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Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men
EPIDEMIOLOGY & RISK FACTORS
ORIGINAL RESEARCH
Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men Wayland Hsiao, MD,1 Ruth Ann Bertsch, MD, PhD,2 Yun-Yi Hung, PhD, MPH,3 and David S. Aaronson, MD1
ABSTRACT
Introduction: Tighter blood pressure control is widely thought to be associated with better erectile function, although the preponderance of data is limited to dichotomous representations of hypertension without an attempt to look at degree of blood pressure control. Aim: To determine the association between optimal blood pressure control over time and the development of erectile dysfunction (ED) in a cohort of potent men. Methods: We performed a retrospective cohort study of newly diagnosed hypertensive men without major medical comorbidities in an integrated healthcare system. Patients were stratified by exposure to hypertension, with varying levels of blood pressure control, as measured by ordinal categories of systolic blood pressure and deviation from the mean systolic pressure. Main Outcome Measures: Incidence of ED was defined by at least 2 primary care or urology diagnoses of ED in our electronic health records within 2 years, at least 2 filled prescriptions for ED medications within 2 years, or 1 diagnosis of ED and 2 filled prescriptions for ED medications. Results: We identified 39,320 newly diagnosed hypertensive men. The overall incidence for ED was 13.9%, with a mean follow-up of 55.1 ± 28.7 months. Higher average systolic blood pressure was associated with a higher risk of ED in a dose-dependent manner (trend test, P < .001). Wide variation in blood pressure control was associated with a higher incidence of ED (OR [95% CI]; 1.359 [1.258e1.469]) and a shorter time to the development of ED (log rank, P < .0001). Clinical Implications: We believe these data may serve as a motivator for hypertensive men to better adhere to their hypertension treatment regimen. Strength & Limitations: The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. Strengths of our study include the large sample size, community cohort, and completeness of follow-up. Conclusion: Among adults diagnosed with hypertension, tighter blood pressure control, as measured by average systolic blood pressure and deviation from the average, is associated with a lower incidence and a longer time to the development of ED. Hsiao W, Bertsch RA, Hung Y-Y, et al. Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men. J Sex Med 2019;16:410e417. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile dysfuntion; Hypertension; Male; Incidence; Human; Risk factors
INTRODUCTION Received September 6, 2018. Accepted January 4, 2019. 1
Department of Urology, Kaiser Permanente, Oakland Medical Center, Oakland, CA, USA;
2
Department of Medicine, Kaiser Permanente, Sacramento Medical Center, Sacramento, CA, USA;
3
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.01.011
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Hypertension is commonly considered a risk factor for erectile dysfunction (ED), whose prevalence is estimated at 30e50% among American middle-aged men.1 Endothelial dysfunction is a proposed mechanism common to both hypertension and ED.2 Unfortunately, hypertension causes few signs or symptoms until end-stage organ damage, and national rates of adherence to hypertension treatment are only about 55e80%.3 This gap indicates that preventing a major vascular event is not sufficient motivation for some patients. J Sex Med 2019;16:410e417
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Both the Massachusetts Male Aging Study and Treatment of Mild Hypertension Study showed that a diagnosis of hypertension was associated with an increased risk of ED.1,4 Cordero et al5 showed that, among 1,242 men on beta-blockers, absence of hypertension was associated with a lower prevalence of ED independent of age, other cardiovascular risk factors, and medication. However, none of the aforementioned studies demonstrated that tight blood pressure over time is associated with a lower risk of ED because these studies rely on baseline measurements of hypertension at a single timepoint,6,7 with no ability to account for the patient’s ability to maintain blood pressure control. It is critical to know whether long-term blood pressure control is associated with the development of ED. If effective blood pressure control protects erectile function, then newly diagnosed hypertensive men should be counseled that better adherence to their antihypertensive regimens not only reduces their risk of myocardial infarction and stroke but also may lower their risk of developing erectile dysfunction. A substantial fraction of men may value their erectile function over the prevention of myocardial infarcts and strokes.8,9 However, we have excellent quality, randomized controlled trials showing that the control of hypertension reduces coronary and cerebrovascular disease.10e12 Don’t we deserve better data on the relationship between hypertension control and the development of erectile dysfunction?
mass index (BMI), baseline cholesterol, diabetes status, medical comorbidities, and surgical history.
Selection of Participants Hypertension Diagnosis and Demographics Our hypertension registry is a prospectively maintained database used to identify and track hypertensive patients to better control their blood pressure. We included all men ages 26e60 years old who were enrolled in the Kaiser Permanente Northern California hypertension registry for the first time between 2008 and 2010. Patients are included in our hypertension registry if they meet 1 of the following criteria: (1) 2 diagnoses of hypertension from primary care; (2) 1 primary care hypertension diagnosis and 1 hospitalization with a primary or secondary diagnosis of hypertension; (3) 1 primary care hypertension diagnosis and 1 filled prescription for hypertension medication within the last 6 months; or (4) 1 primary care hypertension diagnosis and 1 of the following: a stroke-related hospitalization or current enrollment in coronary artery disease, heart failure, or diabetes registry. Membership Criterion We identified a cohort of men who had 3 years of Kaiser Permanente coverage before inclusion in the hypertension registry. Men were required to have uninterrupted coverage for 1 year and >10 months’ membership in a year for 3 years preceding the start date for study inclusion.
To our knowledge, no studies have examined the association between degree of blood pressure control and the incidence rate of ED. To rectify this gap, we performed a retrospective cohort study of hypertensive men with no ED at baseline. We studied the development of ED in this cohort and stratified them by their blood pressure measurements in the last 2 years of study inclusion. We believe that the measurements in the last 2 years of study inclusion allows the best approximation of the level of hypertension control that the patient has achieved during the course of our study. We hypothesize that tighter blood pressure control over time is associated with a lower incidence and delayed onset of ED in a large cohort of newly diagnosed potent, hypertensive men in an integrated healthcare system.
Erectile Function and Penile Structural Exclusions Patients with any evidence of erectile dysfunction 3 years prior to inclusion in the study were excluded. Patients were excluded if the patient had (i) 2 erectile dysfunction diagnoses by either a primary care physician or a urologist or (ii) 2 filled prescriptions for medications for phosphodiesterase 5 inhibitors, intracavernosal injection, or intraurethral suppositories or (iii) penile fracture or penile implant surgery in that 3-year period. Further exclusion criteria are listed in Appendix A.
METHODS
Primary Outcome and Study Endpoint
Data Extraction
Our primary outcome was the development of ED. To meet the definition of ED, patients had to meet 1 of the following criteria: (i) 2 diagnoses of ED either by primary care or urology outpatient visits within a 2-year period or (ii) 2 filled prescriptions for medication for ED (phosphodiesterase inhibitors, injection therapy, or intraurethral suppositories). 1 of the urologists (W.H.) reviewed 30 cases manually to verify that the ED was organic ED and not due to obvious psychogenic causes.
