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Antihypertensive Drug Therapies and the Risk of Ischemic Stroke
Olaf H. Klungel, PharmD, PhD;
Susan R. Heckbert, MD, PhD;
W. T. Longstreth, Jr, MD, MPH;
Curt D. Furberg, MD, PhD;
Robert C. Kaplan, MS, PhD;
Nicholas L. Smith, MPH, PhD;
Rozenn N. Lemaitre, MPH, PhD;
Hubert G. M. Leufkens, PharmD, PhD;
Anthonius de Boer, MD, PhD;
Bruce M. Psaty, MD, PhD
Arch Intern Med. 2001;161:37-43.
ABSTRACT
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Background The relative effectiveness of various antihypertensive drugs with regard
to the reduction of stroke incidence remains uncertain.
Objective To assess the association between first ischemic stroke and use of antihypertensive
drugs.
Methods A population-based case-control study was performed among enrollees
of the Group Health Cooperative of Puget Sound. Case patients included pharmacologically
treated hypertensive patients who sustained a first ischemic stroke (fatal
or nonfatal; n = 380) between July 1, 1989, and December 31, 1996. Control
subjects were a random sample of treated hypertensive enrollees without a
history of a stroke (n = 2790). Medical record review and a telephone interview
of consenting survivors were used to collect information on risk factors for
stroke. Computerized pharmacy records were used to assess antihypertensive
drug use.
Results Among 1237 single-drug users with no history of cardiovascular disease,
the adjusted risk of ischemic stroke was higher among users of a ß-blocker
(risk ratio [RR], 2.03; 95% confidence interval [CI], 1.05-3.94), calcium
channel blocker (RR, 2.30; 95% CI, 1.16-4.56), or angiotensin-converting enzyme
inhibitor (RR, 2.79; 95% CI, 1.47-5.27) than among users of a thiazide diuretic
alone. Among 673 single-drug users with a history of cardiovascular disease,
the RRs were 1.22 (95% CI, 0.63-2.35), 1.18 (95% CI, 0.59-2.33), and 1.45
(95% CI, 0.70-3.02) among users of a ß-blocker, calcium channel blocker,
and angiotensin-converting enzyme inhibitor, respectively, compared with users
of a thiazide diuretic alone.
Conclusions In this study of pharmacologically treated hypertensive patients, antihypertensive
drug regimens that did not include a thiazide diuretic were associated with
an increased risk of ischemic stroke compared with regimens that did include
a thiazide. These results support the use of thiazide diuretics as first-line
antihypertensive agents.
INTRODUCTION
THE PRIMARY purpose of the pharmacological treatment of hypertension
is to prevent major cardiovascular complications such as stroke. The 4 most
widely used antihypertensive drug classes include diuretics, ß-blockers,
calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors.
Randomized clinical trials (RCTs) have not demonstrated major differences
between these antihypertensive drug classes with regard to lowering of blood
pressure,1, 2, 3, 4
quality of life,3, 5 or regression
of left ventricular mass.6, 7, 8
Results of recent meta-analyses of antihypertensive drug treatment compared
with placebo suggest that low-dose diuretic therapy is effective in reducing
the risk of stroke, coronary heart disease, congestive heart failure, and
total mortality, whereas ß-blockers prevent stroke and congestive heart
failure but seem less effective in preventing coronary heart disease,9 especially in the elderly.10
The Systolic Hypertension in Europe Trial has demonstrated that compared with
placebo, the calcium channel blocker nitrendipine reduces the incidence of
stroke in older adults with isolated systolic hypertension.11
These findings from placebo-controlled trials suggest that ß-blockers,
diuretics, and calcium channel blockers are more effective than placebo in
the primary prevention of stroke. Less consistent are the findings from individual
RCTs with separate treatment arms for ß-blockers and diuretics.12, 13, 14, 15 Although
findings from the International Prospective Primary Prevention Study in Hypertension
trial14 suggested similar reductions in stroke
incidence with ß-blockers and diuretics, the Heart Attack Primary Prevention
in Hypertension (HAPPHY)15 and the Medical
Research Council trials12, 13 observed
a larger reduction of stroke incidence with diuretic therapy than ß-blocker
therapy. The Captopril Prevention Project trial16
reported an increased risk of stroke in subjects receiving captopril compared
with ß-blockers or diuretics. However, the recently completed Swedish
Trial in Old Patients with Hypertension-2 Study17
demonstrated that in hypertensive patients older than 70 years, calcium antagonists
and ACE inhibitors apparently did not differ from conventional therapy (ß-blockers
or diuretics) with regard to the reduction of the incidence of cardiovascular
morbidity and mortality, including stroke. The Captopril Prevention Project
and the Swedish Trial in Old Patients with Hypertension-2 trials were not
designed to distinguish between ß-blockers and diuretics.
