From the Department of Clinical Neurosciences, King's College
School of Medicine and Institute of Psychiatry (M.C., H.M.); and Department of
Cardiology (R.W., A.B., M.M.), King's College Hospital, London, UK.
Correspondence to Dr Hugh Markus, Department of Clinical Neurosciences, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK. E-mail h.markus{at}iop.bpmf.ac.uk
Methods—Bilateral transcranial Doppler
recordings were made for 1 hour from the middle cerebral
arteries of 111 successive patients with NVAF taking aspirin alone or
no antithrombotic or anticoagulant therapy. Adequate recordings
could be made in 86 patients. In 79 subjects, recordings were
performed on a second occasion to study temporal variability.
Recordings for a single hour were also made in 30 age-matched
control subjects.
Results—ES were detected in 13 (15.1%) of NVAF subjects but in
no control subjects (P=0.02). ES were detected both in
subjects with symptomatic NVAF (4 of 30 [13.1%],
P=0.04 versus controls) and asymptomatic
NVAF (9 of 56 [16.1%], P=0.02 versus controls). There
was no correlation between the presence of ES and smoking status,
diabetes, hypertension, aspirin use, aspirin dose,
symptomatic status, left atrial size, left
ventricular function, or the presence of left atrial
thrombus detected on transthoracic
echocardiography. Repeating the recording
increased the number of patients with ES to 21 (26.6%). On considering
the results of both recordings, again there was no association
for either recording between the presence of ES and smoking
status, diabetes, hypertension, aspirin use, aspirin dose, age,
symptomatic status, left atrial size, or left
ventricular function. On repeating the recording,
in the symptomatic group only 2 patients (8%) changed
status, in contrast to 15 (29%) in the asymptomatic
group.
Conclusions—ES can be detected in patients with NVAF at a low
frequency. Particularly in asymptomatic patients, ES show
marked temporal variability. We found no correlation between the
presence of previously reported clinical and
echocardiographic markers of increased stroke risk and
the presence of ES. This association requires further investigation
before the clinical utility of this technique in patients with NVAF is
decided.
Most strokes in patients with NVAF are believed to be embolic;
therefore, the ability to detect circulating asymptomatic
emboli might allow a number of aspects of patient management to be
improved. If these asymptomatic emboli have a similar
significance to TIAs, the technique would allow identification of a
high-risk group of patients for anticoagulation. It might also allow
effective monitoring of patients taking aspirin or anticoagulants;
currently, treatment failure can only be determined when stroke has
occurred. Recently, it has been demonstrated that circulating cerebral
emboli can be detected using Doppler ultrasound. In vitro and in
vivo studies have shown the technique to be both sensitive and
specific.7 8 9 Embolic signals (ES) have been
detected in patients with a variety of potential embolic sources,
including symptomatic and asymptomatic carotid
stenosis10 11 and prosthetic
heart valves.12 13 Considering the frequency and
importance of emboli as a cause of stroke on a population basis,
there have been few studies using this technique in subjects with
atrial fibrillation. In the largest study to date, Infeld et
al14 performed recordings in 54 patients
with atrial fibrillation, half of whom had presented with
recent stroke, and in 19 control subjects in sinus rhythm. ES were
detected in 22% of symptomatic subjects and in 7% of
asymptomatic subjects, but many patients were taking
warfarin, which may have reduced the incidence of ES. There have been
no large studies in patients not taking warfarin. In this study, we
recruited successive patients with NVAF who were not taking warfarin or
other anticoagulants and determined the prevalence of
asymptomatic ES. We correlated the presence of ES with
clinical and echocardiographic markers of increased
risk. By repeating the recordings on a second day, we
determined the variability in the frequency of ES over time.
In all patients with NVAF in whom technically successful
transcranial Doppler recordings could be
performed, transthoracic
echocardiography was planned. All echocardiograms
were performed using a Sonos 1500 (Hewlett-Packard Ltd). Left atrial
size was measured in the long axis parasternal view using M-mode, and a
mean of 3 readings was taken. Left ventricular function was
measured using Simpson's method of discs in the long- and short-axis
apical views to estimate the ejection fraction. However, in a number of
patients, endocardial border detection was insufficient for ejection
fraction estimation. Therefore, a subjective measure of left
ventricular function was also recorded for each
subject; left ventricular function was placed into 1 of 5
categories (from 1=normal to 5=very poor). All
echocardiography was performed by an operator
blinded to the results of the transcranial Doppler
recording. In all patients with NVAF, blood was taken for
determination of fibrinogen level, which was derived from the
prothrombin time.
