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(Stroke. 1999;30:1223-1229.)
© 1999 American Heart Association, Inc.
Original Contributions |
Factors Associated With Ischemic Stroke During Aspirin Therapy in Atrial Fibrillation
Analysis of 2012 Participants in the SPAF I–III Clinical Trials
From the University of Texas Health Science Center, San Antonio (R.G.H.); Statistics and Epidemiology Research Corporation, Seattle, Wash (L.A.P., R. McB.); LeBauer Cardiology Associates, Greensboro, NC (R.M.R.); and Hennepin County Medical Center, Minneapolis, Minn (R.W.A.), on behalf of the Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.
Correspondence to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284. E-mail HartR{at}uthscsa.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, but the absolute rate of stroke varies widely among AF patients, importantly influencing the potential benefit of antithrombotic prophylaxis. We explore factors associated with ischemic stroke in AF patients taking aspirin.
Methods—We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I–III trials followed for a mean of 2.0 years, during which 130 ischemic strokes were observed.
Results—Age (relative risk [RR]=1.8 per decade,
P<0.001), female sex (RR=1.6,
P=0.01), history of hypertension (RR=2.0,
P<0.001), systolic blood pressure >160
mm Hg (RR=2.3, P<0.001), and prior stroke or transient
ischemic attack (RR=2.9, P<0.001) were
independently associated with increased stroke risk. Regular
consumption of 
14 alcohol-containing drinks per week was associated
with reduced stroke risk (adjusted RR=0.4, P=0.04).
Among SPAF III participants, estrogen hormone replacement therapy was
associated with a higher risk of ischemic stroke (adjusted
RR=3.2, P=0.007). With the use of these variables, a
risk stratification scheme for primary prevention separated
participants into those with high (7.1%/y, 22% of the cohort),
moderate (2.6%/y, 37% of the cohort), and low (0.9%/y, 41% of the
cohort) rates of stroke. Ischemic strokes in low-risk
participants were less often disabling (P<0.001).
Conclusions—Patients with AF who have high and low rates of stroke during treatment with aspirin can be identified. However, validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management. Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF, but these findings require confirmation.
Key Words: atrial fibrillation • cerebral embolism • estrogens • risk factors • stroke prevention
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Atrial fibrillation (AF) is associated with a substantially increased risk of stroke, and treatment with adjusted-dose warfarin is highly efficacious for stroke prevention.1 The absolute rate of stroke varies widely according to age and the presence of coexistent vascular disease. AF patients with the highest absolute rates of stroke have the greatest magnitude of stroke reduction by warfarin,2 while AF patients with low stroke rates may not benefit substantially from lifelong anticoagulation.3 Hence, accurate estimate of the inherent stroke risk is an important component of the antithrombotic management of AF patients.