To assess the association between antihypertensive drug therapy and
incident ischemic stroke, we conducted a population-based case-control study
among pharmacologically treated hypertensive patients.
SUBJECTS AND METHODS
SETTING
The setting was the Group Health Cooperative of Puget Sound (GHC), a
large staff-model health maintenance organization with more than 400 000
members in western Washington State.
SUBJECTS
Case patients included GHC enrollees, aged 30 to 79 years, who were
treated pharmacologically for hypertension and who sustained an incident fatal
or nonfatal ischemic stroke between July 1, 1989, and December 31, 1996. Potential
ischemic stroke cases were identified from computerized GHC hospital discharge
diagnoses, Washington State death files, and the billing records for GHC enrollees
who received medical care or services from non-GHC providers. Diagnostic criteria
for ischemic stroke were adopted from the Cardiovascular Health Study.18 These criteria included (1) rapid onset of neurologic
deficit or subarachnoid hemorrhage, (2) deficit persisting for longer than
24 hours unless computed tomography or magnetic resonance imaging show evidence
of permanent damage, and (3) no underlying brain trauma, tumor, or infection
to cause symptoms. Control subjects were obtained from a companion study of
risk factors for myocardial infarction at GHC.19
Controls were a randomly selected sample of these GHC enrollees who were treated
pharmacologically for hypertension and were frequency matched to the myocardial
infarction cases by sex, age (within decade), and calendar year.
Each subject was assigned an index date. For the cases, the index date
was the date of the stroke; for controls, the index date was a randomly selected
date within the calendar year for which they had been selected as controls.
In most strata based on sex, 10-year age categories, and index year, the control-case
ratio was larger than 3:1. We excluded cases and controls (1) who were enrollees
for less than 1 year or who had fewer than 4 visits before their index dates,
(2) who had had a previous stroke, (3) who had a diagnosis of congestive heart
failure, (4) who did not have a diagnosis of hypertension in their medical
record, and (5) whose stroke was a complication of a procedure or surgery.
A history of stroke was assessed by medical record review. Subjects with a
history of congestive heart failure were excluded because of concern about
confounding by the indication of congestive heart failure for ACE inhibitors.
DATA COLLECTION AND DEFINITIONS
Information on demographics, health habits, cardiovascular risk factors,
and comorbidities were abstracted from medical records or obtained from a
telephone interview of consenting survivors. Abstraction of the information
from the medical records was performed by trained research assistants who
were aware of case-control status but unaware of the purpose of the study.
The GHC computerized pharmacy database was used to assess antihypertensive
drug use. The pharmacy records contain information about the type, dose, and
quantity of drug dispensed; the prescription fill date; and dosing instructions.
When dosing instructions were missing from the pharmacy database, we used
the instructions available in the medical record. The pharmacy data were searched
for antihypertensive drug prescriptions immediately preceding the index date.