Data were extracted from outpatient visits, inpatient encounters, and emergency department visits in our integrated electronic health record (Epic, Verona, WI, USA). Prescriptions and laboratory data were extracted from pharmacy and laboratory data systems. We also captured demographics, baseline body
Study enrollment started from the first date of hypertension diagnosis and continued to the study endpoint. Our study endpoint was defined as the date of development of ED, development of censoring criterion (which were the same as the exclusion criterion listed above if the diagnosis appeared after
Study Setting Kaiser Permanente Northern California is a large, integrated health care delivery system that provides comprehensive care for more than 4 million members. The Kaiser Foundation Research Institute’s Institutional Review Board approved the study.
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study enrollment), disenrollment from our health plan, death, last known date of follow-up, or study end date of December 31, 2015, whichever occurred first.
Definition of Hypertension and Blood Pressure Measurements We extracted all blood pressure measurements available from outpatient office visits or blood pressure monitoring visits in the last 2 years before study endpoint. We did not use blood pressure measurements associated with emergency department visits, inpatient visits, or procedure-based visits, because it was assumed that illness, anxiety due to the procedure, or the procedure itself would obscure baseline arterial tone. The average number of blood pressure measurements was 4.7 measurements in the 2 years prior to study endpoint. Any patient without blood pressure measurements in each of the last 2 years prior to study endpoint or censoring date was excluded from the study. Averages and standard deviations of blood pressure measurements were calculated. Patients were classified into 4 categories of hypertension based on average systolic blood pressure: <120 mm Hg, 120e139 mm Hg, 140e159 mm Hg, and 160 mm Hg. The average systolic blood pressure of <120 mm Hg was used as a reference level. To evaluate the tightness of blood pressure control, the SD of the average was used. We split these groups into normal variation and wide variation groups, where wide variation was defined as >1 SD of the blood pressure in systolic blood pressure (SBP) measurements. There was a normal distribution of the SBP measurements as confirmed with the Kolmogorov-Smirnov test (P < .01).
Medications for Hypertension We evaluated all medications prescribed and filled in the last 2 years prior to the study end date. For patients who developed ED, these were their blood pressure medications prescribed 2 years prior to the ED incidence date. For patients without ED incidence, these were their blood pressure medications prescribed 2 years prior to end of follow-up (December 31, 2015) or date of censorship. We sorted the number of classes of medications that the patients were on during this 2-year period into the following categories: angiotensin converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, calcium channel blockers, thiazides diuretics, and “other” (nitrates, loop diuretics, potassiumsparing diuretics, alpha blockers, centrally acting antihypertensive, and carbonic anhydrase inhibitors).
Determination of Insulin Resistance We had previously shown that insulin resistance, as determined by a fasting lipid panel, was an effective predictor of cardiovascular outcomes.13 Based on this, we determined the insulin resistance of our patients. The patient was deemed insulin resistant if the triglyceride level was in the highest tertile of the cohort and the high-density lipoprotein cholesterol was in the lowest tertile of the cohort. The patient was deemed insulin
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sensitive if the triglyceride level was in the lowest tertile of the cohort and the high-density lipoprotein cholesterol was in the highest tertile. Patients not meeting criteria for insulin resistance or sensitivity were put in a single intermediate category.
Statistical Analysis A sample size calculation was performed during the planning stage of the study. We assumed an ED incidence rate of 15% among patients with poorly controlled blood pressure not and incidence rate of 10% among patients with controlled blood pressure. We also assumed that 70% of the cohort had good blood pressure control and 30% did not based on previous studies. A 2-group continuity corrected c2 test with a 2-sided significance level of 0.05 will have 80% power to detect a difference between a proportion of 0.15 in the blood pressureenotecontrolled group and a proportion of 0.10 in the blood pressureecontrolled group (odds ratio of 0.63) when the sample sizes are 507 and 1,165, respectively (a total sample size of 1,672). c2 tests were done to test for differences in categorical variables. We compared the time to diagnosis of ED by SBP group in pairs using the Tukey method. We plotted the Kaplan Meier survival curves by blood pressure control. The log-rank test was reported. We performed Cox proportional hazards regression models to estimate the incidence of ED associated with sociodemographic and clinical characteristics. Hazard ratios and 95% CI are presented. Follow-up started on the date of inclusion into the hypertensive registry and continued to the time of the development of ED, censorship, date of disenrollment in the health plan, death, or end of the follow-up (December 31, 2015), whichever occurred first. All analyses were conducted using SAS statistical software, version 9.3 (Cary, NC, USA)
RESULTS Overall Results The final cohort consisted of 39,320 men, age 26e60 years old, with a new diagnosis of hypertension without previously diagnosed ED (Figure 1). The average follow-up was 55.1 ± 28.7 months. The overall incidence of ED in our cohort was 13.9% (5,476 of 39,320). The Charlson comorbidity index (CCI) distribution for our cohort was as follows: CCI score 0 ¼ 96.4% (378,799 of 39,320), CCI score 1 ¼ 1.9% (762 of 39,320), CCI score 2 ¼ 1.7% (659 of 39,320). Other baseline characteristics, antihypertensive medication use, and average blood pressures are summarized in Table 1. The average number of BP measurements was 4.7 during 2 years of follow-up.
Incidence of ED Stratified by Average SBP Survival analysis showed a relationship between the incidence of ED and the level of blood pressure control within the last 2 years of study endpoint (log-rank test, P < .0001) (Figure 2). The incidence rates of ED were lower with better blood pressure J Sex Med 2019;16:410e417
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Figure 1. Cohort selection. Figure 1 is available in color online at www.jsm.jsexmed.org. control. When stratified by average SBP, they were <120 mm Hg, 12.5% (539 of 4,313); 120e139 mm Hg, 13.9% (3,764 of 27,096); 140e159 mm Hg, 14.9% (1,055 of 7,093); and 160 mm Hg, 14.4% (118 of 818) (trend test P < .01). The time to diagnosis of ED was longer in patients with better blood pressure control. The overall time to diagnosis of ED was 29.1 ± 22.4 months. The average time to diagnosis of ED (mean ± SD) was longer in those with lower average SBP: <120, 34.1 ± 21.4 months; 120e139, 30.4 ± 22.4 months; 140e159, 23.2 ± 21.6 months; and 160, 19.1 ± 21.6 months (trend test, P < .0001). Those with normal variation in average SBP control (n ¼ 29,039) had a lower incidence of ED compared with those patients with a wide variation in average SBP (n ¼ 4,763) (14.4% vs 18.1%, P < .0001). J Sex Med 2019;16:410e417
Predictors of ED A Cox proportional hazards model was used to evaluate the predictors of ED (Table 2). Average SBP predicted ED incidence in both unadjusted and adjusted analysis. In addition, variation in SBP > 1 SD was associated with a higher incidence of ED (adjusted hazard ratio [95% CI]: 1.359 (1.258e1.469), P < .0001). Other variables independently associated with an increased risk of ED on univariate analysis included taking 3 antihypertensive medications classes compared with 1 class, increased age, African American race, Hispanic ethnicity, diabetes at baseline, having depression or sleep apnea diagnosed within 2 years of study endpoint, insulin resistance, elevated BMI, and CCI score of 1 or higher. On multivariate analysis, predictors of ED were increasing age, African-American race
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Table 1. Baseline characteristics N (%) Age 26e40 41e50 51e60 Race/Ethnicity Caucasian African-American Hispanic Asian/Pacific Islanders Native American/Multiracial /Other/Unknown BMI <25 25e30 >30 Unknown Average systolic blood pressure (2 years) Average SBP <120 Average SBP 120e139 Average SBP 140-159 Average SBP >160 Average diastolic blood pressure (2 years) Average DBP <80 Average DBP 80-89 Average DBP 90-99 Average DBP 100 Number of classes of antihypertensives 0 1 2 3þ Diabetes at baseline Yes No/Unknown Insulin resistance Indeterminate Insulin resistance Insulin sensitive Missing data Depression at study endpoint Yes No/Unknown Obstructive sleep apnea at study endpoint Yes No/Unknown
7,175 (18.3%) 14,061 (35.8%) 18,084 (46.0%) 19,457 3,459 6,686 6,373 3,345
(49.5%) (8.8%) (17.0%) (16.2%) (8.5%)
4,432 16,872 16,815 1,201
(11.3%) (42.9%) (42.8%) (3.1%)
4,313 27,096 7,093 818
(11.0%) (68.9%) (18.0%) (2.1%)
18,425 16,513 3,695 687
(46.9%) (42.0%) (9.4%) (1.8%)
7,379 12,512 12,906 6,523
(18.8%) (31.8%) (32.8%) (16.6%)
5,497 (14.0%) 33,823 (86.0%) 19,382 5,210 5,117 9,611
(49.3%) (13.3%) (13.0%) (24.4%)
173 (0.44%) 39,147 (99.56%)
1,477 (3.8%) 37,843 (96.2%)
BMI ¼ body mass index; SBP ¼ systolic blood pressure.