Factors associated with stroke among participants in the Stroke Prevention in Atrial Fibrillation (SPAF) I and II trials who received placebo4 5 or aspirin6 have been reported previously. Here, we pool participants from these trials with those from the recently completed SPAF III trial to explore factors associated with ischemic stroke in a large cohort of AF patients given aspirin alone or combined with low, inefficacious doses of warfarin. A risk stratification scheme is derived from factors independently associated with stroke and focuses on primary prevention, since the high rate of stroke associated with previous stroke or transient ischemic attack (TIA) is well documented.2 7 8
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The design, participant features, and main results of the SPAF I, II, and III trials have been reported.2 3 9 10 11 12 In brief, participants were adults with documented sustained or recurrent AF without mitral stenosis or prosthetic cardiac valves who were recruited from inpatient and outpatient facilities at 25 clinical sites. These analyses included participants assigned to aspirin 325 mg/d (enteric-coated). In addition, 290 participants in the SPAF III randomized trial who were assigned to aspirin plus fixed, low-dose warfarin (mean daily dose=2.1 mg) and whose international normalized ratios (INRs) during follow-up were
1.4 were also
included.2 This latter group was included because INRs
<1.5 have been shown to have no substantial effect on stroke
prevention in AF,2 13 14 and these high-risk participants
were observed to have a stroke rate of 12.3%/y, similar to that
expected during treatment with aspirin alone.6 Those with
"lone" AF (ie, no associated cardiovascular
disease) aged <60 years were excluded. Participants from SPAF I
(n=521, 1985–1989), SPAF II (n=309, 1989–1992), and SPAF III (n=1182,
1993–1997) constituted the study population. At study entry, all participants were assessed by physician investigators, coexistent illnesses were recorded with the use of specific definitions, and precordial echocardiography was performed.9 Echocardiograms were interpreted locally by cardiologists using standard criteria, as reported previously.5 Participants were followed every 3 to 6 months in the clinic to assess compliance and to detect strokes. Stroke events were verified and categorized as probably cardioembolic, probably noncardioembolic, or of uncertain cause by a central events committee who were unaware of treatment, using a clinical classification scheme.15 Neuroimaging or autopsy was used to categorize strokes as ischemic versus hemorrhagic in 94%. Disabling strokes were conservatively defined as those with Rankin scores of II (impairing lifestyle) or more, assessed 1 to 3 months later, while fatal stroke resulted in death within 30 days. For this analysis, participant follow-up was censored at the time of first ischemic stroke (ie, only 1 stroke per participant during follow-up was counted).
The following variables were initially considered in exploratory
analyses, selected by the investigators on the basis of
hypothetical links to stroke risk: age, sex, race, current tobacco
smoker, ethanol consumption, prior stroke or TIA, history of
hypertension, systolic (continuous and >160 mm Hg) and
diastolic blood pressures at entry, diabetes mellitus,
history of heart failure, recent (within 100 days) heart failure,
intermittent AF, onset of AF within 1 year, prior myocardial
infarction, any ischemic heart disease, ventricular
rate, peripheral vascular disease, prior carotid
endarterectomy or cervical bruit, pulse pressure,
use of specific classes of medications (diuretics,
ß-blockers, insulin), and random serum cholesterol.
Echocardiographic variables were left atrial
diameter, left ventricular end-systolic and
-diastolic dimensions, fractional shortening (continuous
and 25%), mitral annular calcification (any and moderate to severe
involving >30% of the annulus), severe mitral
regurgitation,16 qualitative abnormalities
of left ventricular wall motion on 2-dimensional
echocardiographic images,5 and left
ventricular mass and mass index. Estrogen hormone
replacement therapy and severity of hypertension were recorded only
for SPAF III participants at entry.
Hypertension was diagnosed if blood pressures were either >160
mm Hg systolic or >90 mm Hg diastolic on
repeated observations over 3 months or by use of long-term
antihypertensive therapy if pretreatment blood pressure measurements
were not available.3 In SPAF III participants,
hypertension was categorized as moderate to severe if
diastolic blood pressure were consistently
>100 mm Hg or multiple antihypertensive medications were
prescribed. Systolic blood pressure >160 mm Hg was
defined by taking 2 blood pressure measurements on separate days, with
1 systolic blood pressure >160 mm Hg and either the
other >150 mm Hg or a documented systolic blood pressure
measurement >160 mm Hg in the prior 3 months.9
Distributions of baseline characteristics were compared between groups
with the use of Student's t test for continuous
variables and a 
2 test for categorical
variables (Fisher's exact test if any expected cell count was
<5). The univariate association of ischemic stroke
with a variable was estimated with a Cox proportional hazards
model, with statistical significance determined by the likelihood ratio
statistic. Factors independently associated with stroke were identified
with forward stepwise Cox proportional hazards modeling techniques
(likelihood ratio test) and combined by inspection to yield a risk
stratification scheme. Stroke rates were calculated with person-years
as the denominator, with 95% CIs computed by the Poisson distribution.
