240

ORIGINAL RESEARCHERECTILE DYSFUNCTION

Increased Risk of Stroke among Men with Erectile Dysfunction:

A Nationwide Population-based Study jsm_1973 240..246

Shiu-Dong Chung, MD,*** Yi-Kuang Chen, MD, Hsiu-Chen Lin, MD, and Herng-Ching Lin, PhD**
*Department of Surgery, Division of Urology, Far Eastern Memorial Hospital, Ban Ciao, Taipei, Taiwan; Graduate
Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Urology,
Taipei County Hospital, Taipei, Taiwan; Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan;

Department of Pediatric Infection, Taipei Medical University and Hospital, Taipei, Taiwan; **School of Health Care
Administration, Taipei Medical University, Taipei, Taiwan

DOI: 10.1111/j.1743-6109.2010.01973.x

ABSTRACT

Introduction. Previous cross-sectional studies have suggested that erectile dysfunction (ED) represents an indepen-
dent risk factor for future cardiovascular events. However, very few studies have attempted to examine the association
between ED and subsequent stroke.
Aim. The aim of this study is to estimate the risk of stroke during a 5-year follow-up period after the rst
ambulatory care visit for the treatment of ED using nationwide, population-based data and a retrospective case-
control cohort design in Taiwan.
Methods. This study used data sourced from the Longitudinal Health Insurance Database. The study cohort
comprised 1,501 patients who received a principal diagnosis of ED between 1997 and 2001 and 7,505 randomly
selected subjects as the comparison cohort. Each patient (N = 9,006) was then individually tracked for 5 years from
their index ambulatory care visit to identify those who had diagnosed episodes of stroke.
Main Outcome Measure. Stratied Cox proportional hazard regressions were performed as a means of comparing
the 5-year stroke-free survival rate for the two cohorts.
Results. Of the sampled patients, 918 (10.2%) developed stroke within the 5-year follow-up period, that is, 188
individuals (12.5% of the patients with ED) from the study cohort and 730 individuals (9.7% of patients in the
comparison cohort) from the comparison cohort. The log-rank test indicated that patients with ED had signicantly
lower 5-year stroke-free survival rates than those in the comparison cohort (P < 0.001). After adjusting for the patients
monthly income, geographical location, hypertension, diabetes, coronary heart disease, peripheral vascular disease,
atrial brillation, and hyperlipidemia, patients with ED were more likely to have a stroke during the 5-year follow-up
period than patients in the comparison cohort (hazard ratio = 1.29, 95% condence interval = 1.08 - 1.54, P < 0.01).
Conclusions. These results suggest that ED is a surrogate marker for future stroke in men. Chung S-D, Chen YK,
Lin HC, and Lin HC. Increased risk of stroke among men with erectile dysfunction: A nationwide
population-based study. J Sex Med 2011;8:240246.
Key Words. Erectile Dysfunction; Stroke; Cardiovascular Disease; Epidemiology

Introduction as hypertension, diabetes mellitus, hyperlipidemia,

and smoking, with vascular disorders, such as coro-

I t is estimated more than 150 million men world-

wide are estimated to have erectile dysfunction
(ED) and the prevalence is increasing as popula-
tions age [13]. The prevalence of ED increases
with age and ED shares almost all risk factors, such
nary heart disease (CHD), and peripheral vascular
and cerebrovascular disease [412].
Increasing evidence supports a signicant cor-
relation between ED and vascular disorders, so
ED may serve as a clinical marker of vascular

