysis, with the exception of dihydropyridines calcium channel blockers. Global cardiovascular risk and the assessment of target organ damage disease are highly encouraged in current hypertension guidelines [10] based on the fact that vascular organ damage in one territory is a marker of risk of further events in another [22,23]. Concerning ED, it has been recently demonstrated that its presence frequently precedes the incidence of cardiovascular events by several years [21] encouraging the preventive relevancy of ED as early maker of vascular disease. The results of the present study agree with these arguments and demonstrate that the antecedents of coronary heart disease or atrial fibrillation are independently associated with ED.

ED is a multifactorial disease [2] and recent data support the hypothesis that vascular damage [24,25] is the major determinant of ED in the field of cardiovascular disease and hypertension [24,25]. Serum levels of vascular inflammatory markers have been related to ED [26] suggesting the role of local vascular damage. In fact, treatment with a selective inhibitor of phosphodiesterase type 5, sildenafil, significantly improves ED in hypertensive patients [27] and achieves higher blood-pressure control [28], althought this has to be considered cautiously and only after medical advice. Sexual stimulation releases nitric oxide into the penile smooth muscle and the inhibition of such phosphodiesterase improves smooth-muscle relaxation and erection [2]. Nebivolol increases vascular nitric oxide release [29] and significantly improves its effect on vascular dilatation [15]. The prevalence of cardiovascular disease in our sample of hypertensive patients was very high but the use of betablockade agents differed between patients with heart failure or coronary heart disease; nebivolol was more frequently used in the presence of heart failure what might reflect the impact of the most recent randomized trial made with this agent, the SENIORS study [30]. As general characteristics were similar between patients treated with each betablocker and a multivariate analysis was performed, the association of lower prevalence of ED in nebivolol-treated patients seems to be fairly acceptable.

ED impairs quality of life [31] and most patients do not ask for medical advice [21]. The IIED questionnaire is a feasible tool for the detection of this relevant syndrome, even when if only incipient or mild symptoms are present; this could explain the high prevalence of ED in our population, from which 38.1% corresponded to mild-ED. Current specific medical treatments for ED can achieve high rates of symptoms improvement [19,27]. A recent report by Scranton et al. [28], demonstrates that initiation of selective phosphodiesterase type 5 inhibitors treatment drives to higher blood pressure control in poorly controlled patients; authors explain such results by the fact that clinically relevant behaviors, mainly more aggressive monitoring and treatment with antihypertensive medications, were attempted once the ED-treatment was started but the impact of ED as a medical diagnosis or disease could also explain higher adherence rates.

The main limitations of our study might be derived from the cross-sectional design that lacks of ability to demonstrate causality; therefore, our results can only identify independent associations between clinical features and research of causal risk factors should be attempted by prospective studies. Another relevant limitation is that nearly 30% of patients initially collected were not included in the final study. The lack of a control-group did not allow to compare our results in patients not treated with betablockers, but the investigators group decided to collect only betablocker-treated patients with the aim of creating an homogeneous sample. We cannot exclude the presence of the so-called Hawthorne effect [32], a bias that reflects the change in subjects attitudes when they are being observed, that has been previously depicted as highly frequent in the field of ED [32,33].

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References

The DELTHA study has an unconditioned support grant form Menarini Laboratories, Spain.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interests
  9. References
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