Stroke rates were compared between groups with the use of a Poisson
regression model (likelihood ratio statistic). All tests were 2-sided,
and statistical significance was accepted at the 0.05 level, with no
adjustment made for multiple comparisons. Analyses were
performed with SPSS/PC for Windows and EGRET statistical software.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the SPAF I–III trials, 1722 participants were assigned aspirin, and an additional 290 were given aspirin plus fixed, low-dose warfarin without substantial prolongation of their INR (mean INR=1.1 during follow-up). Of these 2012 participants, the mean age was 69±10 years, 28% were women, 27% had intermittent AF, and 52%, 9%, 15%, and 8% had histories of hypertension, myocardial infarction, diabetes, and prior stroke or TIA, respectively (Table 1
). A history of clinical
congestive heart failure was present in 19%, and fractional
shortening by echocardiography was <25% in 12%
of participants. Mean follow-up was 2.0 years (range, 2 days to 5.3
years). During a total observation of 3977 patient-years, 130
ischemic and 10 hemorrhagic (5 intraparenchymal, 4 subdural,
and 1 subarachnoid) strokes occurred. Of the ischemic
strokes, 55% (n=71) were classified as probably cardioembolic, 18%
(n=24) as probably noncardioembolic, and the remainder as of uncertain
cause. Nearly two thirds (62%) of ischemic strokes were
disabling or fatal.
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Factors Associated With Ischemic Stroke: Univariate
Comparisons
The annualized rate of ischemic stroke was 3.3%/y (95%
CI, 2.8 to 3.9) and was higher in those with prior stroke or TIA
(n=159; stroke rate=13.0%/y) versus other participants (n=1853; stroke
rate=2.7%/y; P<0.001). When we excluded those with prior
stroke or TIA, the stroke rate in elderly (ie, aged >75 years) women
was substantially higher than that of elderly men (9.7%/y versus
3.2%/y, respectively; P<0.001; Table 2). When we considered all 2012
participants, alcohol use (number of drinks per week) was inversely
related to stroke: none=3.8%/y; 1 to 6 per week=3.0%/y; 7 to 13 per
week=2.6%/y; and 14 per week=1.1%/y (P=0.02). Other
features strongly (P<0.001) associated with stroke by
univariate analysis were increased age,
hypertension (particularly systolic blood pressure), left
ventricular mass index, and left ventricular
diastolic dimension (Table 1
.) Stroke was not
significantly associated with a recent history of heart failure
(relative risk [RR]=1.7, P=0.09), fractional shortening
dichotomized at 25% (RR=1.2, P=0.6) or considered as a
continuous variable (P=0.9), or moderate to severe left
ventricular dysfunction assessed qualitatively by
2-dimensional imaging (RR=1.2, P=0.5), and these
associations were not altered by exclusion of those receiving fixed,
low-dose warfarin.
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Factors Independently Associated With Ischemic Stroke
Six features were significantly and independently associated with
ischemic stroke by multivariate
analysis (Table 3). Prior stroke
or TIA was a powerful independent associate (RR=2.9,
P<0.001). To characterize factors independently associated
with stroke among participants without prior stroke or TIA (ie, for
primary prevention), a separate multivariate
analysis excluding the 159 participants with prior stroke or
TIA was performed, with similar findings (Table 3). Consumption
of 14 alcohol-containing drinks per week was associated with a
reduced risk of ischemic stroke (Table 3). This effect
was not significant with consumption of 7 to 13 drinks per week
(adjusted RR=0.8, P=0.6 compared with nonconsumers). Left
ventricular dysfunction, measured in several ways, was not
independently associated with stroke in these models.