J Sex Med 2011;8:240246 2010 International Society for Sexual Medicine

Increased Risk of Stroke in Patients with ED
integrity to predict future cardiovascular events or
stroke, both of which are leading causes of mor-
tality in Taiwan and other industrialized countries
[1315]. Previous cross-sectional studies have sug-
gested that ED represents an independent risk
factor for future cardiovascular events, even inde-
pendent of classic risk factors such as diabetes and
hypertension [1620]. However, very few studies
have attempted to examine the association
between ED and subsequent stroke.
Using a nationwide population-based dataset,
we examined the impact of ED on the incidence of
stroke by comparing Taiwanese men with a diag-
nosis of ED who did not have history of stroke at
baseline to a cohort of men without ED over a
5-year follow-up period.
Methods
Database
This study used data sourced from the Longitu-
dinal Health Insurance Database (LHID). The
LHID is a representative database of 1,000,000
drawn from the original claims data and registry of
all 25.68 million beneciaries listed under Tai-
wans National Health Insurance program in
2005. This database is made available to scientists
in Taiwan for research purposes. The Taiwan
National Health Research Institutes report that
there is no signicant difference between the
enrollees in the LHID and all enrollees under the
National Health Insurance program, in terms of
gender distribution, age distribution, or size of
average payroll-related insurance payments.
Therefore, the LHID provides researchers a rare
opportunity to trace all medical service utilization
by 1,000,000 enrollees, allowing us to examine the
risk of stroke following a diagnosis of ED.
This study was exempt from full review by the
Institutional Review Board, since the dataset used
consist of de-identied secondary data released to
the public for research purposes.
Study Sample
The study design was a prospective case-cohort
study. In total, 2,082 patients from the LHID were
identied who had visited ambulatory care centers
(including outpatient departments of hospitals or
clinics) for the treatment of ED (with a principal
diagnosis of Impotence, organic [International
Classication of Diseases, Ninth Revision, Clinical
Modication (ICD-9-CM) code 607.84] or Impo-
tence, psychogenic [ICD-9-CM code 302.72])
241
between January 1, 1997 and December 31, 2001.
We rst excluded patients who had been diagnosed
with ED prior to 1997 (N = 54) in order to increase
the likelihood of only including newly onset cases.
We also excluded patients less than 40 years old
(N = 344). Patients who had been diagnosed with
stroke (ICD-9-CM codes 430438) prior to 1997
were likewise excluded (N = 31). In addition, we
excluded patients who had been diagnosed with
prostate cancer or colorectal cancer (N = 27)
during the study period (19962006). Finally, we
excluded patients with a history of cardiovascular
disease, including myocardial infarction or surgical
treatment of coronary artery disease, including
coronary artery bypass graft or angioplasty, angina,
congestive heart failure, cardiac arrest, and cardiac
arrhythmia (N = 125) in accordance with a prior
study [18]. The remaining 1,501 patients with ED
(including 1,289 patients with organic impotence
and 212 patients with psychogenic impotence) were
included in the study cohort. We assigned their rst
ambulatory care visit for the treatment of ED as
their index ambulatory care visits.
We selected the comparison cohort of this study
from the remaining patients in the Registry of
Beneciaries of the LHID. Similarly, we limited
the selected patients to males aged 40 years. We
excluded patients who had been diagnosed with
prostate cancer or colorectal cancer during 1996
and 2006. Then we then randomly extracted 7,505
patients (ve for every patient with ED) matched
in terms of age (treated as a continuous variable)
and the year of index ambulatory care visit using
the SAS program PROC SURVEYSELECT (SAS
System for Windows, Version 8.2). Patients who
had strokes prior to their index ambulatory care
visits were not included in the comparison cohort.
Each patient (N = 9,006) was then individually
tracked for 5 years from their index ambulatory
care visit to identify those who had diagnosed epi-
sodes of stroke (ICD-9-CM codes 430437). Since
the LHID allows us to trace all use of medical
services for all enrollees, we have followed all
sampled patients throughout the study period. In
addition, all hospitals in Taiwan capable of admit-
ting stroke patients were equipped with comput-
erized tomography (CT) or magnetic resonance
imaging (MRI) scanners, which increase the valid-
ity of stroke diagnoses considerably.
Statistical Analysis
The SAS statistical package (http://www.sas.com/
company) was used in all statistical analyses in this
study. We used c2 tests to examine differences in
J Sex Med 2011;8:240246
242 Chung et al.

Table 1 Demographic characteristics and comorbid medical disorders for patients with erectile dysfunction and
comparison cohort in Taiwan, 19972001 (N = 9,006)
Patients with erectile dysfunction Comparison patients
N = 1,501 N = 7,505
Variable Total No. Column % Total No. Column % P value
Age 1.000
4049 399 26.6 1,995 26.6
5059 390 26.0 1,950 26.0
6069 397 26.4 1,985 26.4
>69 315 21.0 1,575 21.0
Hyperlipidemia <0.001
Yes 93 6.2 232 3.1
Hypertension 0.058
Yes 367 24.5 1,667 22.2
Diabetes <0.001
Yes 256 17.1 729 9.7
Coronary heart disease 0.233
Yes 105 7.0 495 6.6
Atrial fibrillation 1.000
Yes 6 0.4 28 0.4
Peripheral vascular disease 0.143
Yes 17 1.13 55 0.73
Geographic region <0.001
Northern 1,133 75.5 4,990 66.5
Central 163 10.9 1,106 14.7
Southern 180 12.0 1,298 17.3
Eastern 25 1.6 111 1.5
Monthly income <0.001
0 709 47.2 3,558 47.4
NT$115,840 205 13.7 835 11.1
NT$15,84125,000 287 19.1 1,952 26.0
NT$25,001 300 20.0 1,160 15.5

