Download Risk for Clinical Thromboembolism Associated with Conversion to

Risk for Clinical Thromboembolism Associated with Conversion to
Sinus Rhythm in Patients with Atrial Fibrillation Lasting Less
Than 48 Hours
Marilyn J. Weigner, MD; Todd A. Caulfield, MD; Peter G. Danias, MD, PhD; David I. Silverman, MD; and
Warren J. Manning, MD
Background: It has been assumed that cardioversion in
patients w i t h atrial fibrillation lasting less than 48 hours is
associated w i t h a low risk for thromboembolism. However,
no clinical data support this assumption.
Objective: To determine the incidence of cardioversionrelated clinical thromboembolism among patients presenting w i t h atrial fibrillation lasting less than 48 hours.
Design: Patients were prospectively identified on admission, and clinical data on the duration of atrial fibrillation
were recorded. Data on cardioversion and thromboembolism were obtained retrospectively from hospital and outpatient records.
Setting: Academic medical center.
Patients: 1822 consecutive patients admitted t o the hospital for atrial fibrillation were screened. Three hundred
seventy-five adults (mean age ± SD, 68 ± 16 years) w i t h
atrial fibrillation that had lasted less than 48 hours were
identified. One hundred eighty-one patients (48.3%) had
a history of atrial fibrillation; 23 (6.1%) had a history of
thromboembolism.
Results: 357 patients (95.2%) converted t o sinus rhythm
during the index admission; spontaneous conversion occurred in 250 patients (66.7%) and active pharmacologic or
electrical conversion was done in 107 patients (28.5%).
Three patients (0.8% [95% CI, 0.2% t o 2.4%]), all of w h o m
had converted spontaneously after ventricular rate control
was begun, had a clinical thromboembolic event: One had
a stroke, 1 had a transient ischemic attack, and 1 had a
peripheral embolus. None of these 3 patients had a history
of atrial fibrillation or thromboembolism, and all had normal left ventricular systolic function.
Conclusion: Among patients presenting w i t h atrial fibrillation that was clinically estimated t o have lasted less than
48 hours, the likelihood of cardioversion-related clinical
thromboembolism is low. These data support the current
recommendation for early cardioversion in these patients.
A
trial fibrillation, the most common sustained
arrhythmia, is responsible for an estimated
266 000 hospital admissions annually (1). This arrhythmia is characterized by lack of coordinated
electrical and mechanical activity in the atria, often
with a rapid ventricular response (2). The loss of
atrial systole leads to depressed cardiac output,
symptoms of dyspnea, and fatigue (2); the resulting
stasis predisposes the patient to the formation of atrial
thrombi and subsequent thromboembolism (2, 3).
Cardioversion of atrialfibrillationto sinus rhythm is
done in an effort to improve cardiac function, relieve
symptoms, and decrease the risk for thrombus formation (2). However, successful cardioversion may
be associated with clinical thromboembolism. Patients with atrial fibrillation lasting 2 days or more
have a 5% to 7% risk for clinical thromboembolism
if cardioversion is not preceded by several weeks of
warfarin therapy (4-7). The risk decreases to 0% to
1.6% with 2 to 4 weeks of warfarin prophylaxis or
shorter-term anticoagulation therapy and screening
by transesophageal echocardiography (4, 6, 8-11).
For patients with atrial fibrillation lasting 2 days
or less, the risk for thromboembolism caused by
cardioversion that was not preceded by prolonged
anticoagulation therapy has been presumed to be
low, and early cardioversion is advocated (2, 12-18).
The assumption that atrial thrombi are rare in this
patient population has recently been challenged:
Transesophageal echocardiography has shown left
atrial thrombi in 14% of patients with atrial fibrillation lasting 3 days or less (3). This has led to
concern about the safety of early cardioversion in
this group. We sought to determine the incidence of
clinical thromboembolism in a large consecutive series of patients who presented with atrial fibrillation
that had lasted less than 48 hours.