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Two additional variables were collected only in SPAF III
participants and were additional independent associates of stroke in
participants without prior stroke or TIA (n=1073). After adjustment for
other factors independently associated with stroke, including a history
of hypertension (Table 3), severity of hypertension provided
additional information (P=0.04). Compared with those without
hypertension, participants with moderate to severe hypertension had a
relative risk of 4.8 (P<0.001), whereas those with
hypertension categorized as borderline or mild had a relative risk of
2.3 (P=0.02). The one third of women who used estrogen
hormone replacement therapy at SPAF III entry (n=90; mean age, 66
years; 9 ischemic strokes) were on average younger
(P<0.001) than those who did not (n=184; mean age, 71
years; 6 ischemic strokes). Estrogen hormone replacement
therapy was associated with higher rates of ischemic stroke
after adjustment for other independent associates (RR=3.2,
P=0.007). The increased risk associated with hormone
replacement therapy was similar for those receiving estrogen alone
(n=68) versus estrogen plus progesterone combinations (n=19).
Significant independent associates of disabling/fatal ischemic strokes were similar: prior stroke or TIA (RR=2.9, P<0.001), systolic blood pressure >160 mm Hg (RR=2.3, P=0.004), age (RR=2.0 per decade, P<0.001), history of hypertension (RR=1.8, P=0.02), and female sex (RR=1.8, P=0.03). In addition, diabetes (RR=1.9, P=0.02) was also independently associated with disabling/fatal stroke.
Stratification of Stroke Risk
With the use of factors independently associated with
ischemic stroke and disabling/fatal ischemic stroke, a
risk stratification scheme was generated for participants without prior
stroke or TIA (ie, for primary prevention) (Table 4). For this scheme, the novel
association of alcohol use 14 drinks per week with reduced stroke was
not considered, nor was the severity of hypertension or hormone
replacement therapy, about which information was available only for
SPAF III participants. Participants categorized as low versus moderate
versus high risk had significantly different rates of ischemic
stroke (0.9%/y, 2.6%/y, 7.1%/y, respectively, P<0.001)
and disabling/fatal ischemic stroke (0.3%/y, 1.6%/y, 5.2%/,
respectively, P<0.001) (Table 4, Figure 1). Forty-one percent (n=763) were
categorized as low risk and had an observed stroke rate of 0.9%/y
(95% CI, 0.6 to 1.6) and a rate of disabling/fatal stroke of 0.3%/y
(95% CI, 0.1 to 0.8) (Figure 2). The
fractions of ischemic strokes categorized as disabling/fatal
were 72%, 60%, and 33% of high-, moderate-, and low-risk patients,
respectively (P=0.02, P=0.009 for linear
association).
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Among those categorized as low-risk, age had little influence on stroke
rate. The stroke rate for men aged >75 years (n=151) was 1.6%/y (95%
CI, 0.7 to 3.9). When we compared those aged 66 to 75 years (n=323)
with those aged 65 years (n=289), the stroke rates were 1.2%/y
versus 0.3%/y, respectively, with no sex-related differences.
Whereas sex had little influence among those aged 75 years
without risk factors, women had much higher rates of stroke compared
with men among those aged >75 years. For participants aged >75 years
without hypertension, elevated systolic blood pressure, or
prior stroke or TIA, the stroke rate among women (mean age, 81 years)
was 7.8%/y (95% CI, 3.7 to 16), significantly exceeding that of men
(mean age, 80 years; 1.2%/y; 95% CI, 0.4 to 3.2;
P=0.002).
The rates of cardioembolic stroke were 0.6%/y, 1.1%/y, and 4.4%/y in low-, moderate-, and high-risk participants, respectively, with corresponding rates of noncardioembolic stroke of 0.2%/y, 0.7%/y, and 0.9%/y. The rate of noncardioembolic stroke was 3 times greater in those at moderate versus low risk (rate ratio=3.5, P=0.04) but similar for those at moderate versus high risk.