Transcranial Doppler Recordings
Analysis was performed off-line by an observer (observer 1)
blinded to both subject group and whether subjects were controls or
not. An ES was identified as a predominantly unidirectional
short-duration intensity increase, accompanied by a characteristic
clicking or chirping sound.15 A threshold of >7
decibels was used because this has been shown to increase interobserver
agreement without too great a loss of
sensitivity.16 Intensity was determined from
measurements made using the color scale on the spectral display of the
peak intensity of the embolic ES, and the intensity of the background
spectra at the same frequency and part of the cardiac cycle, from the
preceding or subsequent cardiac cycle. All possible ES detected were
saved and then reviewed by a second experienced observer (observer 2);
if both observers agreed that the signal was an ES, it was then
included in subsequent analysis. Interobserver reproducibility
in identifying ES was assessed by the 2 observers independently
analyzing a separate recording that was 105 minutes long and
had been prepared from MCA recordings from 6 patients.
Agreement was calculated using the proportion of specific agreement,
which estimates the probability that 1 observer will identify a
specific ES if another observer has identified it, with a probability
of 1 indicating complete agreement.17 Observer 1
detected 90 ES, and the agreement of observer 1 with observer 2 was
0.88. Observer 2 detected 89 ES, and the agreement of observer 2 with
observer 1 was 0.87.
Data Analysis
Results for 1-Hour Recording
There was no difference in the proportion of patients with
symptomatic or asymptomatic NVAF who had ES
(P=0.74). The association of ES with clinical features is
shown in Table 2
Echocardiography was performed in 81 of 86 subjects
with NVAF, of whom 13 were ES-positive and 68 ES-negative. Mean±SD
left atrial size was 3.76±0.87 cm in ES-positive patients and
3.97±0.80 cm in ES-negative patients (P=0.45). Left
ventricular function was poor or very poor (grades 4 or 5)
in 2 (15.4%) ES-positive compared with 3 (4.4%) ES-negative patients
(P=0.38). In those subjects in whom it could be determined
(n=67), there was no difference in ejection fraction between patients
with and without ES (mean±SD: 56.3±16.9% versus 51.5±15.1%;
P=0.40).
Results for Two 1-Hour Recordings
The results were similar when only those patients with continuous NVAF
were considered for the single 1-hour recording and when
both 1-hour recordings were considered (Table 3
Other Analyses
In subjects who were positive for ES, and when considering only the
first recording, the median rate of embolization was greater in
symptomatic than asymptomatic subjects: 1
(range, 0.5 to 5.5) versus 0.5 (0.5 to 1.0) per hour,
(P=0.02). Considering only the second recording,
there was no difference between the 2 groups: symptomatic,
0.5 (0.5 to 1.0); asymptomatic, 1.0 (0.5 to 2.0) per hour
(P=0.14). Considering all ES, there was no difference in the
intensity of ES between asymptomatic and
symptomatic subjects with NVAF (mean±SD intensity:
symptomatic, 10.26±3.4 dB; asymptomatic,
11.32±4.8 dB; P=0.84).
Temporal Variability
In the subjects with NVAF, we found no relationship between the
presence of ES and a number of known markers of increased stroke risk.
ES were not more common in patients with cerebrovascular symptoms, and
in symptomatic patients they were no more common in
patients with recent symptoms. There was no reduction in their
frequency in patients taking aspirin or in patients with
echocardiographic markers of increased risk, such as
increased left atrial size and impaired left ventricular
function. Part of the lack of correlation with the
echocardiographic data may be related to the
insensitivity of transthoracic
echocardiography, particularly in identifying left
atrial thrombus. It was not considered ethical to perform
transesophageal echocardiography in
our primarily elderly patients solely for the sake of this study. The
only association we found with ES was with female gender. There is no
obvious pathophysiological explanation for this,
and it may merely reflect the large number of statistical comparisons
made. In contrast to the lack of association with markers of increased
stroke risk, a number of previous studies in similar numbers of
patients with carotid artery stenosis have found an association
with a variety of markers of increased stroke risk in this group of
patients, including symptomatic
status,11 time from last
symptoms,10 and plaque ulceration and
thrombus.22 23 24
The lack of an association in patients with NVAF between clinical and
echocardiographic markers of risk may have a number of
explanations. First, it may reflect the size of the study population,
but we did not find even a trend toward an increased proportion of ES
in symptomatic patients or patients with recent symptoms.
