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Blood Pressure and Stroke in Heart Failure in the REasons
for Geographic And Racial Differences in Stroke
(REGARDS) Study
Patrick M. Pullicino, MD; Leslie A. McClure, PhD; Virginia G. Wadley, PhD; Ali Ahmed, MD, MPH;
Virginia J. Howard, PhD; George Howard, DrPH; Monika M. Safford, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Background and Purpose—The prevalence of stroke is increased in individuals with heart failure (HF). The stroke
mechanism in HF may be cardiogenic embolism or cerebral hypoperfusion. Stroke risk increases with decreasing
ejection fraction and low cardiac output is associated with hypotension and poor survival. We examine the relationship
among blood pressure level, history of stroke/transient ischemic attack (TIA), and HF.
Methods—We compared the prevalence of self-reported history of stroke or TIA in the REasons for Geographic And
Racial Differences in Stroke (REGARDS) participants with HF (as defined by current digoxin use) and without HF. We
excluded participants with atrial fibrillation or missing data. We examined the relationship between HF and history of
stroke/TIA within tertiles of systolic blood pressure (SBP) adjusting for patient demographic and health characteristics.
Results—Prevalent stroke/TIA were reported by 66 (26.3%) of 251 participants with and 1805 (8.5%) of 21 202
participants without HF (P⬍0.0001). Within each tertile of SBP, the unadjusted OR (95% CI) for prior stroke/TIA
among those with HF compared with those without HF (the reference group) was, 4.0 (2.8 to 5.8) for SBP
⬍119.5 mm Hg, 2.7 (1.8 to 3.9) for SBP ⱖ119.5 but ⬍131.5 mm Hg, and 2.3 (1.6 to 3.2) for SBP ⱖ131.5 mm Hg. After
adjustment, the relationship between prior stroke/TIA and HF remained significant only within the lowest tertile of SBP
(⬍119.5 mm Hg; 3.0; 1.5 to 6.1).
Conclusions—The odds of prevalent self-reported stroke/TIA are increased in participants with HF and most markedly
increased in participants with low SBP. Longitudinal data are needed to determine whether this reflects stroke/TIA
secondary to thromboembolism from poor cardiac function or secondary to cerebral hypoperfusion. (Stroke. 2009;40:
3706-3710.)
Key Words: brain infarction 䡲 cardiac disease 䡲 hypertension
C
ardiac disease is a major independent risk factor for
stroke, ranking third after age and hypertension. Atrial
fibrillation (AF) is the cardiac disorder most frequently
associated with stroke with approximately 105 000 strokes
per year in the United States.1 Heart failure (HF) ranks second
as a cause of cardiogenic stroke with approximately 60 000
strokes per year,2 although HF affects approximately twice
the number of individuals in the population in the United
States (5 million) than are affected by AF (2.3 million).3 Two
community studies have shown the risk of stroke in HF to be
2 to 3 times that of the general population. In the Framingham
study, the adjusted risk of stroke associated with HF was 2.1
in women and 2.7 in men.4 In a recent study in Olmsted
County, Minn, the stroke risk among those with HF was 2.9
times the control population risk over 5 years.5
Hypertension, particularly systolic hypertension, is a
major risk factor for stroke.6,7 Hypertension doubles the
lifetime risk of developing HF,8 but there are inconsistent
data on whether hypertension is a risk factor for stroke in
patients with HF. A population study did not find hypertension to be a risk factor for stroke in HF in a multivariable analysis.5 Hypertension was not a risk factor for
stroke in a study of patients with left ventricular systolic
dysfunction,9 and in Studies of Left Ventricular Dysfunction,
hypertension imparted a small relative risk of stroke only in
men (relative risk, 1.32; 95% CI, 1.04 to 1.69; P⫽0.02) but
no significant risk in women.10 Two recent substudies of the
Digitalis Investigation Group trial,11,12 however, showed a
history of hypertension to be an independent predictor of
stroke (adjusted OR, 1.46; 95% CI, 1.11 to 1.94)12 and a risk
Received July 3, 2009; final revision received August 21, 2009; accepted August 27, 2009.
From the Department of Biosciences (P.M.P.), University of Kent, Kent, UK, and the Department of Neurology and Neurosciences, New Jersey
Medical School, NJ; the Department of Medicine (V.G.W., A.A.), Division of Gerontology, Geriatrics, and Palliative Care and the Division of Preventive
Medicine (M.M.S.), University of Alabama at Birmingham, Birmingham, Ala; the Departments of Biostatistics (L.A.M., G.H.) and Epidemiology (V.J.H.)