compared with white, diabetes at baseline, depression within 2 years of study endpoint, and elevated BMI. The number of classes of hypertensive medicines did not predict ED incidence when controlling for other factors, although those not taking any medicines (either controlled by diet and exercise or not
Figure 2. Curves depicting ED incidence stratified by aSBP. Log-rank test P < .0001. aSBP ¼ average systolic blood pressure; ED ¼ erectile dysfunction. Figure 2 is available in color online at www.jsm.jsexmed.org.
compliant) had a lower incidence of ED on both analyses. Also, sleep apnea and CCI were not associated with erectile function after controlling for other factors.
DISCUSSION In a cohort of potent, newly diagnosed hypertensive men, we evaluated the association of SBP control with the incidence of ED. Worse SBP control is associated with an increase in the incidence of ED at each ordinal level of SBP. In addition, men with little variability in SBP during the study period had a lower risk of developing ED and a longer time before the development of ED. Previous work has shown that hypertension is a risk factor for the development of ED. But, to our knowledge, our study is the first to show so rigorously that tighter blood pressure control over time is associated with a lower incidence and a delayed onset of ED in hypertensive men. This study brings the literature closer to resolving the motivating clinical question, “Does controlling hypertension preserve erectile function?”14 Most studies of ED and hypertension use a binary value for hypertension (present or absent), and many studies have shown an association with hypertension and either the prevalence of ED or its development longitudinally.1,4,6 Until now, the 2 studies that provide the closest approximations of a dose-response relationship between hypertension and ED were 2 surveys that took into account the duration of hypertension.7,15 A major weakness of these studies is their inability to take into account the long-term degree of blood pressure control. Using the number of years of having a diagnosis of hypertension alone puts the well-controlled hypertensive man in the same risk category as the poorly controlled hypertensive man, which is not true for cardiovascular outcomes.10 Using a single baseline measurement to stratify patients into categories in the future assumes that there is no effect of hypertension control over time and does not allow the patient to cooperate and try to control their hypertension. As such, we believe our categorization of patients using multiple blood pressure measurements from the last 2 years of inclusion in the study allows us to separate J Sex Med 2019;16:410e417
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Table 2. Cox proportional hazard model predicting incidence of ED Unadjusted hazard ratio Variables SBP in prior 2 years Average SBP <120 mm Hg Average SBP 120e139 mm Hg Average SBP 140e159 mm Hg Average SBP 160 mm Hg SBP control Normal variation in SBP Wide variation in SBP (>1 St Dev) Only 1 outpatient measurement in 2 years prior to study end Age (5 increment in age, y) Race/Ethnicity White African-American Asian/Pacific Islander Hispanic Native American/Multiracial/Other/Unknown Diabetes Yes No Depression Yes No Obstructive sleep apnea Yes No Insulin resistance Indeterminant Sensitive Resistant Missing BMI <25 25e30 >30 Missing Charlson Comorbidity Index 0 1 >1 Number of antihypertensive medications classes 0 1 2 3þ
Adjusted hazard ratio P value
(95% CI)
P value
(reference) (1.069, 1.281) (1.344, 1.654) (1.345, 2.003)
.0006 <.0001 <.0001
1 1.235 1.488 1.844
<.0001 <.0001 <.0001
1 (reference) 1.516 (1.409, 1.632) 0.503 (0.455, 0.556)
<.0001 <.0001
1 (reference) 1.359 (1.258, 1.469) 0.555 (0.501, 0.614)
<.0001 <.0001
1.122 (1.103, 1.142)
<.0001
1.095 (1.075, 1.115)
<.0001
(95% CI) 1 1.17 1.491 1.641
1 1.374 0.749 1.086 0.975
(reference) (1.262, 1.497) (0.69, 0.814) (1.01, 1.168) (0.873, 1.088)
<.0001 <.0001 .025 .652
1 1.356 0.759 1.059 0.989
(reference) (1.128, 1.353) (1.337, 1.655) (1.504, 2.26)
(reference) (1.243, 1.479) (0.697, 0.827) (0.984, 1.14) (0.885, 1.104)
<.0001 <.0001 .129 .838
1.968 (1.847, 2.096) 1 (reference)
<.0001
1.825 (1.708, 1.949) 1 (reference)
<.0001
1.682 (1.212, 2.334) 1 (reference)
.002
1.587 (1.143, 2.205) 1 (reference)
.006
1.218 (1.075, 1.38) 1 (reference)
.002
1.089 (0.959, 1.235) 1 (reference)
.188
.645
(0.889, 1.046) (reference) (0.942, 1.153) (0.726, 0.88)
.383 .426 <.0001
(reference) (1.126, 1.373) (1.111, 1.363) (0.677, 1.026)
<.0001 <.0001 .086
0.981 1 1.088 0.72
(0.906, 1.063) (reference) (0.987, 1.2) (0.655, 0.79)
.091 <.0001
0.964 1 1.042 0.799
1 1.289 1.361 0.812
(reference) (1.169, 1.421) (1.235, 1.5) (0.661, 0.998)
<.0001 <.0001 .048
1 1.243 1.231 0.833
1 (reference) 1.288 (1.082, 1.534) 1.24 (1.013, 1.517) 0.678 1 1.063 1.196
(0.622, 0.74) (reference) (0.996, 1.134) (1.109, 1.29)
.005 .037 <.0001 .067 <.0001
1 (reference) 1.099 (0.922, 1.31) 0.927 (0.756, 1.137) 0.759 1 1.035 1.011
(0.696, 0.829) (reference) (0.97, 1.105) (0.935, 1.093)
.291 .468 <.0001 .297 .781
BMI ¼ body mass index; ED ¼ erectile dysfunction; SBP ¼ systolic blood pressure.