sociodemographic characteristics between patients
with and without ED (monthly income and the
geographical location of the patients residence
[Northern, Central, Eastern and Southern Taiwan])
and select comorbid medical disorders (hyperten-
sion, diabetes, CHD, peripheral vascular disease,
atrial brillation, and hyperlipidemia). In this study,
comorbid conditions were only counted if they
occurred either in the inpatient setting or in two or
more ambulatory care claims coded 6 months before
and after the index ambulatory care visits. We also
used the KaplanMeier method and log-rank test to
estimate the 5-year stroke-free survival rate and
compared the risk of stroke for these two cohorts. In
addition, stratied Cox proportional hazard regres-
sion (stratied by age group, 4049, 5059, 6069,
and >69) was carried out to calculate the 5-year
stroke-free survival rate between patients with and
without ED. The results are presented as hazard
ratios (HRs) along with 95% condence intervals
(95% CI), using a signicance level of 0.05.
Results
Of the sample of 9,006 subjects, the mean age
was 58.5 years (standard deviation = 11.4 years).
Table 1 shows the features of the whole study
population at baseline and of the patients stratied
by cohort. After matching for age and the year of
index ambulatory care visits, patients with ED
were more likely to have comorbidities of hyper-
lipidemia (P < 0.001) and diabetes (P < 0.001) at
baseline than patients without ED. In addition,
patients with ED had a greater tendency to have
higher monthly incomes (P < 0.001) and to reside
in the northern part of Taiwan (P < 0.001) com-
pared with patients without ED. However, there
were no signicant differences in the distributions
of hypertension (P = 0.058), CHD (P = 0.233),
peripheral vascular disease (P = 0.143), and atrial
brillation (P = 1.000) at baseline for the two
cohorts.
Table 2 presents the distribution of stroke
between patients with and without ED. Of the
9,006 sampled patients, 918 (10.2%) had strokes
during the 5-year follow-up period, 188 (12.5% of
the patients with ED) from the study cohort and
730 (9.7% of patients without ED) from the com-
parison cohort. The log-rank test reveals that
patients with ED had signicantly lower 5-year
stroke-free survival rates compared with patients
in the comparison cohort (P < 0.001). The