School of Public Health, University of Alabama at Birmingham, Birmingham, Ala; and the Department of Medicine (A.A.), Veteran Affairs Medical
Center, Birmingham, Ala.
Correspondence to Patrick M. Pullicino, MD, Room 103, Research and Development Centre, University of Kent, Canterbury, CT2 7PD, Kent, UK.
E-mail [email protected]
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.109.561670
3706
Pullicino et al
factor for hospitalization for stroke (hazard ratio, 1.52; 95%
CI, 1.11 to 2.08) among patients with HF.
Reduced ejection fraction has been found to be a risk factor
for stroke in several studies,9,10,13,14 but there are some
inconsistencies and an interaction with cerebrovascular disease may be important for the development of stroke in
patients with low ejection fraction.2 Both hypotension15 and
low ejection fraction16 have been found to be risk factors for
cognitive impairment in patients with HF, and cognitive
impairment may signal undiagnosed or “whispering” stroke.17
Decreasing blood pressure is associated with worse survival in
HF, because hypotension probably reflects poor cardiac pump
function in advanced HF.18 This study was initiated to
investigate the association among blood pressure level, prevalent stroke, and HF.
Methods
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Design
The REasons for Geographic And Racial Differences in Stroke
(REGARDS) study is a population-based study of adults aged ⱖ45
years in the United States19 seeking to determine causes of racial and
geographic differences in stroke. Enrollment began in January 2003
and was completed in October 2007. The cohort consists of 30 228
participants, 45% men and 55% women (50/50 planned); 58% white
and 42% black (50/50 planned); 56% residing in the Stroke Belt
region of southeastern United States and 44% in the remaining 40
contiguous United States (50/50 planned), each of whom is being
followed biannually by telephone to ascertain cognitive assessment,
stroke, and cardiovascular outcomes.19
Procedures
REGARDS is approved by the Institutional Review Boards of all
participating institutions. Participants were recruited from commercially available lists of US residents using mail and telephone contact
methods. Those who agreed to participate answered demographic,
quality-of-life, health behavior, and medical history information;
reported HF symptoms (2 questions); and reported stroke history and
symptoms using the Questionnaire for Verifying Stroke-free Status,20 all through a computer-assisted telephone interview. During a
subsequent home visit, written informed consent was obtained as
well as blood and urine samples, electrocardiogram, and blood
pressure and body mass index measures. Medication audits also were
performed during the home visit. Further methodological details are
available elsewhere.19
Measures
Heart Failure
We used current use of digoxin at baseline as the proxy for HF
diagnosis. The only current clinical indications for digoxin are AF
and HF; digoxin use has a specificity of approximately 99% and a
sensitivity of approximately 28% for the diagnosis of HF.21
History of Stroke/Transient Ischemic Attack
The Questionnaire for Verifying Stroke-free Status20 contains 8
items. The first 2 items elicit history of physician-verified stroke,
ministroke, or transient ischemic attack (TIA); a positive response on
either of these items indicates a positive stroke/TIA history.
Demographics
Age, sex, race, and region were ascertained by self-report.
Socioeconomic Status
Socioeconomic status was represented by income and education
levels. Annual income was categorized into 3 levels: ⬍$25 000,
ⱖ$25 000, and unreported. Education was categorized into 2 levels:
high school or below and greater than high school.
Blood Pressure and Stroke in Heart Failure
Table 1.
3707
Description of Population Overall and by HF Status
Total
Participants
21 453
Prior stroke/TIA*
1871
No HF,
No. (%)
HF,
No. (%)
21 202
251
1805 (8.5)
66 (26.3)
Race (white)
12 604
12 459 (58.7)
145 (57.7)
Male sex*
10 065
9903 (46.7)
162 (65.5)
Income ⱖ$25 000*
15 056
14 911 (70.3)
145 (57.8)
Current alcohol use*
11 478
11 385 (53.7)
93 (37.1)
Current smoker†
3180
3154 (14.9)
26 (10.4)
Diabetes*
4506
4393 (20.7)
113 (45.1)
12 433
12 ,250 (57.8)
183 (72.9)
4465
4318 (20.4)
147 (58.6)
Hypertension*
Ischemic heart
disease*
Mean age (SD)*
64.5 (⫾9.2) years
70.0 (⫾8.7) years
Mean hemoglobin
(SD)†
13.7 (⫾1.4) g/dL
13.3 (⫾1.6) g/dL
*P⬍0.0001.