Second, particularly in patients with asymptomatic NVAF,
when recordings were repeated there was marked variability in
which subjects were ES-positive, and this variability may weaken any
association with markers of clinical risk. Third, it is possible that
even if the majority of strokes in patients with NVAF are embolic in
origin, the asymptomatic ES we detected are not clinically
relevant and are not a good predictor of which patients will have
clinically symptomatic emboli in this situation. It is
likely that these asymptomatic ES are caused by small
emboli, whereas stroke is likely to result from larger, less frequent
emboli. Fourth and more controversial, embolism might not
represent the primary pathogenic mechanism in many patients
with NVAF. It has been suggested that the stroke risk in this group of
subjects may partly reflect the high frequency and severity of
cardiovascular risk factors in this population, who
also have a higher prevalence of atheromatous disease,
which itself directly causes stroke. The effect of anticoagulation in
reducing stroke risk does not prove a causal association via a
mechanism of cardiogenic embolism; anticoagulation could conceivably
reduce stroke risk via reducing large artery to artery embolism and in
situ thrombosis in these patients, as well as by reducing cardiogenic
embolism.25 However, pathological studies support
the concept that at least some strokes in these patients are caused by
emboli.25 Further studies are required to
determine the relevance of asymptomatic ES in this
population. Initially, this should include determining the effect of
warfarin, which is known to reduce stroke risk, on ES frequency;
we are currently studying this in another group of patients with
NVAF.
It is possible that factors other than the mere presence or absence of
ES could determine whether individual subjects are
symptomatic. These could include the frequency or nature of
the emboli. Although ES, in subjects who had ES, occurred at a higher
rate in symptomatic compared with asymptomatic
patients on the first recording, this difference could not be
replicated when the data from the second recording was
analyzed separately. The significant difference on the first
recording may merely reflect the large number of comparisons
made in our analysis. Some limited information on the nature
and size of emboli can be derived from the intensity of
ES.9 However, there was no difference in the mean
intensity of ES in the symptomatic and
asymptomatic groups.
To determine variability over time and optimal recording
protocols, we repeated the recording in subjects with NVAF
wherever possible. In the symptomatic group, only 2
patients (8%) changed status in contrast to 15 (29%) in the
asymptomatic group. Only 1 patient in this latter group
remained ES-positive on both occasions. This variability makes the
technique potentially less useful as a method of monitoring disease
activity in individual patients. Further studies are required to
determine how many recordings need to be performed before the
proportion of ES-positive patients reaches a maximum and to determine
optimal recording protocols to be used in studies of the
predictive value of ES in predicting stroke risk in this group of
patients.
In conclusion, we have demonstrated that asymptomatic ES
occur in patients with NVAF who are not being treated with
anticoagulants at a significantly greater frequency than in age-matched
control subjects. Perhaps surprisingly, we found no correlation between
the presence of ES and a number of known clinical and
echocardiographic markers of increased stroke risk,
although the reasons for this lack of association require further
investigation.
Received April 30, 1998;
revision received June 24, 1998;
accepted June 24, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Asymptomatic Embolization in Subjects With Atrial Fibrillation Not Taking Anticoagulants
A Prospective Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Embolism
is believed to be the major cause of stroke in patients with
nonvalvular atrial fibrillation (NVAF). The detection of
asymptomatic embolic signals (ES) in individuals with NVAF
might allow identification of patients at high risk of stroke and
monitoring of therapy in individual subjects. We determined the
frequency of asymptomatic ES in patients with NVAF who were
not taking warfarin.
Key Words: atrial fibrillation • cerebrovascular diseases • cerebral embolism • ultrasonics
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Nonvalvular atrial fibrillation (NVAF), the most
common sustained disorder of cardiac rhythm, is associated with an
increased stroke risk of approximately 5% in patients over the age of
65 years when compared with age-matched control subjects in sinus
rhythm.1 A number of studies have shown that this
risk can be reduced by about 40% by full anticoagulation with
warfarin, without a marked excess risk of
bleeding.2 3 However, these figures are from
well-controlled clinical trial populations, and in a normal population
the bleeding rates may be higher. The risk of bleeding in the elderly
has varied between studies, and the risk-benefit ratio of warfarin in
this population is uncertain. Aspirin has been advocated as an
alternative therapy and may be appropriate for those at low embolic
risk or at high risk of anticoagulation-induced
hemorrhage.2 The ability to identify
those patients with NVAF who are at particularly high risk of stroke
would allow improved targeting of anticoagulant therapy and
improvements in both cost-benefit and risk-benefit ratios. Potential
markers of high embolic risk suggested in previous studies include left
atrial size, hypertension, myocardial infarction, history of stroke or
transient ischemic attack (TIA), and
diabetes.4 5 6
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Subjects
Successive subjects identified with NVAF who were taking no
antiplatelet therapy or were taking aspirin were considered for the
study. Patients taking warfarin or heparin were excluded.
