Atrial Fibrillation: A Major Contributor to
Stroke in the Elderly
The Framingham Study
Philip A. Wolf, MD; Robert D. Abbott, PhD; William B. Kannel,
\s=b\ Chronic atrial fibrillation without valvular disease has
been associated with increased stroke incidence. The impact
of atrial fibrillation on the risk of stroke with increasing age
was examined in 5184 men and women in the Framingham
Heart Study. After 30 years of follow-up, chronic atrial fibrilla-
tion appeared in 303 persons. Age-specific incidence rates
steadily increased from 0.2 per 1000 for ages 30 to 39 years to
39.0 per 1000 for ages 80 to 89 years. The proportion of strokes
associated with this arrhythmia was 14.7%, 68 of the total 462
initial strokes, increasing steadily with age from 6.7% for ages
50 to 59 years to 36.2% for ages 80 to 89 years. In contrast to the
impact of cardiac failure, coronary heart disease, and hyper-
tension, which declined with age, atrial fibrillation was a
significant contributor to stroke at all ages.
(Arch Intern Med 1987;147:1561-1564)
Atrial fibrillation in association with rheumatic heart
^ disease and mitral stenosis is well known to predispose
to stroke.1,2 In the past, chronic atrial fibrillation without
valvular heart disease was considered an innocuous condi¬
tion. In recent years, however, chronic atrial fibrillation in
the absence of rheumatic valvular heart disease has been
found to be associated with more than a fivefold increased
incidence of stroke, even when age and hypertensive status
are taken into account.3"6 Most of these strokes have the
clinical characteristics of cerebral embolus.7 Since the inci¬
dence of chronic atrial fibrillation increases sharply with
age above the 6th decade, it has been suggested that an
increasing proportion of strokes occurring with advancing
age may be related to this cardiac rhythm disturbance.4'7,8
With a growing elderly population, chronic atrial fibrilla¬
tion represents a readily identified and potentially preven¬
table stroke precursor. To assess its relative impact on
Accepted for publication June 6, 1987.
From the Department of Neurology (Dr Wolf) and the Section of
Preventive Medicine and Epidemiology, Evans Memorial Department of
Clinical Research and Department of Medicine (Drs Wolf and Kannel),
University Hospital, Boston University School of Medicine; and the Statis-
tical Resource Section, National Heart, Lung, and Blood Institute, Be-
thesda, Md (Dr Abbott).
Reprint requests to 720 Harrison Ave, No. 1105, Boston, MA 02118 (Dr
Wolf).
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MD
stroke in the elderly, data on this issue were analyzed using
30 years of follow-up in the Framingham Heart Study.
METHODS
The impact of age the incidence of chronic nonrheumatic atrial
on
fibrillation and on the incidence of stroke associated with this
arrhythmia was examined in the Framingham cohort of 5184 men
and women who were free of stroke and atrial fibrillation at entry
to the study. When first examined in 1948, subjects were ages 30 to
62 years. In addition to a baseline examination, subjects were
examined every two years during a 30-year course of follow-up.
Sampling procedures, criteria, and methods of examination have
been described elsewhere.9 On each of the biennial examinations,
subjects were routinely queried by a physician concerning habits,
medications, and illnesses during the preceding two years. Phys¬
ical examinations and laboratory studies were made, and details
surrounding all interim illnesses were sought.
Criteria for the diagnosis of rheumatic heart disease were mainly
clinical and included a history consistent with prior rheumatic
fever and auscultatory evidence of valvular disease on two or more
of the first six biennial examinations between 1948 and 1962.
Documentation of a diastolic murmur in the mitral or aortic area
without any other clear cause was considered definite evidence of
rheumatic heart disease, as was a grade 4 or greater systolic
murmur in either the mitral or aortic area or a grade 3 murmur if
the subject also had a history of rheumatic fever. The auscultatory
findings were confirmed by a second physician, and both examina¬
tions were done with the patient sitting and supine. Each subject
also received both posteroanterior and lateral roentgenographic
examinations of the chest and selected subjects also underwent
fluoroscopy if the roentgenograms suggested atrial enlargement.
In recent years evidence of rheumatic valvular disease obtained on
invasive testing, by echocardiography, at cardiac surgery, or at
autopsy was also used.