†P⬍0.05.
Health Behaviors
Alcohol and smoking histories were defined as follows: alcohol
consumption— dichotomized as current versus previous or no (lifelong abstinence) use; and smoking— current versus never or past
smoker.
Vascular Comorbidities
The following definitions were used: diabetes—fasting glucose
ⱖ126 mL/dL, nonfasting glucose ⱖ200 mL/dL, or self-reported use
of diabetes medications; hypertension—systolic blood pressure
(SBP) ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg
(average of 2 blood pressure measurements), or self-reported use of
hypertension medications; AF— based on electrocardiographic diagnosis or a positive response to the question “Has a doctor or other
health professional ever told you that you had atrial fibrillation?”;
ischemic heart disease, based on self-reported history of myocardial
infarction, coronary bypass, angioplasty, or stenting or based on
electrocardiographic evidence of myocardial infarction; hemoglobin
level was determined from blood assays.
Statistical Methods
Descriptive statistics were computed overall and for those with and
without HF. Logistic regression models were fitted to examine the
relationship between HF and history of stroke/TIA. Incremental
multivariable models were assessed with covariates entered into the
models in groups. Groups of variables are defined as follows:
demographics—age, sex, race, and region; socioeconomic status
factors— education and income; health behaviors—alcohol use and
smoking; and comorbidities— diabetes, hypertension, heart disease,
and hemoglobin. Frequency of stroke/TIA history among those with
and without HF was compared within each tertile of SBP.
The relationship between HF and prior stroke/TIA was examined
as a function of SBP tertile. The tertiles were defined as: t1, SBP
⬍119.5 (n⫽7222); t2, 119.5⬍SBP⬍131.5 (n⫽7896); and t3,
131.5⬍SBP (n⫽8192). After assessing the interaction between SBP
tertile and HF, analyses were stratified by SBP tertile, and the
relationship was examined before and after adjustment for all factors
in the final model. The SBP tertile analysis was repeated using only
subjects with a history of hypertension.
Results
Table 1 presents the description of the population both overall
and by HF status. Of the 30 228 participants recruited to
REGARDS, 223 were excluded due to no information regard-
3708
Stroke
December 2009
Table 2.
Association Between HF and Stroke/TIA
Table 3. Odds of Prior Stroke/TIA for Participants With HF
Compared With Participants Without HF by SBP Tertiles
OR
95% CI
Unadjusted
3.8
2.8 –5.0
Adjusted for demographics (age, sex, race, region)
3.0
2.2–4.0
SBP
Additional adjustment for socioeconomic status
(education, income)
2.8
2.1–3.8
⬍119.5 mm Hg
4.0 (2.8 –5.8)
3.3 (1.6 – 6.5)
ⱖ119.5, ⬍131.5 mm Hg
2.7 (1.8–3.9)
2.0 (0.9–4.6)
ⱖ131.5 mm Hg
2.3 (1.6–3.2)
1.9 (1.0–3.6)
Additional adjustment for health behaviors
(alcohol, smoking)
2.8
Additional adjustment for co morbidities (diabetes,
hypertension, heart disease, hemoglobin)
2.2
2.1–3.7
1.5–3.4
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ing prior stroke, 3691 were excluded due to no reported
income information, an additional 2920 participants were
excluded due to missing one or more covariates, and 1942
participants with AF were excluded. The final sample size for
analysis was 21 453.
Among this community-dwelling cohort, prevalent stroke/
TIA was present in 26.3% and 8.5% of participants with and
without HF, respectively (P⬍0.0001). Table 2 presents the
results of the incremental logistic regression modeling. The
results indicate that the likelihood of prior stroke is higher
among those with HF. This association was attenuated after
multivariable adjustment, but remained significant with an
OR of 2.2 (95% CI, 1.5 to 3.4).