Among 159 participants with prior stroke or TIA a median of 3.1 years
before study entry, the rate of ischemic stroke was 13.0%/y on
aspirin. Those with prior stroke or TIA within 12 months of entry had
higher stroke rates than those with more remote events
(P<0.001). Application of the risk stratification scheme
(Table 4) to those with prior stroke or TIA showed stroke rates
of 20%/y (95% CI, 13 to 32), 10%/y (95% CI, 5.0 to 20), and 5.9%/y
(95% CI, 1.9 to 18) among those meeting criteria for high, moderate,
and low risk, respectively (P=0.05).
When both ischemic strokes and intracranial hemorrhages
were considered, the rates of all strokes were 1.1%/y (95% CI, 0.7 to
1.7), 2.7%/y (95% CI, 2.0 to 3.7), and 7.6%/y (95% CI, 5.8 to 10)
among those categorized as low, moderate, and high risk, respectively
(P<0.001) (Figure 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These exploratory analyses of a large number of AF patients given aspirin confirm the link between several previously identified features and ischemic stroke. In addition, regular alcohol consumption and hormone replacement therapy emerged as significantly associated with lower and higher stroke rates, respectively. Left ventricular dysfunction, assessed in several ways, was not independently associated with stroke in this cohort, and consequently, results of precordial echocardiography did not contribute to risk stratification. According to the risk stratification scheme developed here, a substantial fraction (
40%) of this large cohort of AF
patients had low rates of ischemic stroke (0.9%/y) and
disabling/fatal stroke (0.3%/y) when given aspirin. Most participants
aged >75 years were categorized as high risk, while younger
participants in this cohort were evenly split between low and moderate
risk (Figure 2).
The overall rate of ischemic stroke in this cohort taking
aspirin (3.3%/y) was similar to that in other recent studies of AF
patients given aspirin,17 18 19 suggesting that large
fractions of younger AF patients given aspirin have low to moderate
rates of stroke. On the other hand, AF patients in general medical
practice are, on average, older than participants in this cohort, and
consequently the fraction at high risk may be larger.20
The effect of aspirin therapy on stroke rates in this cohort cannot be
determined in the absence of an untreated, randomized control group. In
pooled analysis of randomized trials in AF, aspirin has been
associated with a 20% reduction in stroke.1 21
Exploratory analyses of these pooled data suggest that aspirin
may be more efficacious for primary prevention,21 for
those with hypertension or congestive heart failure,21 and
for prevention of noncardioembolic strokes.15 Hence,
factors associated with ischemic stroke among untreated AF
patients may be different. While aspirin is recognized to accentuate
intracranial hemorrhage,22 the rate of primary
intracerebral hemorrhage was low in this cohort
(0.1%/y).
Left ventricular systolic dysfunction, indicated by a history of heart failure or by precordial echocardiographic indices, was not associated with ischemic stroke in these patients. The relationship between ventricular dysfunction and stroke in AF patients has varied in recent analyses of this issue. Among placebo-treated participants in the SPAF I study, recent heart failure and left ventricular dysfunction by 2-dimensional echocardiography were both independently associated with stroke.4 5 In a pooled analysis of placebo-treated participants in 5 clinical trials, heart failure was not independently associated with stroke,8 but left ventricular systolic dysfunction by echocardiography was a strong independent associate in 3 of these trials that collected echocardiographic data.23 Previous analysis of SPAF I and II participants taking aspirin showed poor left ventricular function to be independently associated with stroke, particularly in those with additional risk factors.6 The use of aspirin by all participants in this analysis may have blunted the association of stroke with ventricular dysfunction.21 Pathogenetically, left ventricular dysfunction could contribute to formation of left atrial thrombi by augmenting stasis of blood flow in the atrium due to inhibition of passive atrial emptying. If so, ventricular diastolic dysfunction (not well characterized in our study) should theoretically be a better indicator than indices of systolic dysfunction. The contribution of ventricular dysfunction to stroke in AF and to clinical risk stratification requires further study.24 25
Estrogen hormone replacement therapy was independently associated with ischemic stroke in analyses restricted to SPAF III participants (data about hormone replacement therapy were not collected in the earlier SPAF studies). Hormone replacement therapy is known to affect laboratory measures of hemostasis,26 but the results of studies assessing the clinical effects on stroke are conflicting.27 28 29 30 31 32 Postmenopausal hormone replacement therapy appears to increase the risk of venous thromboembolism.33 34 35 36 37 38 Thrombi forming in the left atrium of AF patients are pathologically closer to venous than arterial thrombi, and the emergence of hormone replacement therapy as independently associated with stroke in patients with AF is intriguing. Additional studies of this issue are needed.