J Sex Med 2011;8:240246

Increased Risk of Stroke in Patients with ED
Table 2 Crude and adjusted hazard ratios for stroke among the sampled patients during the five-year follow-up starting
from index ambulatory care visit
Total sample
N = 9,006
Presence of stroke No.
Five-year follow-up period
Yes 918
No 8,088
Crude HR (95% CI)
Adjusted HR (95% CI)
Notes: Adjustments are made for patients monthly income, geographical location, hypertension, peripheral vascular disease, diabetes, coronary heart disease,
atrial fibrillation, and hyperlipidemia; *Indicates P < 0.001; **indicates P < 0.01.
HR = hazard ratio.
KaplanMeier curves for strokes in patients strati-
ed by ED are presented in Figure 1. Among the
patients who had stroke during the follow-up
period, the average time between index ambula-
tory care visits and the onset of stroke was 909 days
(standard deviation = 538 days); 870 and 920 days
for patients with and without ED, respectively
(P = 0.674).
The crude and adjusted HRs for stroke by
cohort is also presented in Table 2. Stratied Cox
proportional hazard regression (stratied by age
group) suggests that the crude HR of stroke for
patients with ED during the 5-year follow-up
period was 1.35 (95% CI = 1.13 - 1.60, P < 0.001)
compared to those in the comparison cohort. After
adjusting for the patients monthly income, geo-
Figure 1 Stroke-free survival rates for patients with erectile
dysfunction and comparison group in Taiwan, 19972001.
243
Patients with erectile dysfunction Comparison patients
N = 1,501 N = 7,505
% No. % No. %
10.2 188 12.5 730 9.7
89.8 1,313 87.5 6,775 90.3
1.35* (1.131.60) 1.00
1.29** (1.081.54) 1.00
graphical location, hypertension, diabetes, CHD,
peripheral vascular disease, atrial brillation, and
hyperlipidemia, the stratied Cox proportional
hazard regression shows that patients with ED
were more likely to have strokes during the 5-year
follow-up period (HR = 1.29, 95% CI = 1.08 -
1.54, P = 0.005) than patients in the comparison
cohort.
We further analyzed the risk of stroke by sepa-
rating patients with ED into organic ED and psy-
chogenic ED. We found that the adjusted HR of
stroke for patients with organic ED was 1.36 times
greater (95% CI = 1.13 - 1.64, P = 0.001) than
patients in the comparison cohort. However, there
was no increased risk of stroke during the 5-year
follow-up period for patients with psychogenic
ED as compared to those in the comparison
cohort.
Discussion
Although the link between ED and cardiovascular
diseases including stroke has been previously
documented, large-scale prospective studies are
still very limited. In addition, according to our
understanding, this is the rst nationwide
population-based study to investigate the relation-
ship between ED and subsequent stroke in an
Asian population. Consistent with previous
reports, men with ED have more comorbidities
than men who do not, including diabetes and
hyperlipidemia. More importantly, men with ED
were more likely to have strokes than those
without, after adjustment for monthly income,
geographical location, hypertension, diabetes,
CHD, peripheral vascular disease, atrial brilla-
tion, and hyperlipidemia. The results of our study
are in accordance with ndings elsewhere by
Araujo et al. and Schouten et al. which both found
J Sex Med 2011;8:240246
244
that the presence of ED was a strong indicator of
stroke. ED might therefore serve as a clinical
marker for cerebrovascular diseases [16,19].
One study by Thompson et al. analyzed the
data collected from The Prostate Cancer Preven-
tion Trial and provided the rst evidence of a
strong association between ED and subsequent
cardiovascular disease [18]. However, their results
showed a statistically signicant association
between ED incidence and subsequent CHD after
covariate adjustment (P = 0.04), whereas the risk
of stroke was merely suggestive (P = 0.06).
Another study by Ponholzer et al. [17] reported
that 2,561 men with moderate to severe ED had an
increased risk of stroke over 10 years (24.7% and
43.6%, respectively) compared to men without
ED. One longitudinal population-based cohort
study involving 1,248 cardiovascular disease
(CVD)-free men conducted by Schouten et al.
concluded that the presence of ED was a strong
indicator of myocardial infarction, stroke, and
sudden death, independently of the Framingham
risk factor prole [16]. Furthermore, Araujo et al.
suggested that ED is an independent risk factor for
a stroke [21]. They followed 1,209 men from the
Massachusetts Male Aging Study over a 15-year
period and reported that in the group of 1,209
men, those who had ED were approximately three
times more likely to have a stroke during the
15-year follow-up compared to those without ED.
In normal physiology of penile erection, nitric
oxide (NO) plays an important role. After sexual
arousal, the parasympathetic nerves in the penis
generate NO, which initiates signal cascades by
cyclic adenosine or guanidine monophosphate
within the corpus cavernosum, producing vasodila-
tation by increasing dilation of the corporeal sinu-
soids to induce penile erection [22]. The
pathophysiology of ED is multifactorial and
includes arterial, neurogenic, hormonal, cavern-
osal, iatrogenic, and psychogenic causes. It is now
widely accepted that organic ED in a substantial
majority of men is due to underlying vascular
causes, especially atherosclerosis [22]. Endothelial
dysfunction, which has been well documented in
diabetes, hypertension, and hyperlipidemia, is
thought to be the main etiologic factor in systemic
and peripheral vascular diseases, including ED [23].
Endothelial dysfunction, which is associated with