For stroke, including transient ischemie attacks, surveillance
was maintained by daily monitoring of all admissions to the only
local general hospital. If stroke was suspected, the patient was
seen in the hospital by the study neurologist. Neurologic symp¬
toms or signs noted by the study physician at a biennial examina¬
tion were followed by a detailed evaluation in the neurology clinic.
The circumstances surrounding every illness and the death of each
study subject were evaluated by review of all available medical
information, including hospital and physician records and postmor¬
tem data. The clinical data were reviewed by a panel of physicians
to determine if minimal criteria were met for the diagnosis of the
disease under study and to determine the underlying cause of
death. A neurologist participated in reviews of all suspected stroke
cases.
 Thirty-year follow-up, the Framingham study.
During the period under study nearly all subjects were admitted
to a hospital by their personal physicians when stroke or transient
ischemie attack was suspected. Most had lumbar puncture, brain
scan, electroencephalogram, and skull roentgenograms prior to
computed tomographic scan availability. In recent years, at least
one computed tomographic scan of the head was done soon after
hospital admission on most subjects with stroke or transient
ischemie attack. Cerebral arteriography was done infrequently in
study subjects with stroke when an obvious cardiac source for
cerebral embolism such as chronic atrial fibrillation was present.
In addition to noting the presence of atrial fibrillation on the 12-
lead electrocardiogram during a biennial examination, the ar¬
rhythmia was sought during review of all interim hospitalizations.
Onset was considered to be the time of first documentation by
electrocardiogram available for review. Chronic atrial fibrillation
was defined as the persistence of the rhythm disturbance from
onset without electrocardiographically documented appearance of
regular sinus rhythm. Atrial fibrillation was frequently docu¬
mented for the first time on admission to a hospital for stroke. In
those instances, no judgment as to the short-term duration of the
arrhythmia could be made. Anticoagulants were not in use to any
great extent in this group of subjects either at the time of initial
stroke or stroke recurrence. Since it was often difficult to distin¬
guish with certainty thrombotic from embolie infarcts, all strokes
occurring in persons with chronic nonrheumatic atrial fibrillation
were counted without making a judgment as to the probable stroke
mechanism. In this way stroke occurrence in the presence of atrial
fibrillation could be studied without having to deal with "self-
fulfilling" criteria for stroke type, which for cerebral embolism
includes a readily identified source for emboli such as atrial
fibrillation.
Analyses relating atrial fibrillation to stroke were restricted to
persons with atrial fibrillation who were free of rheumatic heart
disease. To help describe the incidence of chronic atrial fibrillation,
the 30 years of follow-up were divided into 15 bienniums of
experience. Subjects free of atrial fibrillation at the beginning of
each biennium were then followed for two years, and an incidence
rate was calculated by combining all bienniums of experience and
noting the number of occurrences of atrial fibrillation. Similar two-
year rates were calculated for first-stroke events among subjects
with and without atrial fibrillation.
To estimate the excess rate of stroke among subjects with this
arrhythmia that could be attributed to having atrial fibrillation,
attributable risks for each decade of life were computed.10 Hyper¬
tension is the most potent risk factor for stroke, and since its
frequency increases with age, the relative impact of atrial fibrilla¬
tion was also examined controlling for systolic blood pressure. This
was accomplished by estimating each age-specific attributable risk
adjusted for the effect of blood pressure. The attributable risks for
all age groups were then centered around the average blood
pressure for the entire sample. The result yielded age-specific
attributable risks adjusted to an average blood pressure, similar to
the risk factor adjustment commonly used in analysis of
covariance.u
To further describe the changing effects of atrial fibrillation on
stroke with advancing age, relative risks of stroke were estimated
by ten-year age group. For comparison, relative risks of stroke
associated with cardiac failure, coronary heart disease, and hyper-
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tension were also estimated. Relative risks approximate the ratio
of the risk of stroke due to the presence of one of the preceding
stroke risk factors as compared with its absence. Each estimate of
relative risk associated with a specific risk factor was adjusted for
the confounding effects of the other risk factors. Estimates of
relative risk were based on logistic regression models for grouped
event times, suitable for survival data analysis.12
RESULTS
After 30 years of follow-up, atrial fibrillation developed in
163 men and 140 women (Table 1). Incidence of atrial
fibrillation was higher in men than women; in both sexes
incidence was clearly related to age. Incidence rose steadily
from 0.4 and 0.0 per 1000 at age 30 to 39 years to 45.9 and
35.8 per 1000 at age 80 to 89 years in men and women,
respectively. The incidence trebled in men and doubled in
women in each successive decade of life. The two-year, age-
specific incidence of stroke that developed in 68 persons
with atrial fibrillation was compared with the incidence of
stroke occurring in 394 persons who were free of this
arrhythmia (Table 2). Stroke was preceded by atrial fibrilla¬
tion in 44 persons and was present at the time of hospital
admission and presumably at the time of onset of stroke in
another 24 subjects. The atrial fibrillation-associated
strokes represented 14.7% of the total 462 initial stroke
events observed during the 30 years of follow-up. The
proportion of atrial fibrillation-associated stroke to total
stroke was clearly related to age, increasing steadily from
6.7% for ages 50 to 59 years to 36.2% for ages 80 to 89 years.