Methods
Ann Intern Med. 1997;126:615-620.
From the Beth Israel Deaconess Medical Center and Harvard
Medical School, Boston, Massachusetts; and the John Dempsey
Hospital and University of Connecticut Health Center, Farmington, Connecticut. For current author addresses, see end of text.
We prospectively screened 1214 adults who were
admitted to Beth Israel Hospital, Boston, from 1
January 1990 to 25 September 1995 and 608 adults
who were admitted to the University of Connecticut
Health Center, Farmington, Connecticut, from 28
September 1991 to 29 April 1996 with a diagnosis
© 1997 American College of Physicians
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615
that included atrial fibrillation. From this group, we
identified 375 patients who had atrial fibrillation
that was clinically estimated (on the basis of patient
symptoms, which included acute onset of palpitations, dyspnea, angina, and dizziness) to have lasted
less than 48 hours. Patients were excluded if their
duration of atrial fibrillation could not be clinically
determined or was clinically estimated to have
lasted more than 48 hours. Patients were also excluded if they initially presented with acute thromboembolism (n = 1) or if they were receiving longterm warfarin treatment and had a therapeutic
prothrombin time at presentation (>1.6 times control prothrombin time). Patients who had previously
had thromboembolic events were not excluded.
No attempt was made to modify the practice of
the patients' attending physicians. Clinical and echocardiography data and outcomes were gathered
from the patients' medical records. We recorded
data on the use of cardiovascular and anticoagulant
medications at admission and on the initiation or
discontinuation of therapy with these medications
during hospitalization. Data on transthoracic echocardiography were gathered from clinical studies
done either at admission (n = 187) or during the
previous 6 months (n = 93). Left atrial dimension
was measured in the parasternal long-axis view using M-mode echocardiography (19). Left atrial
length was measured in the apical four-chamber
view from the mitral annulus to the posterior left
atrium. The extent of mitral regurgitation was assessed by pulsed and color Doppler ultrasonography
and given a grade of 0 (none) to 3 (severe) (20).
Left ventricular systolic function was considered abnormal if evidence of global or regional hypokinesis
was found. We recorded only clinical embolic events
(stroke, transient neurologic event, pulmonary embolism, or systemic embolism) that occurred during
the index hospitalization and within 1 month after
conversion.
The total duration of atrial fibrillation was estimated as the time from onset of acute symptoms to
time of conversion to sinus rhythm in the hospital,
as documented by 12-lead electrocardiography or
rhythm strip. Conversion was considered active if an
antiarrhythmic agent known to be effective in the
conversion of atrial fibrillation to sinus rhythm (for
example, quinidine, procainamide, amiodarone, flecainide, sotalol, or propafenone) was given or if
elective direct-current cardioversion was used (2).
Conversion was considered spontaneous if it occurred without the use of such medications or procedures or if it occurred after the initiation of therapy with or an increase in the dosage of a
ventricular rate-controlling agent (such as digoxin,
)3-receptor antagonists, or calcium channel blockers)
(15, 21-24).
616
All data are expressed as the mean ± SD. The
effect of anticoagulation therapy on thromboembolism was assessed using the Fisher exact test (SPSS
for Windows, version 6.1, SAS Institute, Cary,
North Carolina). Confidence intervals were determined using the method of Daly (25).
No funding sources had any role in the collection, analysis, or interpretation of the data. The
funding sources did not review the manuscript at
any time and were not involved in submitting the
paper for publication.