impaired vasodilatation, precedes the development
of atherosclerotic lesions through the impaired
release of NO, which is modulated by parasympa-
thetic nonadrenergic, noncholinergic nerves and
by vascular endothelial cells [24]. In addition, oxi-
J Sex Med 2011;8:240246
Chung et al.
dative stress or free radical damage interferes with
the NO pathway and is directly toxic to the endot-
helium, and is thus a causal mechanism in clinically
evident occlusive cardiovascular disease. The
aforementioned pathophysiologies also result in
increased adhesion and aggregation of platelets and
neutrophils and the release of vasoconstrictor sub-
stances [25,26]. As penile arteries have smaller
diameter compared to coronary, internal carotid, or
other major arteries, luminary obstruction may lead
to the development of ED prior to cardiac events or
stroke. Kaiser et al. assessed disease in vascular beds
other than the penis [27]; 30 men with Doppler-
proven ED without cardiovascular disease did not
differ from 27 healthy age-matched control sub-
jects on measures for peripheral vascular structure
and function, except for measures that assessed
systemic endothelial function using ow-mediated
brachial artery vasodilatation studies. They
found that men with ED exhibited signicantly
lower brachial artery ow-mediated, endothelium-
dependent vasodilation and endothelium-
independent vasodilation, which suggests the
presence of a peripheral vascular abnormality in the
NO pathway [27].
Lojanapiwat et al. examined 41 ED patients and
30 age-matched normal control subjects with car-
diovascular risks and endothelial function, com-
paring the percentage of change in the brachial
arterial diameter after brachial arterial occlusion
[28]. The results showed a signicant difference
between the normal control group and the ED
group, demonstrating endothelial dysfunction in
ED patients without clinical cardiovascular risks.
They concluded that the patients who developed
ED had endothelial dysfunction prior to the clini-
cal symptoms and laboratory ndings of cardiovas-
cular risk [28]. Cerebrovascular reactivity
evaluates the cerebral endothelial function, pro-
viding information on cerebrovascular reserve
capacity. Vicenzini et al. reported that cerebrovas-
cular reactivity was reduced in patients with ED
without other signs of clinical atherosclerosis [29].
They suggested that ED is a possible risk factor for
cerebrovascular disease. According to the second
Princeton consensus, it is necessary to evaluate the
men with ED and no cardiac symptoms carefully
to exclude the possibility of silent cardiovascular
disease [30]. We recommend that men with ED
and other risk factors for cardiovascular disease be
counseled on lifestyle modication [30].
This study suffers from a few limitations that
should be addressed. The rst limitation of this
study is the use of ICD coding to diagnose ED.
Increased Risk of Stroke in Patients with ED
Discussing sexuality is relatively culturally taboo in
Taiwan. These factors might contribute to the
seemingly low frequency of ED as compared with
studies from Western countries [31,32]. In recent
clinical studies, information on ED was collected
using the International Index Erectile Function
(IIEF) or IIEF-5 questionnaire, which includes
more objective items, rather than using an ICD
code. Nevertheless, in our nationwide population-
based analysis, we have collected conventional risk
factors and comorbidities at baseline, and ED
remained a signicant risk factor after adjusting for
these confounding factors. Second, individual
information, such as smoking, alcohol consump-
tion, obesity, and marital status, all of which may
contribute to stroke, was not available through the
administrative dataset. Third, the stroke diagnoses
are sourced from an administrative database, and
therefore, they may be less accurate than diagnoses
undertaken individually through a standardized
procedure. However, virtually all hospitals in
Taiwan capable of admitting stroke patients are
equipped with CT or MRI scanners, which increase
the validity of stroke diagnoses considerably.
In conclusion, we provide large-scale data
evaluating the relationship between ED and the
risk of developing stroke. These results strongly
suggest that men with ED are at a signicantly
increased risk for stroke within 5 years of their
presenting for treatment of ED.
Acknowledgment
This study is based in part on data from the National
Health Insurance Research Database provided by the
Bureau of National Health Insurance, Department of
Health, Taiwan and managed by the National Health
Research Institutes. The interpretations and conclu-
sions contained herein do not represent those of the
Bureau of National Health Insurance, Department of
Health, or the National Health Research Institutes.
Corresponding Author: Herng-Ching Lin, PhD,
School of Health Care Administration, Taipei Medical
University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Tel: +886 2 2736 1661 ext. 3613; Fax: +886 2 2378 9788;
E-mail: henry11111@tmu.edu.tw
Conict of Interest: None.
Statement of Authorship
Category 1
(a) Conception and Design
Herng-Ching Lin; Shiu-Dong Chung; Yi-Kuang
Chen
245
(b) Acquisition of Data
Herng-Ching Lin
(c) Analysis and Interpretation of Data
Herng-Ching Lin; Hsiu-Chen Lin
Category 2
(a) Drafting the Article
Shiu-Dong Chung; Herng-Ching Lin; Yi-Kuang
Chen; Hsiu-Chen Lin
(b) Revising It for Intellectual Content
Shiu-Dong Chung; Yi-Kuang Chen; Hsiu-Chen
Lin; Herng-Ching Lin
Category 3
(a) Final Approval of the Completed Article
Shiu-Dong Chung; Yi-Kuang Chen; Hsiu-Chen
Lin; Herng-Ching Lin
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