those with good blood pressure control from those who do not control their blood pressure well. Whether poor blood pressure control is due to medication compliance, class of medications prescribed, or the biologic recalcitrance of severe hypertension unfortunately cannot be answered by our data. J Sex Med 2019;16:410e417
Longitudinal data with protracted follow-up affords many ways to measure hypertension control. The National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set measure, which relies on the last known blood pressure measurement, is helpful in population studies looking at
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hypertension adherence. However, to test the hypothesis that sustained blood pressure control could mitigate ED, we stratified our patient population by average systolic arterial blood pressure of each individual over the last 2 years of follow-up in the study. This seems to be novel in the ED and hypertension literature. With a median of 4.7 SBP measurements over 2 years, there were enough measurements to get a sense of overall blood pressure control for that individual. Focusing on systolic blood pressure, as opposed to mean arterial or diastolic pressure, has precedent as an excellent marker for the cardiovascular risk attributable to hypertension. SBP is more predictive of cardiovascular outcomes than diastolic in the Framingham datasets,16 the Multiple Risk Factor Intervention Trial,17,18 and even the cohort of Northern California Kaiser Permanente members from which our dataset is derived.19 Because mean arterial pressure (MAP) is an average of systolic and diastolic BP and is weighted more heavily to the diastolic BP, using MAP would diminish the signal from the strongest marker of cardiovascular risk. Also, all of the major cardiovascular risk assessment calculators use SBP rather than MAP or diastolic pressure.20 Admittedly, without evaluation of diastolic blood pressure, we are not able to take into account pulse pressure and other variables associated with diastolic blood pressure. Using the standard deviation of the SBP as another marker of risk for vasculopathy also has validity. Multiple large cohorts have found that the standard deviation of the visit-to-visit SBP can predict cardiovascular outcomes and their surrogates.21,22 The number of classes of medicines prescribed in the last 2 years did not seem to correlate with ED incidence. This would seem to argue against a straight dose relationship of BP meds to ED. However, this study did not have the scope to collect doses of medications and, thus, could not test the assertion that higher doses of hypertension medications lead to more ED. The results do hint that possibly what dominates the pathogenesis of ED is not the metabolic milieu, which creates recalcitrant hypertension requiring multiple classes of BP medications, but rather the resulting arterial pressure itself causing ED. More studies are required to test this hypothesis. Finally, it is notable that 18.8% of patients were not on any hypertension medications the last 2 years before study endpoint. Of this group of men not taking hypertensive medications, 74% had an average SBP 120e139 mm Hg, and 17% had an average SBP 140 mm Hg. Clearly, the risks of stroke and heart attack are not motivating this group to adhere to hypertension management paradigms. This group may represent recalcitrant patients that would benefit from further motivation (ie, fear of ED) to control their blood pressures.
Strengths and Limitations The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. We didn’t systematically screen for ED at study entry, and we must rely on the accuracy of our clinical diagnoses and
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prescription data, which may potentially underdiagnose mild ED in patients who don’t seek treatment. However, it is debatable whether this mild level of ED is clinically relevant. Another weakness is the lack of standardized validated questionnaires to evaluate the degree of erectile dysfunction. However, a single question about ED has been shown to be as sensitive as a full questionnaire in many settings.23,24 Finally, although we stratified patients by blood pressure control, we were not able to control for baseline health status (besides the CCI) and other lifestyle behaviors. Certainly, our study would be stronger with more data on lifestyle behaviors, such as diet and exercise. Also an emerging body of literature indicates that testosterone and aldosterone levels are independent risk factors for hypertension.25e27 We did find that 150 patients (0.38%) had a diagnosis of primary hyperaldosteronism, and 532 patients (1.35%) had a diagnosis of low testosterone, which would seem low. Unfortunately, we lacked testosterone and aldosterone levels in our patients, and these 2 conditions may have been underdiagnosed in our cohort. Strengths of our study include the large sample size, community cohort, and completeness of follow-up.
CONCLUSION Tighter blood pressure control is associated with a lower incidence and delayed onset of ED. We believe that, because hypertension often has few symptoms until end-stage organ damage or other late sequelae occur, our findings are helpful for doctors attempting to motivate their male hypertensive patients to adhere better to antihypertensive regimens.
Corresponding Author: Wayland Hsiao, MD, 3600 Broadway, Specialty Medical Office Building, Suite 40, Oakland, CA 94611, USA. Tel: (510)752-5067; Fax: (510)752-1673; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: Supported by a grant from the Kaiser Permanente Northern California Community Benefit Program.
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Hypertension Control and Erectile Dysfunction Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997;29:8-14. 5. Cordero A, Bertomeu-Martínez V, Mazón P, et al. Erectile dysfunction may improve by blood pressure control in patients with high-risk hypertension. Postgrad Med 2010;122:51-56. 6. Borgquist R, Leósdóttir M, Nilsson P, et al. Self-rated health and classical risk factors for coronary heart disease predict development of erectile dysfunction 25 years later. Int J Clin Pract 2008;62:206-213. 7. Bener A, Al-Ansari A, Al-Hamaq AOAA, et al. Prevalence of erectile dysfunction among hypertensive and nonhypertensive Qatari men. Med Kaunas Lith 2007;43:870-878. 8. Scranton RE, Goldstein I, Stecher VJ. Erectile dysfunction diagnosis and treatment as a means to improve medication adherence and optimize comorbidity management. J Sex Med 2013;10:551-561. 9. McLaughlin T, Harnett J, Burhani S, et al. Evaluation of erectile dysfunction therapy in patients previously nonadherent to long-term medications: A retrospective analysis of prescription claims. Am J Ther 2005;12:605-611. 10. Group TSR. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-2116. 11. Brunström M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: A systematic review and meta-analysis. JAMA Intern Med 2018;178:28-36. 12. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291-1297. 13. Bertsch RA, Merchant MA. Study of the use of lipid panels as a marker of insulin resistance to determine cardiovascular risk. Perm J 2015;19:4-10. 14. Rodriguez CJ, Swett K, Agarwal SK, et al. Systolic blood pressure levels among adults with hypertension and incident cardiovascular events: The atherosclerosis risk in communities study. JAMA Intern Med 2014;174:1252-1261. 15. Roth A, Kalter-Leibovici O, Kerbis Y, et al. Prevalence and risk factors for erectile dysfunction in men with diabetes, hypertension, or both diseases: A community survey among 1,412 Israeli men. Clin Cardiol 2003;26:25-30. 16. Kannel WB, Wolf PA, Verter J, et al. Epidemiologic assessment of the role of blood pressure in stroke: The Framingham Study. 1970. JAMA 1996;276:1269-1278. 17. Tin LL, Beevers DG, Lip GYH. Systolic vs diastolic blood pressure and the burden of hypertension. J Hum Hypertens 2002;16:147-150.