The tertile analysis (Table 3) shows that the odds of
stroke/TIA are higher for participants with HF than without
HF within all SBP tertiles, and the association was strongest
among those in the lowest SBP tertile. Participants with HF
were equally distributed among the 3 tertiles. In the unadjusted model, the probability value for the interaction between HF and tertile of SBP was marginally significant
(0.067). Relative to those without HF, the unadjusted ORs
(95% CI) for prior stroke/TIA among those with HF within
ascending tertiles of SBP were, respectively, 4.0 (2.8 to 5.8),
2.7 (1.8 to 3.9), and 2.3 (1.6 to 3.2), which remained
significant after multivariable adjustment in the lowest tertile
(⬍119.5 mm Hg; 3.3; 1.6 to 6.5). On repeating the analysis
using only subjects with a history of hypertension, the
unadjusted OR (95% CI) for prior stroke/TIA among those
with HF within ascending tertiles of SBP were, respectively,
3.9 (2.0 to 7.4), 2.0 (1.0 to 3.9), and 3.2 (2.0 to 5.1). After
multivariable adjustment, the observed associations were
attenuated, although the relationship remained significant
among participants in the lowest tertile: (OR, 1.27; 95% CI,
1.1 to 6.6).
Discussion
Our findings confirm that after multivariable adjustment, HF
(defined as patients without AF using digoxin), is associated
with an increase in prevalent stroke/TIA. In HF participants,
prior stroke/TIA was present 2.2 times the prevalence in
participants without HF. The frequency of HF in patients with
stroke (14%)22 is higher than in the general population,18 and
patients with HF constitute an important subgroup of patients
with stroke, because they have a poor outcome and high rates
of mortality and stroke recurrence.22 The high prevalence of
stroke/TIA history in participants with HF in our study
(26.3%) may partly be due to the high enrollment rate of
Unadjusted OR
(95% CI) for
Prior Stroke/TIA
Adjusted Multivariable
OR (95% CI) for
Prior Stroke/TIA*
*Adjusted for demographics, socioeconomic status, health behaviors, functional status, and comorbidities.
blacks (who constitute 42% of the REGARDS population).
Blacks have a much higher rate of HF than whites.23 Another
factor is that TIAs were included in our study in addition to
stroke.
The association of stroke/TIA history with lower SBP
raises the possibility that cerebral hypoperfusion could be an
important pathogenetic mechanism for stroke in patients with
HF. Vulnerability of the brain to hypoperfusion in HF is also
supported by a report of increased risk of cognitive impairment15 with lower blood pressures in patients with HF.
Increasing severity of HF and decreasing ejection fraction are
associated with decreased cerebrovascular reactivity24 and
decreased global cerebral blood flow.25 Cerebral infarcts are
larger in patients with left ventricular systolic dysfunction
than in control subjects with normal ejection fraction,26
particularly distal to a high-grade stenosis,27 and focal cerebral hypoperfusion distal to a stenosis could be a mechanism
for an increased prevalence of stroke in patients with HF. The
second SBP tertile analysis we performed using only participants with a history of hypertension is against cerebral
hypoperfusion being an important pathogenetic mechanism in
stroke in HF, however. This analysis showed a lower odds
ratio for stroke in the lowest SBP tertile compared with the
first SBP tertile analysis of participants with both normotensives and hypertensives. Hypertensives have altered cerebrovascular reactivity and require higher SBP to maintain cerebral blood flow than normotensives,28 and this makes them
more vulnerable to hypotension. We would have expected
there would be a higher OR of stroke/TIA in the lowest SBP
tertile in hypertensives than in the population with both
normotensives and hypertensives if the pathogenesis of stroke
in HF was due to cerebral hypoperfusion.
An alternative explanation is that low blood pressure
selects out patients with HF with poor cardiac function and
low cardiac output. These patients may be at increased risk of
intraventricular thrombus formation and cerebral embolism
due to poor function of the left ventricle. This is supported by
the finding that decreasing blood pressure is associated with
increasing mortality in an analysis of pooled HF studies.18
Low blood pressure in these patients is most likely due to
poor cardiac output because its association with decreased
survival is independent of pharmacological treatment.18 This
association of low blood pressure and poor survival in
patients with HF is the opposite to what is seen in the general
population.29 If patients with HF and low SBP are at
increased risk of cardiogenic embolism, anticoagulation treatment has the potential of reducing the risk of stroke in these
Pullicino et al
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patients. This is currently being investigated in the Warfarin
versus Aspirin in Reduced Cardiac Ejection Fraction study.30
This is the first cohort study to show a connection between
lower SBP levels and risk of stroke/TIA in HF. These
cross-sectional results may have potential implications for
management of blood pressure in patients with HF. Pharmacological treatments for HF, including angiotensin-converting
enzyme inhibitors and ␤-blockers, lower the blood pressure.