When a subject who was assumed to be at least 80% compliant received enough
pills to last until the index date, that person was classified as a potential
current user on that date. This process was repeated to assess use at 30 and
60 days before the index date. A current user of antihypertensive drugs was
defined as a user for at least 30 days before and on the index date. This
definition excludes recent starters or switchers of antihypertensive drug
therapies, whose drug course was first prescribed or changed within 30 days
of the index date.
A subject was considered pharmacologically treated for hypertension
when a recording of antihypertensive drug use for the indication of hypertension
was present in the medical records and when the subject was classified as
a current antihypertensive drug user at the index date according to data available
in the computerized pharmacy database.
STATISTICAL ANALYSES
Complete data were uniformly available from the medical records for
case-control status and medical conditions such as pharmacological treatment
of hypertension, angina, and diabetes. In preliminary analysis of demographic
and behavioral risk factor data, such as smoking, physical activity, race,
marital status, and educational level, the agreement between medical record
and self-reported measures (telephone interview) was good to excellent. Self-reported
data, if available, were used for these variables; if not, then data from
the medical record were used. Data were missing on smoking (1.1% of subjects),
physical activity (8.0%), race (2.4%), educational level (27.0%), total cholesterol
level (4.8%), duration of treatment for hypertension (10.5%), and pretreatment
blood pressure (30.1%). We used an approximate Bayesian bootstrap method to
impute missing values. This multiple imputation method is a modification of
the hot-deck method and takes account of the imputation variability.20 In sensitivity analysis, the results using multiple
imputed data were similar to those in the analysis limited to subjects with
complete data.
All statistical tests were 2-tailed. We used stratification and logistic
regression to control for potential confounders of the association between
antihypertensive drug therapy and ischemic stroke, and odds ratios to estimate
the relative risk (RR). Data were analyzed using commercially available software
(SAS, Version 6.12; SAS Institute, Cary, NC).
The association of ischemic stroke with antihypertensive drug therapies
was assessed separately for subjects with and without clinical cardiovascular
disease (CVD). We defined CVD as possible, probable, or definite diagnoses
of angina, claudication, cardiac arrhythmias (including atrial or ventricular
arrhythmia) or history of myocardial infarction, transient ischemic attack,
coronary angioplasty, coronary bypass surgery, or carotid endarterectomy.
First, we compared single-drug users of one of the major antihypertensive
drug classes and users of major 2-drug combinations, with single-drug users
of benzothiadiazide (thiazide) diuretics as the reference group. Second, we
compared antihypertensive drug regimens that did not include a thiazide diuretic
with regimens that included a thiazide diuretic, among single-drug users and
users of 2 antihypertensive drugs from different drug classes.
RESULTS
During the study period, 611 treated hypertensive patients were hospitalized
for or died out of the hospital of a first ischemic stroke. We also identified
3505 population-based controls who were eligible. We excluded 92 cases and
199 controls with congestive heart failure, 113 cases and 453 controls who
were not sufficiently compliant with their antihypertensive drug regimens
to be classified as current users, and 66 cases and 181 controls who recently
started or switched any antihypertensive drug therapy. In total, 231 cases
and 715 controls were excluded for 1 or more of these reasons. We included
380 ischemic stroke cases (21 fatal and 359 nonfatal) and 2790 controls who
were treated pharmacologically for hypertension.
The clinical characteristics of cases and controls are summarized in Table 1. Compared with controls, cases
were older and more likely to be men and had a higher systolic blood pressure
at treatment and before treatment. A number of risk factors for ischemic stroke
were more common among cases than controls.