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18. Leonetti G, Cuspidi C, Facchini M, et al. Is systolic pressure a better target for antihypertensive treatment than diastolic pressure? J Hypertens Suppl Off J Int Soc Hypertens 2000; 18:S13-S20. 19. Flint AC, Conell C, Ren X, et al. Abstract P400: Relative contributions of systolic and diastolic blood pressure to adverse cardiovascular outcomes in an outpatient cohort of 1.3 million adults. Hypertension 2017;70:AP400; AP400. 20. Cardiovascular disease risk assessment for primary prevention: Risk calculators—UpToDate n.d. Available at: https://www. uptodate.com/contents/cardiovascular-disease-risk-assessmentfor-primary-prevention-risk-calculators?search¼cardiovascular %20disease%20risk%20assessment%20for%20primary% 20prevention:%20Risk%20calculators&source¼search_result &selectedTitle¼1w150&usage_type¼default&display_rank¼1. Accessed March 13, 2018. 21. Malik EZ, Abdulhadi B, Mezue KN, et al. Clinical hypertension: Blood pressure variability. Dis Mon 2018;64:5-13. 22. Gosmanova EO, Mikkelsen MK, Molnar MZ, et al. Association of systolic blood pressure variability with mortality, coronary heart disease, stroke, and renal disease. J Am Coll Cardiol 2016;68:1375-1386. 23. Giuliano FA, Leriche A, Jaudinot EO, et al. Prevalence of erectile dysfunction among 7689 patients with diabetes or hypertension, or both. Urology 2004;64:1196-1201. 24. Tal R, Rabbani F, Scardino PT, et al. Measuring erectile function after radical prostatectomy: Comparing a single question with the International Index of Erectile Function. BJU Int 2012; 109:414-417. 25. Chang C-H, Chueh S-CJ, Wu V-C, et al. Risk of severe erectile dysfunction in primary hyperaldosteronism: A population based propensity score matching cohort study. Surgery https://doi.org/10.1016/j.surg.2018.08.020; E-pub ahead of print. 26. Wu F, Mao S, Yu T, et al. Elevated plasma aldosterone is an independent risk factor for erectile dysfunction in men. World J Urol 2016;34:999-1007. 27. Jiang Y, Ye J, Zhao M, et al. Cross-sectional and longitudinal associations between serum testosterone concentrations and hypertension: Results from the Fangchenggang Area Male Health and Examination Survey in China. Clin Chim Acta Int J Clin Chem 2018;487:90-95.
SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi.org/10.1016/j.jsxm.2019.01.011.
ORIGINAL RESEARCH
Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men Wayland Hsiao, MD,1 Ruth Ann Bertsch, MD, PhD,2 Yun-Yi Hung, PhD, MPH,3 and David S. Aaronson, MD1
ABSTRACT
Introduction: Tighter blood pressure control is widely thought to be associated with better erectile function, although the preponderance of data is limited to dichotomous representations of hypertension without an attempt to look at degree of blood pressure control. Aim: To determine the association between optimal blood pressure control over time and the development of erectile dysfunction (ED) in a cohort of potent men. Methods: We performed a retrospective cohort study of newly diagnosed hypertensive men without major medical comorbidities in an integrated healthcare system. Patients were stratified by exposure to hypertension, with varying levels of blood pressure control, as measured by ordinal categories of systolic blood pressure and deviation from the mean systolic pressure. Main Outcome Measures: Incidence of ED was defined by at least 2 primary care or urology diagnoses of ED in our electronic health records within 2 years, at least 2 filled prescriptions for ED medications within 2 years, or 1 diagnosis of ED and 2 filled prescriptions for ED medications. Results: We identified 39,320 newly diagnosed hypertensive men. The overall incidence for ED was 13.9%, with a mean follow-up of 55.1 ± 28.7 months. Higher average systolic blood pressure was associated with a higher risk of ED in a dose-dependent manner (trend test, P < .001). Wide variation in blood pressure control was associated with a higher incidence of ED (OR [95% CI]; 1.359 [1.258e1.469]) and a shorter time to the development of ED (log rank, P < .0001). Clinical Implications: We believe these data may serve as a motivator for hypertensive men to better adhere to their hypertension treatment regimen. Strength & Limitations: The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. Strengths of our study include the large sample size, community cohort, and completeness of follow-up. Conclusion: Among adults diagnosed with hypertension, tighter blood pressure control, as measured by average systolic blood pressure and deviation from the average, is associated with a lower incidence and a longer time to the development of ED. Hsiao W, Bertsch RA, Hung Y-Y, et al. Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men. J Sex Med 2019;16:410e417. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile dysfuntion; Hypertension; Male; Incidence; Human; Risk factors
INTRODUCTION Received September 6, 2018. Accepted January 4, 2019. 1
Department of Urology, Kaiser Permanente, Oakland Medical Center, Oakland, CA, USA;
2
Department of Medicine, Kaiser Permanente, Sacramento Medical Center, Sacramento, CA, USA;
3
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.01.011
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Hypertension is commonly considered a risk factor for erectile dysfunction (ED), whose prevalence is estimated at 30e50% among American middle-aged men.1 Endothelial dysfunction is a proposed mechanism common to both hypertension and ED.2 Unfortunately, hypertension causes few signs or symptoms until end-stage organ damage, and national rates of adherence to hypertension treatment are only about 55e80%.3 This gap indicates that preventing a major vascular event is not sufficient motivation for some patients. J Sex Med 2019;16:410e417
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Both the Massachusetts Male Aging Study and Treatment of Mild Hypertension Study showed that a diagnosis of hypertension was associated with an increased risk of ED.1,4 Cordero et al5 showed that, among 1,242 men on beta-blockers, absence of hypertension was associated with a lower prevalence of ED independent of age, other cardiovascular risk factors, and medication. However, none of the aforementioned studies demonstrated that tight blood pressure over time is associated with a lower risk of ED because these studies rely on baseline measurements of hypertension at a single timepoint,6,7 with no ability to account for the patient’s ability to maintain blood pressure control. It is critical to know whether long-term blood pressure control is associated with the development of ED. If effective blood pressure control protects erectile function, then newly diagnosed hypertensive men should be counseled that better adherence to their antihypertensive regimens not only reduces their risk of myocardial infarction and stroke but also may lower their risk of developing erectile dysfunction. A substantial fraction of men may value their erectile function over the prevention of myocardial infarcts and strokes.8,9 However, we have excellent quality, randomized controlled trials showing that the control of hypertension reduces coronary and cerebrovascular disease.10e12 Don’t we deserve better data on the relationship between hypertension control and the development of erectile dysfunction?
mass index (BMI), baseline cholesterol, diabetes status, medical comorbidities, and surgical history.
Selection of Participants Hypertension Diagnosis and Demographics Our hypertension registry is a prospectively maintained database used to identify and track hypertensive patients to better control their blood pressure. We included all men ages 26e60 years old who were enrolled in the Kaiser Permanente Northern California hypertension registry for the first time between 2008 and 2010. Patients are included in our hypertension registry if they meet 1 of the following criteria: (1) 2 diagnoses of hypertension from primary care; (2) 1 primary care hypertension diagnosis and 1 hospitalization with a primary or secondary diagnosis of hypertension; (3) 1 primary care hypertension diagnosis and 1 filled prescription for hypertension medication within the last 6 months; or (4) 1 primary care hypertension diagnosis and 1 of the following: a stroke-related hospitalization or current enrollment in coronary artery disease, heart failure, or diabetes registry. Membership Criterion We identified a cohort of men who had 3 years of Kaiser Permanente coverage before inclusion in the hypertension registry. Men were required to have uninterrupted coverage for 1 year and >10 months’ membership in a year for 3 years preceding the start date for study inclusion.