Asymptomatic subjects with NVAF were prospectively
identified from clinics providing cardiac and health care for the
elderly and from routine screening of
electrocardiographs and 24-hour
electrocardiograms performed within the
cardiology department. Symptomatic subjects
were recruited from successive patients presenting to the neurology
service and the acute stroke unit. Subjects were classified as
symptomatic if they had experienced stroke or TIA within 1
year of the first recording. Spouses and urology outpatients in
sinus rhythm and with no history of stroke or TIA were used as
age-matched control subjects. Both control and NVAF subjects underwent
a carotid duplex ultrasound scan and were excluded if carotid
stenosis (>50% diameter) was present. Subjects were
defined as smokers if they currently smoked cigarettes, as hypertensive
if they were taking hypertensive therapy or if blood pressure was
>160 mm Hg systolic or >95 mm Hg
diastolic, and as diabetic if they had insulin-dependent or
non–insulin-dependent diabetes mellitus.
Transcranial Doppler ultrasonography was
performed using a Pioneer TC4040 (Nicolet-EME Ltd) with a 2-MHz
transducer. A sample volume of 10 mm and a sweep speed of 5
seconds were used for all patients. A 128-point fast Fourier transform
(FFT) was used for spectral analysis. FFT time-window overlap
was >66%. The subject was placed in a sitting position, the middle
cerebral artery (MCA) was identified via the transtemporal
window, and the transducer was fixed in position using a standard
headset. Bilateral recordings were performed for 1 hour.
Mean±SD depth of insonation of the MCA was 53.0±4.0 mm on the
left and 52.4±3.9 mm on the right. The Doppler signal was
stored on digital audiotape using a TCD-D7 recorder (Sony Ltd). In
all subjects who consented, the recording was repeated on 1
further occasion approximately 1 week later to determine variability.
The results of the first study were not known at the time of the second
recording. All subjects gave informed consent, and the study
was approved by the local hospital ethics committee.
Not all patients agreed to participate in 2 recordings,
and therefore a first analysis was performed using only the
results of the first recording for all patients. These
analyses were then repeated using combined data from both
recordings in those patients for whom 2 recordings had
been made. For all calculations, a patient was defined as being
ES-positive if ES were detected in either MCA and on either
recording in the analysis of data from both occasions.
The rate of embolization was expressed as the number of ES per hour of
recording from each MCA, ie, a patient with a successful
bilateral recording for 1 hour had 2 hours of successful
recording. The difference in the proportion of NVAF subjects
with ES compared with controls was determined by the
2 test. The association between the presence
of ES and clinical characteristics, symptomatic status, or
echocardiographic criteria was determined using
2 tests (with Yates' correction where
appropriate) or t tests as indicated. In those patients in
whom ES were detected, comparison was made between the number of
ES per hour and a number of clinical parameters; as the
distribution of ES frequency was skewed, nonparametric
statistics were used for this analysis (Mann-Whitney
U test and Spearman's rank correlation coefficient as
appropriate).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Subject Characteristics
One hundred eleven successive subjects identified with NVAF were
prospectively recruited. Twenty-three had no acoustic window;
therefore, recordings were performed in 88. Two further
patients were excluded after echocardiography
showed other significant cardiac disease (mixed mitral valve disease in
1, hypertrophic cardiomyopathy in 1). Therefore,
recordings were analyzed in 86 patients with NVAF. Of
these, 56 were asymptomatic with a mean±SD age of
75.2±9.2 years, and 30 were symptomatic with a mean age of
73.7±9.4 years. Seven had paroxysmal NVAF, and the remainder had
chronic continuous NVAF. In symptomatic patients, the mean
number of days between symptoms and first recording was 49.6
days (range, 1 to 227 days). In 84 of the 86 subjects, bilateral
recordings were performed, but in 2 subjects the MCA could only
be identified on 1 side, and therefore unilateral recordings
were performed. Seven subjects did not have a further recording
because of refusal to return or illness; therefore, 79 subjects had a
second 1-hour recording. All 7 patients with paroxysmal NVAF
had successful bilateral recordings on 2 occasions. Thirty
normal control subjects were prospectively recruited with a mean±SD
age of 71.9±7.9 years. In all, a single 1-hour bilateral
recording was performed. The clinical characteristics of the 86
NVAF subjects and the 30 controls are shown in Table 1
.