The identification of regular alcohol consumption as independently associated with reduced stroke risk in AF is a novel finding. This could conceivably be an artifact of underreporting or underdetection of minor stroke events in heavy alcohol users. However, moderate alcohol consumption has been associated with a decreased risk of venous thrombosis in older people.39 At present, whether regular alcohol use affects stroke risk in AF patients remains unclear, and hence this variable is not considered in our risk stratification scheme.
Our results relating stroke to age, hypertension, systolic blood pressure >160 mm Hg, and diabetes in AF patients confirm other studies.4 8 27 40 41 Female sex was associated with additional risk of stroke, but only for those aged >75 years. This curious finding was consistent in each of the SPAF trials.42 This conceivably reflects a particularly high rate of stroke among elderly women with AF, a lack of efficacy of aspirin in these patients, or both. We speculate that elderly women with AF are particularly prone to disabling cardioembolic strokes and derive little benefit from aspirin.6 43 The risk stratification scheme was robust for further stratification of stroke risk in those with prior stroke or TIA. However, the rate of ischemic stroke among those with prior stroke or TIA remained significantly higher when adjusted for other variables, suggesting that the factors associated with stroke identified in these analyses do not completely account for the high risk of stroke seen in those with prior events.
Those categorized as moderate risk (ie, diabetics and those aged 75
years with hypertension) had the highest proportion of presumed
noncardioembolic strokes. The efficacy of adjusted-dose warfarin
relative to aspirin for prevention of stroke in AF appears to be
greater for cardioembolic infarcts than for noncardioembolic infarcts
(although existing clinical classification schemes are imperfect and
inadequately validated).44 Hence, anticoagulation instead
of aspirin for this moderate-risk group may not reduce stroke to the
same relative extent as for unselected AF patients (50% reduction
in RR)1 or for high-risk AF patients (70% reduction in
RR).2 7 This construct is supported by the results of 2
recent randomized trials, in which the reduction in RR by warfarin over
aspirin was modest (30%) among AF patients, with overall rates of
stroke in the range of 2%/y to 3%/yr.10 17
Among AF patients taking aspirin, age, hypertension, and prior stroke or TIA were confirmed as independently associated with subsequent ischemic stroke. We regard the specific risk stratification scheme developed here as hypothesis generating, requiring confirmation in a separate cohort of AF patients before it can be applied to clinical management with confidence, since multivariate models tend to overestimate the strength of associations when applied to other cohorts. Our previous SPAF III risk stratification scheme has been prospectively tested and shown to be valid.3 Another published scheme derived from pooled analysis of placebo-treated patients in several clinical trials, while not separately validated, combined clinical definitions that differed slightly between trials, perhaps enhancing generalizability to clinical practice.8 More research about the application of risk stratification schemes in AF to clinical practice is needed.19 AF patients with importantly different rates of ischemic stroke can be identified. Selection of antithrombotic therapy for stroke prevention should consider the widely different stroke rates among individual patients with AF.
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Acknowledgments |
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This study was supported by a grant (RO1 NS 24-224) from the Division of Stroke and Trauma, National Institute of Neurological Disorders and Stroke, Bethesda, Md.
Received January 14, 1999; revision received March 24, 1999; accepted March 24, 1999.