Since atrial fibrillation, in the absence of rheumatic heart
disease, often develops in persons with coronary heart
disease and congestive cardiac failure, which along with
hypertension are risk factors for stroke, adjusted relative
risks were estimated that compared the risk of stroke for
those with and without each of these conditions (Table 3). In
the three youngest decades, cardiac failure, coronary heart
disease, hypertension, and atrial fibrillation made a signifi¬
cant independent contribution to incidence of stroke after
taking the other risk factors into account. In the oldest
decade, however, ages 80 to 89 years, it was only atrial
fibrillation that remained a significant risk factor. In con¬
trast, the effect of hypertension and the other cardiac
conditions declined with age, and in those aged 80 to 89
years, their impact was no longer substantial or significant.
Risk of stroke that could be attributed to atrial fibrilla¬
tion, even after adjusting for the effect of systolic blood
pressure, continued to show a consistent increase with age,
rising from 7.3% in subjects aged 60 to 69 years to 30.8% in
those aged 80 to 89 years (Table 4). Data were insufficient to
estimate a corresponding attributable risk for the youngest
age group, but presumably it remained small because of the
low prevalence of atrial fibrillation. In contrast to these
 "Thirty-year follow-up, the Framingham study.

latter findings, no clear trend among subjects older than 50

years could be demonstrated in the corresponding calcula¬
tions made for heart failure or coronary heart disease.
COMMENT
It is well established that atrial fibrillation in the pres¬
ence of rheumatic valvular disease, particularly mitral
stenosis, is an arrhythmia that predisposes to systemic
embolism, including embolie stroke. In recent years, on the
basis of clinical,6,13,14 pathologic,15,16 and epidemiologie stud¬
ies,M chronic atrial fibrillation in the absence of rheumatic
heart disease has been recognized as an important precur¬
sor of stroke. Prior estimates of the increasing risk of stroke
from atrial fibrillation with increased age have come from
clinical and autopsy series, each with its inherent bias of
selection. This estimate of the impact of age on atrial
fibrillation-associated stroke was derived from prospective *Each relative risk is adjusted for the other stroke risk factors. Numbers in
parentheses indicate 95% confidence limits; values, significant excess of
epidemiologie study and probably represents the least strokes.
distorted assessment of risk. tP<.01.
Stroke associated with chronic atrial fibrillation, in the tP<.001.
absence of rheumatic heart disease, assumes major impor¬ §P<.05.
tance with advancing age. Elderly persons with this ar¬
rhythmia are often stroke prone as a result of hypertension
and associated cardiovascular and cerebrovascular diseases
predisposing to cerebral infarction. In addition, atrial
fibrillation may reduce cerebral blood flow and cardiac
output by as much as 30%." On the basis of available data,
however, it is estimated that at least two thirds of strokes in
patients with chronic nonvalvular atrial fibrillation occur as
a result of cardiogenic embolism.18"20
It seems likely from these data that the frequently
associated congestive heart failure and coronary heart
disease do not account for the increased risk of stroke with
increasing age in persons with chronic atrial fibrillation
(Table 3). Furthermore, in this cohort, persons with this
arrhythmia, unassociated with either rheumatic, coronary,
or hypertensive heart disease, ie, lone atrial fibrillation,
also had an increased risk of stroke of four times the rate of a
group of matched control subjects.21
Hypertension has not been shown to be a strong precur¬ "Thirty-year follow-up, the Framingham study.