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Table 1. Characteristics of Ischemic Stroke Cases and Controls*
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Because of concern about confounding by indication, we compared characteristics
of controls who were users of thiazide diuretics with controls who used other
antihypertensive drugs separately for subjects with and without a history
of CVD (Table 2). Among controls
with no history of CVD, users of thiazide diuretics were slightly older and
had a slightly longer history of treated hypertension, and fewer had diabetes
than users of nonthiazides. Other risk factors for stroke were similar for
users of thiazide diuretics compared with users of other antihypertensive
drugs. Among control subjects with a history of CVD, users of thiazide diuretics
were slightly younger, had a lower treated systolic blood pressure, and were
less likely to have diabetes, angina, or a history of cardiovascular procedures
than users of an antihypertensive drug regimen that did not include a thiazide
diuretic.
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Table 2. Characteristics of Users of Thiazide Diuretics Compared With
Users of Other Antihypertensive Drugs*
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STROKE RISK ASSOCIATED WITH INDIVIDUAL ANTIHYPERTENSIVE DRUG CLASSES
VS THIAZIDE DIURETICS ALONE
Among 127 cases and 1566 controls free of CVD, the adjusted risk of
ischemic stroke was 2.03- to 2.79-fold higher among users of single-drug therapy
with ß-blockers, calcium channel blockers, or ACE inhibitors than among
users of a thiazide diuretic alone (Table
3). The use of ß-blockers, calcium channel blockers, or ACE
inhibitors in combination with a thiazide diuretic was not significantly associated
with an increased risk of ischemic stroke compared with the use of a thiazide
diuretic alone. The use of any 2 antihypertensive drugs not including a thiazide
diuretic was associated with a 2.48-fold increase in the risk of ischemic
stroke compared with the use of a thiazide diuretic alone. Among 186 cases
and 912 controls with a history of CVD, the use of calcium channel blockers
in combination with a thiazide diuretic or a nonthiazide 2-drug combination
were each associated with an increased risk of ischemic stroke, compared with
users of thiazide diuretics alone (Table
3). Use of other single antihypertensive drugs or 2-drug combinations,
compared with the use of thiazide diuretics alone, was not significantly associated
with an increased risk of ischemic stroke.
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Table 3. Adjusted Association Between Ischemic Stroke and Antihypertensive
Drug Therapies*
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STROKE RISK ASSOCIATED WITH NONTHIAZIDE ANTIHYPERTENSIVE DRUGS VS THIAZIDE
DIURETICS
The second analysis was conducted among 348 cases and 2608 controls
who used 1 or 2 antihypertensive drugs (Table 4). Among 142 cases and 1652 controls free of CVD, subjects
who did not use a thiazide diuretic had, after adjustment for potential confounding
factors, an increased risk of ischemic stroke compared with subjects who used
a thiazide diuretic (RR, 1.85; 95% confidence interval [CI], 1.26-2.71). Among
subjects with a history of clinical CVD who did not use a thiazide diuretic,
the increased adjusted risk of ischemic stroke compared with users of thiazide
diuretics was not statistically significant (RR, 1.25; 95% CI, 0.87-1.80).
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Table 4. Adjusted Association Between Ischemic Stroke and Thiazide
Diuretic Therapy for Hypertension*
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Additional adjustment for educational level, marital status, duration
of treated hypertension, treated diastolic blood pressure, pretreatment diastolic
blood pressure, body mass index (calculated as weight in kilograms divided
by the square of height in meters, physical activity, glucose and potassium
levels, and use of alcohol had trivial effects on the findings.
Stratified analysis revealed no effect modification of the association
between ischemic stroke and use of thiazide diuretics in subgroups based on
sex, median age (70 years), presence of diabetes, smoking status, median pretreatment
blood pressure (diastolic, 100 mm Hg; systolic, 170 mm Hg), median treated
blood pressure (diastolic, 84 mm Hg; systolic, 152 mm Hg), median total serum
cholesterol level (6.16 mmol/L [238 mg/dL]), and median serum potassium level
(4.1 mmol/L). The results were virtually the same for the use of thiazide
diuretics below the daily modal dose and above or at the daily modal dose
(25 mg for hydrochlorothiazide, 25 mg for chlorthalidone, and 5 mg for metolazone)
and for the use of thiazide diuretics alone or in combination with potassium-sparing
agents.