To our knowledge, no studies have examined the association between degree of blood pressure control and the incidence rate of ED. To rectify this gap, we performed a retrospective cohort study of hypertensive men with no ED at baseline. We studied the development of ED in this cohort and stratified them by their blood pressure measurements in the last 2 years of study inclusion. We believe that the measurements in the last 2 years of study inclusion allows the best approximation of the level of hypertension control that the patient has achieved during the course of our study. We hypothesize that tighter blood pressure control over time is associated with a lower incidence and delayed onset of ED in a large cohort of newly diagnosed potent, hypertensive men in an integrated healthcare system.
Erectile Function and Penile Structural Exclusions Patients with any evidence of erectile dysfunction 3 years prior to inclusion in the study were excluded. Patients were excluded if the patient had (i) 2 erectile dysfunction diagnoses by either a primary care physician or a urologist or (ii) 2 filled prescriptions for medications for phosphodiesterase 5 inhibitors, intracavernosal injection, or intraurethral suppositories or (iii) penile fracture or penile implant surgery in that 3-year period. Further exclusion criteria are listed in Appendix A.
METHODS
Primary Outcome and Study Endpoint
Data Extraction
Our primary outcome was the development of ED. To meet the definition of ED, patients had to meet 1 of the following criteria: (i) 2 diagnoses of ED either by primary care or urology outpatient visits within a 2-year period or (ii) 2 filled prescriptions for medication for ED (phosphodiesterase inhibitors, injection therapy, or intraurethral suppositories). 1 of the urologists (W.H.) reviewed 30 cases manually to verify that the ED was organic ED and not due to obvious psychogenic causes.
Data were extracted from outpatient visits, inpatient encounters, and emergency department visits in our integrated electronic health record (Epic, Verona, WI, USA). Prescriptions and laboratory data were extracted from pharmacy and laboratory data systems. We also captured demographics, baseline body
Study enrollment started from the first date of hypertension diagnosis and continued to the study endpoint. Our study endpoint was defined as the date of development of ED, development of censoring criterion (which were the same as the exclusion criterion listed above if the diagnosis appeared after
Study Setting Kaiser Permanente Northern California is a large, integrated health care delivery system that provides comprehensive care for more than 4 million members. The Kaiser Foundation Research Institute’s Institutional Review Board approved the study.
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study enrollment), disenrollment from our health plan, death, last known date of follow-up, or study end date of December 31, 2015, whichever occurred first.
Definition of Hypertension and Blood Pressure Measurements We extracted all blood pressure measurements available from outpatient office visits or blood pressure monitoring visits in the last 2 years before study endpoint. We did not use blood pressure measurements associated with emergency department visits, inpatient visits, or procedure-based visits, because it was assumed that illness, anxiety due to the procedure, or the procedure itself would obscure baseline arterial tone. The average number of blood pressure measurements was 4.7 measurements in the 2 years prior to study endpoint. Any patient without blood pressure measurements in each of the last 2 years prior to study endpoint or censoring date was excluded from the study. Averages and standard deviations of blood pressure measurements were calculated. Patients were classified into 4 categories of hypertension based on average systolic blood pressure: <120 mm Hg, 120e139 mm Hg, 140e159 mm Hg, and 160 mm Hg. The average systolic blood pressure of <120 mm Hg was used as a reference level. To evaluate the tightness of blood pressure control, the SD of the average was used. We split these groups into normal variation and wide variation groups, where wide variation was defined as >1 SD of the blood pressure in systolic blood pressure (SBP) measurements. There was a normal distribution of the SBP measurements as confirmed with the Kolmogorov-Smirnov test (P < .01).
Medications for Hypertension We evaluated all medications prescribed and filled in the last 2 years prior to the study end date. For patients who developed ED, these were their blood pressure medications prescribed 2 years prior to the ED incidence date. For patients without ED incidence, these were their blood pressure medications prescribed 2 years prior to end of follow-up (December 31, 2015) or date of censorship. We sorted the number of classes of medications that the patients were on during this 2-year period into the following categories: angiotensin converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, calcium channel blockers, thiazides diuretics, and “other” (nitrates, loop diuretics, potassiumsparing diuretics, alpha blockers, centrally acting antihypertensive, and carbonic anhydrase inhibitors).
Determination of Insulin Resistance We had previously shown that insulin resistance, as determined by a fasting lipid panel, was an effective predictor of cardiovascular outcomes.13 Based on this, we determined the insulin resistance of our patients. The patient was deemed insulin resistant if the triglyceride level was in the highest tertile of the cohort and the high-density lipoprotein cholesterol was in the lowest tertile of the cohort. The patient was deemed insulin
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sensitive if the triglyceride level was in the lowest tertile of the cohort and the high-density lipoprotein cholesterol was in the highest tertile. Patients not meeting criteria for insulin resistance or sensitivity were put in a single intermediate category.
Statistical Analysis A sample size calculation was performed during the planning stage of the study. We assumed an ED incidence rate of 15% among patients with poorly controlled blood pressure not and incidence rate of 10% among patients with controlled blood pressure. We also assumed that 70% of the cohort had good blood pressure control and 30% did not based on previous studies. A 2-group continuity corrected c2 test with a 2-sided significance level of 0.05 will have 80% power to detect a difference between a proportion of 0.15 in the blood pressureenotecontrolled group and a proportion of 0.10 in the blood pressureecontrolled group (odds ratio of 0.63) when the sample sizes are 507 and 1,165, respectively (a total sample size of 1,672). c2 tests were done to test for differences in categorical variables. We compared the time to diagnosis of ED by SBP group in pairs using the Tukey method. We plotted the Kaplan Meier survival curves by blood pressure control. The log-rank test was reported. We performed Cox proportional hazards regression models to estimate the incidence of ED associated with sociodemographic and clinical characteristics. Hazard ratios and 95% CI are presented. Follow-up started on the date of inclusion into the hypertensive registry and continued to the time of the development of ED, censorship, date of disenrollment in the health plan, death, or end of the follow-up (December 31, 2015), whichever occurred first. All analyses were conducted using SAS statistical software, version 9.3 (Cary, NC, USA)
RESULTS Overall Results The final cohort consisted of 39,320 men, age 26e60 years old, with a new diagnosis of hypertension without previously diagnosed ED (Figure 1). The average follow-up was 55.1 ± 28.7 months. The overall incidence of ED in our cohort was 13.9% (5,476 of 39,320). The Charlson comorbidity index (CCI) distribution for our cohort was as follows: CCI score 0 ¼ 96.4% (378,799 of 39,320), CCI score 1 ¼ 1.9% (762 of 39,320), CCI score 2 ¼ 1.7% (659 of 39,320). Other baseline characteristics, antihypertensive medication use, and average blood pressures are summarized in Table 1. The average number of BP measurements was 4.7 during 2 years of follow-up.