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C. van Walraven, R. G. Hart, G. A. Wells, P. Petersen, P. J. Koudstaal, A. L. Gullov, B. S. P. Hellemons, B. G. Koefed, and A. Laupacis A Clinical Prediction Rule to Identify Patients With Atrial Fibrillation and a Low Risk for Stroke While Taking Aspirin Arch Intern Med, April 28, 2003; 163(8): 936 - 943. [Abstract] [Full Text] [PDF]
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 F. H Rutten, E. Hak, W. A. Stalman, T. J. Verheij, and A. W Hoes Is treatment of atrial fibrillation in primary care based on thromboembolic risk assessment? Fam. Pract., February 1, 2003; 20(1): 16 - 21. [Abstract] [Full Text] [PDF]
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S Illien, S Maroto-Jarvinen, G von der Recke, C Hammerstingl, H Schmidt, S Kuntz-Hehner, B Luderitz, and H Omran Atrial fibrillation: relation between clinical risk factors and transoesophageal echocardiographic risk factors for thromboembolism Heart, February 1, 2003; 89(2): 165 - 168. [Abstract] [Full Text] [PDF]
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D. S.G. Conway, J. Heeringa, D. A.M. Van Der Kuip, B. S.P. Chin, A. Hofman, J. C.M. Witteman, and G. Y.H. Lip Atrial Fibrillation and the Prothrombotic State in the Elderly: The Rotterdam Study Stroke, February 1, 2003; 34(2): 413 - 417. [Abstract] [Full Text] [PDF]
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N. Radford, T. Church, F. E. Speizer, B. E. Pearson Murphy, S. R. Davis, H. G. Burger, W. H. Goodson III, H. R. Franke, I. Lev, A. Lahad, et al. Risks of Postmenopausal Hormone Replacement JAMA, December 11, 2002; 288(22): 2819 - 2824. [Full Text] [PDF]
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 I. C. Van Gelder, V. E. Hagens, H. A. Bosker, J. H. Kingma, O. Kamp, T. Kingma, S. A. Said, J. I. Darmanata, A. J.M. Timmermans, J. G.P. Tijssen, et al. A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation N. Engl. J. Med., December 5, 2002; 347(23): 1834 - 1840. [Abstract] [Full Text] [PDF]
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R. H. Falk Management of Atrial Fibrillation -- Radical Reform or Modest Modification? N. Engl. J. Med., December 5, 2002; 347(23): 1883 - 1884. [Full Text] [PDF]
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M. S. Mouradian, S. R. Majumdar, A. Senthilselvan, K. Khan, and A. Shuaib How Well Are Hypertension, Hyperlipidemia, Diabetes, and Smoking Managed After a Stroke or Transient Ischemic Attack? Stroke, June 1, 2002; 33(6): 1656 - 1659. [Abstract] [Full Text] [PDF]
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B. G. Angeja, M. G. Shlipak, A. S. Go, S. C. Johnston, P. D. Frederick, J. G. Canto, H. V. Barron, D. Grady, and for the National Registry of Myocardial Infarction Hormone therapy and the risk of stroke after acute myocardial infarction in postmenopausal women J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1297 - 1301. [Abstract] [Full Text] [PDF]
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V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology Circulation, October 23, 2001; 104(17): 2118 - 2150. [Full Text] [PDF]
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Guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology Eur. Heart J., October 2, 2001; 22(20): 1852 - 1923. [PDF]
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A. J. Makin, D. S. G. Conway, G. Y. H. Lip, L. Frost, S. P. Johnsen, G. Engholm, E. Henneberg, and S. Husted Systemic Thromboembolism in Atrial Fibrillation Arch Intern Med, August 13, 2001; 161(15): 1920 - 1924. [Full Text] [PDF]
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 D S G CONWAY and G Y H LIP Anticoagulation and atrial fibrillation Postgrad. Med. J., July 1, 2001; 77(909): 487 - 487. [Full Text] [PDF]