COMMENT
In this population-based case-control study among pharmacologically
treated hypertensive patients without clinically recognized CVD, the use of
antihypertensive drug regimens that did not include a thiazide diuretic was
associated with an 85% increased risk of ischemic stroke compared with the
use of an antihypertensive drug regimen that included a thiazide diuretic.
Even among users of 2 antihypertensive drugs, the use of nonthiazide antihypertensive
drug regimens was associated with a higher risk of ischemic stroke (40%).
This association persisted after adjustment for many potential confounding
factors, and was consistent across a variety of subgroups. Among subjects
with clinically manifest CVD, this association was less pronounced.
The International Prospective Primary Prevention Study in Hypertension
trial, in which ß-blocker therapy was compared with non–ß-blocker
(mostly diuretic) therapy, showed no significant difference in stroke incidence
between the treatment groups (RR, 0.97; 95% CI, 0.64-1.47). However, this
trial may not allow a valid comparison of stroke risk because 67% of the patients
allocated to ß-blocker therapy also received a diuretic. The HAPPHY trial
found a nonsignificantly higher risk of stroke for ß-blockers compared
with diuretics (RR, 1.29; 95% CI, 0.84-1.83). Findings from the Medical Research
Council trials clearly suggest a higher risk of stroke with ß-blocker
therapy than with diuretic therapy in middle-aged subjects (RR, 2.28; 95%
CI, 1.31-3.96),12 and a nonsignificantly higher
risk in older subjects (RR, 1.23; 95% CI, 0.86-1.79).13
Results from the Captopril Prevention Project trial showed an increased risk
of stroke with captopril therapy compared with ß-blocker or diuretic
therapy (RR, 1.25; 95% CI, 1.01-1.55). This increased risk of stroke may have
been due to a failure of randomization.21 In
a clinical trial designed to assess the effects of antihypertensive therapy
on carotid atherosclerosis,22 subjects randomized
to receive the calcium channel blocker isradipine had a higher rate of stroke
events than those randomized to receive hydrochlorothiazide (RR, 2.00; 95%
CI, 0.50-7.93). In the Swedish Trial in Old Patients with Hypertension-2 trial,
subjects allocated to receive ACE inhibitors and calcium antagonists, respectively,
had a similar risk of stroke compared with subjects allocated to receive ß-blocker
or diuretic therapy (respective RRs, 0.90 [95% CI, 0.74-1.08] and 0.88 [95%
CI, 0.73-1.06]). These findings from RCTs tend to favor thiazide diuretics
over other antihypertensive drug therapies for reduction of stroke risk and
are consistent with the findings from our study. Additional support for a
particular benefit of thiazide diuretics comes from the recent interim analysis
of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial.23 Compared with patients who received
chlorthalidone, patients treated with the  -blocker doxazosin mesylate
had an increased risk of stroke (RR, 1.19; 95% CI, 1.01-1.40).
One possible explanation for these findings may lie in the fact that
systolic blood pressure is more strongly associated with the occurrence of
stroke than diastolic blood pressure,24 and
that thiazide diuretics may be more effective in lowering systolic blood pressure
than other antihypertensive drugs, whereas the effect of thiazide diuretics
on diastolic blood pressure is similar to that of other major antihypertensive
drug classes.3, 4, 12, 13, 16, 22, 23
Systolic blood pressure during treatment was also slightly lower among users
of thiazide diuretics in this study. Adjustment for systolic blood pressure
during treatment had little effect on our results. For example, among those
receiving monotherapy, the risk of ischemic stroke associated with not using
compared with using a thiazide diuretic decreased from 2.42 to 2.30. However,
we were not able to test this hypothesis adequately, because many of the current
users of thiazide diuretics were not using a thiazide diuretic at the time
when their blood pressure during treatment was recorded.