Reducing SBP to the “lowest level tolerated” has been
recommended in patients with HF.31 If patients with HF are at
risk for hypoperfusion-related cerebral injury, excessive lowering of SBP could increase the risk of stroke, particularly in
patients with prior stroke in whom the risk of stroke recurrence is higher. Further research is needed to determine
whether SBP-lowering in patients with HF may carry a risk of
stroke and, if so, to attempt to determine safe lower limits for
SBP in these patients.
The limitations of this study include its cross-sectional
nature. Because our study was a cross-sectional analysis of a
cohort study, we are unable to establish a time directionality
between onset of HF and of stroke/TIA. It is possible that the
association of lower SBP and prevalent stroke could reflect
more aggressive blood pressure control in participants with
HF after a stroke compared with patients with HF without
stroke. This is unlikely, however, because hypertension is a
risk factor for recurrent stroke and remains elevated after
stroke despite antihypertensive treatment.32 Definitive determination of the directionality of the relationship between HF
or hypotension and stroke will require a longitudinal study
and the ongoing REGARDS and REGARDS-MI studies,
which are tracking incident stroke and cardiac events and
hospitalizations, will provide an appropriate context for such
a study. The basing of diagnosis of HF on digoxin use is also
a limitation of the study. Use of digoxin to diagnose HF may
have resulted in patients with diastolic HF being excluded
from our HF group. Diastolic HF is not an established risk
factor for stroke/TIA and studies reporting HF as a risk factor
for stroke4,5 have not separated HF into systolic and diastolic
groups. Diagnosis of HF by digoxin use has been found to
have a very high specificity but modest sensitivity.21 The low
sensitivity may have biased our results toward the null but is
unlikely to have qualitatively affected our results, because the
prevalence of HF in the general population is only approximately 5% at the mean age of our study participants,33 and
misclassified participants with HF would only constitute a
small minority of our “no HF” group. Exclusion of patients
who were not using digoxin from our HF group is unlikely to
have altered our study results because the rate of stroke is
almost identical in patients with HF using digoxin or not
using digoxin.34 A major strength of this study is the large
cohort size, which has allowed for a statistically robust
analysis in subgroups of SBP tertiles. The large proportion of
black participants in this study is also a strength.
Acknowledgments
We acknowledge the participating investigators and institutions
for their valuable contributions: The University of Alabama at
Birmingham, Birmingham, Ala (study Principal Investigator,
Statistical and Data Coordinating Center, Survey Research Unit):
George Howard, DrPH, Leslie McClure, PhD, Virginia Howard,
Blood Pressure and Stroke in Heart Failure
3709
PhD, Libby Wagner, MA, Virginia Wadley, PhD, Rodney Go, PhD,
Monika Safford, MD, Ella Temple, PhD, Margaret Stewart, MSPH,
and David Rhodes, RN; University of Vermont (Central Laboratory):
Mary Cushman, MD; Wake Forest University (ECG Reading Center): Ron Prineas, MD, PhD; Alabama Neurological Institute (Stroke
Validation Center, Medical Monitoring): Camilo Gomez, MD, and
Susana Bowling, MD; University of Arkansas for Medical Sciences
(Survey Methodology): LeaVonne Pulley, PhD; University of Cincinnati (Clinical Neuroepidemiology): Brett Kissela, MD, and Dawn
Kleindorfer, MD; Examination Management Services, Inc (in-person
visits): Andra Graham; Medical University of South Carolina (Migration Analysis Center): Daniel Lackland, DrPH; Indiana University School of Medicine (Neuropsychology Center): Frederick Unverzagt, PhD; National Institute of Neurological Disorders and
Stroke, National Institutes of Health (funding agency): Claudia
Moy, PhD.
Source of Funding
The REGARDS research project is supported by a cooperative
agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department
of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official
views of the National Institute of Neurological Disorders and Stroke
or the National Institutes of Health. Representatives of the funding
agency have been involved in the review of the article but not
directly involved in the collection, management, analysis, or interpretation of the data. Additional partial funding was provided by an
investigator-initiated grant-in-aid from Amgen Corporation. Amgen
did not have any role in the design and conduct of the study; the
collection, management, analysis, and interpretation of the data; or
the preparation or approval of the manuscript.
Disclosures
None.
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Stroke. 2009;40:3706-3710; originally published online October 15, 2009;
doi: 10.1161/STROKEAHA.109.561670
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