Incidence of ED Stratified by Average SBP Survival analysis showed a relationship between the incidence of ED and the level of blood pressure control within the last 2 years of study endpoint (log-rank test, P < .0001) (Figure 2). The incidence rates of ED were lower with better blood pressure J Sex Med 2019;16:410e417
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Figure 1. Cohort selection. Figure 1 is available in color online at www.jsm.jsexmed.org. control. When stratified by average SBP, they were <120 mm Hg, 12.5% (539 of 4,313); 120e139 mm Hg, 13.9% (3,764 of 27,096); 140e159 mm Hg, 14.9% (1,055 of 7,093); and 160 mm Hg, 14.4% (118 of 818) (trend test P < .01). The time to diagnosis of ED was longer in patients with better blood pressure control. The overall time to diagnosis of ED was 29.1 ± 22.4 months. The average time to diagnosis of ED (mean ± SD) was longer in those with lower average SBP: <120, 34.1 ± 21.4 months; 120e139, 30.4 ± 22.4 months; 140e159, 23.2 ± 21.6 months; and 160, 19.1 ± 21.6 months (trend test, P < .0001). Those with normal variation in average SBP control (n ¼ 29,039) had a lower incidence of ED compared with those patients with a wide variation in average SBP (n ¼ 4,763) (14.4% vs 18.1%, P < .0001). J Sex Med 2019;16:410e417
Predictors of ED A Cox proportional hazards model was used to evaluate the predictors of ED (Table 2). Average SBP predicted ED incidence in both unadjusted and adjusted analysis. In addition, variation in SBP > 1 SD was associated with a higher incidence of ED (adjusted hazard ratio [95% CI]: 1.359 (1.258e1.469), P < .0001). Other variables independently associated with an increased risk of ED on univariate analysis included taking 3 antihypertensive medications classes compared with 1 class, increased age, African American race, Hispanic ethnicity, diabetes at baseline, having depression or sleep apnea diagnosed within 2 years of study endpoint, insulin resistance, elevated BMI, and CCI score of 1 or higher. On multivariate analysis, predictors of ED were increasing age, African-American race
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Table 1. Baseline characteristics N (%) Age 26e40 41e50 51e60 Race/Ethnicity Caucasian African-American Hispanic Asian/Pacific Islanders Native American/Multiracial /Other/Unknown BMI <25 25e30 >30 Unknown Average systolic blood pressure (2 years) Average SBP <120 Average SBP 120e139 Average SBP 140-159 Average SBP >160 Average diastolic blood pressure (2 years) Average DBP <80 Average DBP 80-89 Average DBP 90-99 Average DBP 100 Number of classes of antihypertensives 0 1 2 3þ Diabetes at baseline Yes No/Unknown Insulin resistance Indeterminate Insulin resistance Insulin sensitive Missing data Depression at study endpoint Yes No/Unknown Obstructive sleep apnea at study endpoint Yes No/Unknown
7,175 (18.3%) 14,061 (35.8%) 18,084 (46.0%) 19,457 3,459 6,686 6,373 3,345
(49.5%) (8.8%) (17.0%) (16.2%) (8.5%)
4,432 16,872 16,815 1,201
(11.3%) (42.9%) (42.8%) (3.1%)
4,313 27,096 7,093 818
(11.0%) (68.9%) (18.0%) (2.1%)
18,425 16,513 3,695 687
(46.9%) (42.0%) (9.4%) (1.8%)
7,379 12,512 12,906 6,523
(18.8%) (31.8%) (32.8%) (16.6%)
5,497 (14.0%) 33,823 (86.0%) 19,382 5,210 5,117 9,611
(49.3%) (13.3%) (13.0%) (24.4%)
173 (0.44%) 39,147 (99.56%)
1,477 (3.8%) 37,843 (96.2%)
BMI ¼ body mass index; SBP ¼ systolic blood pressure.
compared with white, diabetes at baseline, depression within 2 years of study endpoint, and elevated BMI. The number of classes of hypertensive medicines did not predict ED incidence when controlling for other factors, although those not taking any medicines (either controlled by diet and exercise or not
Figure 2. Curves depicting ED incidence stratified by aSBP. Log-rank test P < .0001. aSBP ¼ average systolic blood pressure; ED ¼ erectile dysfunction. Figure 2 is available in color online at www.jsm.jsexmed.org.
compliant) had a lower incidence of ED on both analyses. Also, sleep apnea and CCI were not associated with erectile function after controlling for other factors.
DISCUSSION In a cohort of potent, newly diagnosed hypertensive men, we evaluated the association of SBP control with the incidence of ED. Worse SBP control is associated with an increase in the incidence of ED at each ordinal level of SBP. In addition, men with little variability in SBP during the study period had a lower risk of developing ED and a longer time before the development of ED. Previous work has shown that hypertension is a risk factor for the development of ED. But, to our knowledge, our study is the first to show so rigorously that tighter blood pressure control over time is associated with a lower incidence and a delayed onset of ED in hypertensive men. This study brings the literature closer to resolving the motivating clinical question, “Does controlling hypertension preserve erectile function?”14 Most studies of ED and hypertension use a binary value for hypertension (present or absent), and many studies have shown an association with hypertension and either the prevalence of ED or its development longitudinally.1,4,6 Until now, the 2 studies that provide the closest approximations of a dose-response relationship between hypertension and ED were 2 surveys that took into account the duration of hypertension.7,15 A major weakness of these studies is their inability to take into account the long-term degree of blood pressure control. Using the number of years of having a diagnosis of hypertension alone puts the well-controlled hypertensive man in the same risk category as the poorly controlled hypertensive man, which is not true for cardiovascular outcomes.10 Using a single baseline measurement to stratify patients into categories in the future assumes that there is no effect of hypertension control over time and does not allow the patient to cooperate and try to control their hypertension. As such, we believe our categorization of patients using multiple blood pressure measurements from the last 2 years of inclusion in the study allows us to separate J Sex Med 2019;16:410e417
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Table 2. Cox proportional hazard model predicting incidence of ED Unadjusted hazard ratio Variables SBP in prior 2 years Average SBP <120 mm Hg Average SBP 120e139 mm Hg Average SBP 140e159 mm Hg Average SBP 160 mm Hg SBP control Normal variation in SBP Wide variation in SBP (>1 St Dev) Only 1 outpatient measurement in 2 years prior to study end Age (5 increment in age, y) Race/Ethnicity White African-American Asian/Pacific Islander Hispanic Native American/Multiracial/Other/Unknown Diabetes Yes No Depression Yes No Obstructive sleep apnea Yes No Insulin resistance Indeterminant Sensitive Resistant Missing BMI <25 25e30 >30 Missing Charlson Comorbidity Index 0 1 >1 Number of antihypertensive medications classes 0 1 2 3þ
Adjusted hazard ratio P value
(95% CI)
P value
(reference) (1.069, 1.281) (1.344, 1.654) (1.345, 2.003)
.0006 <.0001 <.0001
1 1.235 1.488 1.844
<.0001 <.0001 <.0001
1 (reference) 1.516 (1.409, 1.632) 0.503 (0.455, 0.556)
<.0001 <.0001
1 (reference) 1.359 (1.258, 1.469) 0.555 (0.501, 0.614)
<.0001 <.0001
1.122 (1.103, 1.142)
<.0001