A biological mechanism independent of blood pressure cannot be excluded,
as suggested by a post hoc analysis of the Swedish Trial in Old Patients with
Hypertension trial in which two thirds of the actively treated patients received
a ß-blocker and a thiazide diuretic.25
After matching on achieved blood pressure and controlling for initial blood
pressure, the subjects receiving active treatment had a 42% decreased risk
of stroke compared with those receiving placebo (RR, 0.58; 95% CI, 0.35-0.98),
suggesting a non–blood pressure mediated benefit of antihypertensive
therapy with ß-blockers or diuretics beyond that achieved by merely lowering
blood pressure. Moreover, recently it was demonstrated that diuretics may
have an additional therapeutic advantage by restoring nocturnal blood pressure
decline in patients with sodium-sensitive hypertension.26
The strengths of this observational study are the use of population-based
case-control subjects, the completeness of case identification, the comparable
ascertainment of potential confounding factors, and the use of pharmacy records
to assess antihypertensive drug use in a comparable and unbiased fashion for
cases and controls. We used restriction, stratification, and multivariate
adjustment to minimize the influence of confounding.
An important limitation of this observational study is that antihypertensive
drug treatment was not randomly assigned. Physicians and patients selected
antihypertensive drug therapies, and this may have introduced bias. Despite
adjustment for potential confounding factors, residual confounding due to
incomplete or inaccurate measurement of covariates or unmeasured confounders
cannot be excluded.
The preferred design to compare these antihypertensive drug therapies
in terms of their risk or benefit with regard to cardiovascular outcomes is
the controlled RCT. However, when clinical trial results are lacking or conflicting,
well-designed observational studies can complement them. Furthermore, the
highly selected nature of participants of RCTs and the strict, protocol-driven
conditions under which trials are conducted may limit the generalizability
of findings from RCTs to general practice. The common use of a large number
of alternative antihypertensive drugs makes evaluation of these therapies
in an observational setting feasible. The high degree of similarity in several
important clinical characteristics between users of thiazide diuretics and
users of other antihypertensive drugs among subjects without CVD suggests
minimal confounding by those characteristics that were measurable.
CONCLUSIONS
This study suggests a particular benefit of thiazide diuretics in reducing
the risk of ischemic stroke. Although the mechanism is not clear, the findings
are consistent with those of previous RCTs. Ongoing large-scale clinical trials
should help clarify this issue.27 The Sixth
Report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure currently recommends diuretics and ß-blockers.28 In the absence of additional clinical trial evidence,
the results of our study support the use of thiazide diuretics as first-line
antihypertensive agents.
AUTHOR INFORMATION
Accepted for publication July 10, 2000.
The research reported in this article was supported in part by grants
HL40628, HL43201, and HL60739 from the National Heart, Lung, and Blood Institute,
Bethesda, Md. Dr Psaty is a Merck/SER Clinical Epidemiology Fellow, sponsored
by the Merck Co Foundation, Rahway, NJ, and the Society for Epidemiologic
Research, Baltimore, Md. Dr Kaplan was a Howard Hughes Medical Institute Predoctoral
Fellow when this work was conducted.
From the Cardiovascular Health Research Unit, Departments of Epidemiology
(Drs Klungel, Heckbert, Longstreth, Kaplan, Smith, and Psaty), Medicine (Drs
Longstreth, Lemaitre, and Psaty), Neurology (Dr Longstreth), and Health Services
(Dr Psaty), University of Washington, Seattle; the Department of Pharmacoepidemiology
and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht,
the Netherlands (Drs Klungel, Leufkens, and de Boer); and the Department of
Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem,
NC (Dr Furberg).
Corresponding author and reprints: Olaf H. Klungel, PharmD, PhD,
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute
of Pharmaceutical Sciences, Sorbonnelann 16, 3584 CA Utrecht, the Netherlands
(e-mail: o.h.klungel{at}pharm.uu.nl).
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