View this table:
[in a new window]
Table 1. Characteristics of NVAF and Control
Groups
ES were detected in 13 (15.1%) of NVAF subjects but in no
controls (P=0.02). They were detected in subjects with both
symptomatic NVAF (4 of 30 [13.1%], P=0.04
versus controls) and asymptomatic NVAF (9 of 56 [16.1%],
P=0.02 versus controls). . There was
no association between the presence of ES and smoking status, diabetes,
hypertension, aspirin use, aspirin dose, or symptomatic
status. ES were detected in more female than male patients with NVAF
(76.9% versus 23.1%, P=0.04). There was no difference in
mean±SD fibrinogen levels between ES-positive and ES-negative subjects
(4.68±1.2 versus 4.56±1.2 g/L, P=0.45).
View this table:
[in a new window]
Table 2. Relationship Between Presence of ES and
Cardiovascular Risk Factors, Aspirin Therapy, and Echocardiographic
Indices in All Subjects With
NVAF
Considering all 79 subjects with NVAF who had 2
recordings, ES were detected in 21 (26.6%). There was no
difference in the proportion of symptomatic and
asymptomatic patients with ES detected on either occasion:
5/27 (18.5%) versus 16/52 (30.8%), P=0.24. As for the
single recording, there was no association between patients who
were ES-positive on either recording and smoking status,
diabetes, hypertension, aspirin use, aspirin dose, age,
symptomatic status, left atrial size, left
ventricular function, or ejection fraction (see Table 2
). ).
View this table:
[in a new window]
Table 3. Relationship Between Presence of ES and
Cardiovascular Risk Factors, Aspirin Therapy, and Echocardiographic
Indices in Subjects With Continuous
NVAF1
Considering all symptomatic NVAF subjects, there was
no correlation between the frequency of ES and time from last symptoms
to current recording for either the first or second
recording period (first recording, 
=0.16,
P=0.40; second recording, =-0.02,
P=0.91). There was also no association between the presence
of ES and recent symptoms when the data were analyzed using a
cutoff of 28 days as indicating recent symptoms (first
recording: recent symptoms, 2/16 ES-positive; no recent
symptoms, 2/14 ES-positive [P=0.9]; second
recording: recent symptoms, 3/12 ES-positive; no recent
symptoms, 2/15 ES-positive [P=0.4]).
In the symptomatic group, only 2 patients
changed status between the 2 recordings. Three subjects were
ES-positive on both recordings and 22 ES-negative on both
recordings. Two subjects were ES-negative on the first
recording but positive on the second recording, while
no subjects were ES-positive on the first recording and
ES-negative on the second recording. In contrast, in
asymptomatic patients there was marked variability between
the results of recordings performed on the 2 occasions. In this
group, only 1 subject remained ES-positive on both recordings,
while 36 patients were ES-negative on both recordings. Seven
subjects who were ES-negative on the first recording became
ES-positive on the second recording, while 8 subjects who were
ES-positive on the first recording became ES-negative on the
second recording.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Our results demonstrate that ES can be detected in subjects with
NVAF who are not taking anticoagulants and are significantly more
common in this group than in age-matched normal control subjects.
However, ES were only found in a minority of subjects with NVAF and at
a low frequency; in subjects with ES, the median rate was 1 per hour or
less. There have been few studies of the prevalence of ES in atrial
fibrillation, and in the majority of cases, atrial fibrillation has
been only a small subgroup in a larger study of patients with potential
embolic sources,18 19 20 21 but these studies also
have reported ES in this group of patients. The largest study to
date14 recorded for 30 minutes in 54 patients
with atrial fibrillation and found ES in 2 of 27
asymptomatic patients compared with 6 of 27
symptomatic patients. However, interpretation of these
results is complicated because many of the patients, and a larger
proportion of symptomatic than asymptomatic
patients, were taking anticoagulants. This is known to reduce stroke
rate and therefore might reduce the rate of asymptomatic
embolization. Our study prospectively recruited a larger, more
homogenous group of patients with NVAF, but despite the fact that none
was taking warfarin, the rate of embolization remained low. The rate of
embolization is lower than that reported in carotid artery
stenosis, the condition in which most studies with Doppler
embolic signal detection have been
performed.11
Acknowledgments
This work was funded by a project grant from the Stroke
Association of the UK. We thank Dr H. Hambley for performing fibrinogen
assays. We thank the consultants who allowed us to study
patients under their care, especially Professor S. Jackson, Professor
C. Swift, Dr A. Blackburn, Dr J. Evans, and Dr P. Bath.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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