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B. F. Gage, A. D. Waterman, W. Shannon, M. Boechler, M. W. Rich, and M. J. Radford Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation JAMA, June 13, 2001; 285(22): 2864 - 2870. [Abstract] [Full Text] [PDF]
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R. G. Hart and J. L. Halperin Atrial Fibrillation and Stroke : Concepts and Controversies Stroke, March 1, 2001; 32(3): 803 - 808. [Full Text] [PDF]
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J. A. Simon, J. Hsia, J. A. Cauley, C. Richards, F. Harris, J. Fong, E. Barrett-Connor, and S. B. Hulley Postmenopausal Hormone Therapy and Risk of Stroke : The Heart and Estrogen-progestin Replacement Study (HERS) Circulation, February 6, 2001; 103(5): 638 - 642. [Abstract] [Full Text] [PDF]
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G. W. Albers, J. E. Dalen, A. Laupacis, W. J. Manning, P. Petersen, and D. E. Singer Antithrombotic Therapy in Atrial Fibrillation Chest, January 1, 2001; 119 (2009): 194S - 206S. [Full Text] [PDF]
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R. G. Hart Anticoagulation therapy for patients with atrial fibrillation Can. Med. Assoc. J., October 1, 2000; 163(8): 956 - 957. [Full Text] [PDF]
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A. S. Go, E. M. Hylek, K. A. Phillips, L. H. Borowsky, L. E. Henault, Y. Chang, J. V. Selby, and D. E. Singer Implications of Stroke Risk Criteria on the Anticoagulation Decision in Nonvalvular Atrial Fibrillation : The Anticoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study Circulation, July 4, 2000; 102(1): 11 - 13. [Abstract] [Full Text] [PDF]
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S. Stern, D. Altkorn, and W. Levinson Anticoagulation for Chronic Atrial Fibrillation JAMA, June 14, 2000; 283(22): 2901 - 2903. [Full Text] [PDF]
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S. MacMahon Blood Pressure and the Risk of Cardiovascular Disease N. Engl. J. Med., January 6, 2000; 342(1): 49 - 52. [Full Text]
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R. G. Hart, L. A. Pearce, R. M. Rothbart, J. H. McAnulty, R. W. Asinger, J. L. Halperin, and for the Stroke Prevention in Atrial Fibrillation I Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy J. Am. Coll. Cardiol., January 1, 2000; 35(1): 183 - 187. [Abstract] [Full Text] [PDF]
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W. M. Feinberg, L. A. Pearce, R. G. Hart, M. Cushman, E. S. Cornell, G. Y.H. Lip, and E. G. Bovill Markers of Thrombin and Platelet Activity in Patients With Atrial Fibrillation : Correlation With Stroke Among 1531 Participants in the Stroke Prevention in Atrial Fibrillation III Study Stroke, December 1, 1999; 30(12): 2547 - 2553. [Abstract] [Full Text] [PDF]
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R. G. Hart and J. L. Halperin Atrial Fibrillation and Thromboembolism: A Decade of Progress in Stroke Prevention Ann Intern Med, November 2, 1999; 131(9): 688 - 695. [Abstract] [Full Text] [PDF]
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R. G HART Warfarin in atrial fibrillation: underused in the elderly, often inappropriately used in the young Heart, November 1, 1999; 82(5): 539 - 540. [Full Text]
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R. G. Hart, O. Benavente, R. McBride, and L. A. Pearce Antithrombotic Therapy To Prevent Stroke in Patients with Atrial Fibrillation: A Meta-Analysis Ann Intern Med, October 5, 1999; 131(7): 492 - 501. [Abstract] [Full Text] [PDF]
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J. H. Lichtman, H. M. Krumholz, Y. Wang, M. J. Radford, and L. M. Brass Risk and Predictors of Stroke After Myocardial Infarction Among the Elderly: Results From the Cooperative Cardiovascular Project Circulation, March 5, 2002; 105(9): 1082 - 1087. [Abstract] [Full Text] [PDF]
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