1.095 (1.075, 1.115)
<.0001
(95% CI) 1 1.17 1.491 1.641
1 1.374 0.749 1.086 0.975
(reference) (1.262, 1.497) (0.69, 0.814) (1.01, 1.168) (0.873, 1.088)
<.0001 <.0001 .025 .652
1 1.356 0.759 1.059 0.989
(reference) (1.128, 1.353) (1.337, 1.655) (1.504, 2.26)
(reference) (1.243, 1.479) (0.697, 0.827) (0.984, 1.14) (0.885, 1.104)
<.0001 <.0001 .129 .838
1.968 (1.847, 2.096) 1 (reference)
<.0001
1.825 (1.708, 1.949) 1 (reference)
<.0001
1.682 (1.212, 2.334) 1 (reference)
.002
1.587 (1.143, 2.205) 1 (reference)
.006
1.218 (1.075, 1.38) 1 (reference)
.002
1.089 (0.959, 1.235) 1 (reference)
.188
.645
(0.889, 1.046) (reference) (0.942, 1.153) (0.726, 0.88)
.383 .426 <.0001
(reference) (1.126, 1.373) (1.111, 1.363) (0.677, 1.026)
<.0001 <.0001 .086
0.981 1 1.088 0.72
(0.906, 1.063) (reference) (0.987, 1.2) (0.655, 0.79)
.091 <.0001
0.964 1 1.042 0.799
1 1.289 1.361 0.812
(reference) (1.169, 1.421) (1.235, 1.5) (0.661, 0.998)
<.0001 <.0001 .048
1 1.243 1.231 0.833
1 (reference) 1.288 (1.082, 1.534) 1.24 (1.013, 1.517) 0.678 1 1.063 1.196
(0.622, 0.74) (reference) (0.996, 1.134) (1.109, 1.29)
.005 .037 <.0001 .067 <.0001
1 (reference) 1.099 (0.922, 1.31) 0.927 (0.756, 1.137) 0.759 1 1.035 1.011
(0.696, 0.829) (reference) (0.97, 1.105) (0.935, 1.093)
.291 .468 <.0001 .297 .781
BMI ¼ body mass index; ED ¼ erectile dysfunction; SBP ¼ systolic blood pressure.
those with good blood pressure control from those who do not control their blood pressure well. Whether poor blood pressure control is due to medication compliance, class of medications prescribed, or the biologic recalcitrance of severe hypertension unfortunately cannot be answered by our data. J Sex Med 2019;16:410e417
Longitudinal data with protracted follow-up affords many ways to measure hypertension control. The National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set measure, which relies on the last known blood pressure measurement, is helpful in population studies looking at
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hypertension adherence. However, to test the hypothesis that sustained blood pressure control could mitigate ED, we stratified our patient population by average systolic arterial blood pressure of each individual over the last 2 years of follow-up in the study. This seems to be novel in the ED and hypertension literature. With a median of 4.7 SBP measurements over 2 years, there were enough measurements to get a sense of overall blood pressure control for that individual. Focusing on systolic blood pressure, as opposed to mean arterial or diastolic pressure, has precedent as an excellent marker for the cardiovascular risk attributable to hypertension. SBP is more predictive of cardiovascular outcomes than diastolic in the Framingham datasets,16 the Multiple Risk Factor Intervention Trial,17,18 and even the cohort of Northern California Kaiser Permanente members from which our dataset is derived.19 Because mean arterial pressure (MAP) is an average of systolic and diastolic BP and is weighted more heavily to the diastolic BP, using MAP would diminish the signal from the strongest marker of cardiovascular risk. Also, all of the major cardiovascular risk assessment calculators use SBP rather than MAP or diastolic pressure.20 Admittedly, without evaluation of diastolic blood pressure, we are not able to take into account pulse pressure and other variables associated with diastolic blood pressure. Using the standard deviation of the SBP as another marker of risk for vasculopathy also has validity. Multiple large cohorts have found that the standard deviation of the visit-to-visit SBP can predict cardiovascular outcomes and their surrogates.21,22 The number of classes of medicines prescribed in the last 2 years did not seem to correlate with ED incidence. This would seem to argue against a straight dose relationship of BP meds to ED. However, this study did not have the scope to collect doses of medications and, thus, could not test the assertion that higher doses of hypertension medications lead to more ED. The results do hint that possibly what dominates the pathogenesis of ED is not the metabolic milieu, which creates recalcitrant hypertension requiring multiple classes of BP medications, but rather the resulting arterial pressure itself causing ED. More studies are required to test this hypothesis. Finally, it is notable that 18.8% of patients were not on any hypertension medications the last 2 years before study endpoint. Of this group of men not taking hypertensive medications, 74% had an average SBP 120e139 mm Hg, and 17% had an average SBP 140 mm Hg. Clearly, the risks of stroke and heart attack are not motivating this group to adhere to hypertension management paradigms. This group may represent recalcitrant patients that would benefit from further motivation (ie, fear of ED) to control their blood pressures.
Strengths and Limitations The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. We didn’t systematically screen for ED at study entry, and we must rely on the accuracy of our clinical diagnoses and
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prescription data, which may potentially underdiagnose mild ED in patients who don’t seek treatment. However, it is debatable whether this mild level of ED is clinically relevant. Another weakness is the lack of standardized validated questionnaires to evaluate the degree of erectile dysfunction. However, a single question about ED has been shown to be as sensitive as a full questionnaire in many settings.23,24 Finally, although we stratified patients by blood pressure control, we were not able to control for baseline health status (besides the CCI) and other lifestyle behaviors. Certainly, our study would be stronger with more data on lifestyle behaviors, such as diet and exercise. Also an emerging body of literature indicates that testosterone and aldosterone levels are independent risk factors for hypertension.25e27 We did find that 150 patients (0.38%) had a diagnosis of primary hyperaldosteronism, and 532 patients (1.35%) had a diagnosis of low testosterone, which would seem low. Unfortunately, we lacked testosterone and aldosterone levels in our patients, and these 2 conditions may have been underdiagnosed in our cohort. Strengths of our study include the large sample size, community cohort, and completeness of follow-up.
CONCLUSION Tighter blood pressure control is associated with a lower incidence and delayed onset of ED. We believe that, because hypertension often has few symptoms until end-stage organ damage or other late sequelae occur, our findings are helpful for doctors attempting to motivate their male hypertensive patients to adhere better to antihypertensive regimens.
Corresponding Author: Wayland Hsiao, MD, 3600 Broadway, Specialty Medical Office Building, Suite 40, Oakland, CA 94611, USA. Tel: (510)752-5067; Fax: (510)752-1673; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: Supported by a grant from the Kaiser Permanente Northern California Community Benefit Program.
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SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi.org/10.1016/j.jsxm.2019.01.011.