sor of nonrheumatic atrial fibrillation,5,6 but hypertension is fSignificant increase with age before and after adjusting for systolic blood
the most powerful precursor of stroke." Of the strokes that pressure (P<.05). Numbers in parentheses indicate 95% confidence limits.
occurred in the atrial fibrillation group, 62 subjects (91%) ^Insufficient data.
had had hypertension, either definite or borderline, at some
time before the onset of atrial fibrillation. In the group This finding suggests that an increase in the percent of
without atrial fibrillation, 306 (78%) of the stroke victims strokes attributed to atrial fibrillation with age is indepen¬
had also been hypertensive prior to the stroke. When dent of hypertension and is not due to an increase in the
focusing on only those subjects with prior or coexisting prevalence of hypertension that also occurs with age. This is
hypertension, the percent of strokes attributed to atrial consistent with the reduction in the effect of hypertension
fibrillation increased steadily with age from 6.2% in those on stroke that occurs with age as shown in Table 3.
aged 60 to 69 years to 31.3% in those aged 80 to 89 years. It is clearly not sufficient to wait until stroke occurs and

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 then act to try to prevent recurrence, since the initial stroke
occurring with chronic atrial fibrillation is often a major
infarcì resulting in severe disability or death. In one series
of hospitalized patients with stroke associated with atrial
fibrillation, 71% died or had severe permanent neurologic
deficit from the initial embolie stroke.18 Imminence of
stroke is clearly related to onset of atrial fibrillation. In this
series, 24% of the subjects with initial strokes associated
with atrial fibrillation were first discovered to have the
arrhythmia at the time of hospital admission for stroke.22
Furthermore, one third of stroke events that occurred took
place within six months of onset of this atrial arrhythmia.22
For these reasons, watchful waiting does not seem indicated
in recent-onset atrial fibrillation.
Not all persons with nonrheumatic atrial fibrillation
sustain a cerebral embolus, and some live many years
without stroke. Subgroups of patients with chronic atrial
fibrillation who may be at increased risk of stroke include
patients with congestive heart failure,5 those with larger
left atrial size,23 or those with associated submitrai calcifica¬
tion.24 Echocardiographic identification of atrial clot is
rarely accomplished, although pathologic studies suggest
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that such clots are common.15,16 Further systematic study of
echocardiographic variables such as left atrial size or sub-
mitral calcification is needed to try to identify a subset of
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At present there is no convincing evidence that anti-
platelet agents will prevent stroke in patients with atrial
fibrillation. A controlled clinical trial to determine the
relative benefit and hazards of warfarin sodium anticoagu¬
lation therapy in persons with this arrhythmia is overdue.
Prevention of the cardiac impairments that increase stroke
risk, such as atrial fibrillation, coronary heart disease,
congestive failure, and left ventricular hypertrophy seen on
electrocardiogram, holds the greatest promise of prevent¬
ing cerebral infarction related to nonrheumatic atrial fibril¬
lation.
This investigation was supported in part by grants NIH-IPO-INS-16367
and l-ROl-NS-17950-01 with contract NOl-NS-2-2398 (Dr Wolf) from
the National Institute of Neurological and Communicative Disorders
and Stroke, Bethesda, Md, and contracts NIH-NO1-HV-38038 and
l-ROl-HL-32884 (Dr Kannel) from the National Heart, Lung, and Blood
Institute.
12. Wu M, Ware J: On the use of repeated measurements in regression
analysis with dichotomous responses. Biometrics 1979;35:513-521.
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sinoatrial disorder. N Engl J Med 1976;295:190-192.
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patients with atrial fibrillation. Arch Neurol 1984;41:708-710.
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509-513.
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systemic embolism in necropsy material. Acta Med Scand 1969;185:373-379.
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on regional cerebral blood flow. Stroke 1980;11:35-38.
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19. Mohr JP, Caplan LR, Melski JW, et al: The Harvard Cooperative
Stroke Registry: A prospective registry. Neurology 1978;28:754-762.
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factor for stroke. Stroke 1985;16:182-188.
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prognosis of lone atrial fibrillation: 30-year follow-up in the Framingham
study. JAMA 1985;254:3449-3453.
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and imminence of stroke: The Framingham study. Stroke 1983;14:664-667.
23. Caplan LR, D'Cruz I, Hier DB, et al: Atrial size, atrial fibrillation,
and stroke. Ann Neurol 1986;19:158-161.
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Framingham study). Am J Cardiol 1983;51:1375-1378.