Results
Patient Sample
We studied 375 patients (214 women and 161
men; mean age, 68 ± 16 years [range, 20 to 97
years]) who presented to the hospital with atrial
fibrillation that had lasted less than 48 hours. During the index hospitalization, 357 patients (95.2%)
converted to sinus rhythm; 250 (66.7%) converted
spontaneously, and 107 (28.5%) were actively converted. Underlying systemic disorders that predisposed patients to atrial fibrillation were hypertension (156 patients [41.7%]), infection (25 patients
[6.7%]), excessive alcohol intake (22 patients
[5.9%]), rheumatic heart disease (7 patients [1.9%]),
and other factors (7 patients [1.9%]). One hundred
fourteen patients (30.4%) had a clinical history suggestive of coronary artery disease, as documented by
previous cardiac catheterization, myocardial infarction, or angina pectoris. No underlying disorder was
identified in 91 patients (24.3%). Thirty-nine patients (10.4%) had a history of myocardial infarction, 181 (48.3%) had a history of atrial fibrillation,
and 23 (6.1%) had a history of thromboembolism.
Medications at Presentation
At the time of presentation with atrial fibrillation, some patients were receiving anticoagulant and
antiplatelet medications, including aspirin (93 patients [24.8%]) and warfarin (12 patients [3.2%]).
Patients receiving warfarin had subtherapeutic prothrombin times (<1.6 times control prothrombin
time) at presentation. Some patients were receiving
ventricular rate-controlling medications, such as
digoxin (88 patients [23.5%]), /3-receptor antagonists (84 patients [22.4%]), and calcium channel
blockers (80 patients [21.3%]). Forty-nine patients
(13.1%) were receiving a type I A, IC, or III antiarrhythmic agent at presentation.
Therapy Initiated at Admission and before
Conversion
Anticoagulation or antiplatelet therapy was initiated in more than 60% of patients after they pre-
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sented with atrial fibrillation. Agents included intravenous heparin (133 patients [35.5%]), oral aspirin
(69 patients [18.4%]), and oral warfarin (26 patients
[6.9%]). New medications that were added to treat
slowing of atrioventricular nodal conduction included digoxin (129 patients [34.4%]), calcium channel blockers (105 patients [28%), and j3-receptor
antagonists (77 patients [20.5%]). Antiarrhythmic
agents added to actively convert patients to sinus
rhythm were quinidine (42 patients [11.2%]), procainamide (26 patients [6.9%]), and other antiarrhythmic
agents (6 patients [1.6%]). The duration of the index hospitalization was 4.6 ± 2.4 days.
Transthoracic Echocardiography
The following data were derived from transthoracic echocardiography (n = 280). Patients had a
left atrial dimension of 4.2 ± 0.7 cm (normal, <4.0
cm) and a left atrial length was 5.7 ± 0.7 cm (normal, <5.2 cm). Left ventricular systolic function was
normal in 213 patients (76.1%). Focal hypokinetic
wall-motion abnormalities were seen in 49 patients
(17.5%), and 18 patients (6.4%) had global hypokinesis. Mild mitral regurgitation was found in 157
patients (56.1%), and moderate or severe mitral
regurgitation was found in 61 patients (21.8%). No
patient had transesophageal echocardiography.
Cardioversion-Related Thromboembolism
Three hundred fifty-seven patients (95.2%) converted to sinus rhythm during the index hospitalization. The estimated mean total duration of atrial
fibrillation before conversion was 1.7 ± 1.4 days.
Three patients (0.8% [95% CI, 0.2% to 2.4%]) had
clinical thromboembolic events after conversion to
sinus rhythm and are described below.
Patient 1
An 86-year-old woman with a history of hypertension presented with new-onset palpitations and
new atrial fibrillation (<24 hours' duration), as seen
on electrocardiography at admission. At the time of
admission, she was being treated with aspirin and
digoxin. After presentation, therapy with diltiazem
hydrochloride and metoprolol was initiated. Transthoracic echocardiography showed a left atrial dimension of 4.4 cm, mild to moderate aortic insufficiency,
mild mitral leaflet thickening, mild mitral annular
calcification, and moderate mitral regurgitation.
Left ventricular systolic function was normal. Conversion to sinus rhythm occurred spontaneously
later on the day of admission (total duration of
atrial fibrillation, 24 hours). Less than 12 hours
after conversion, the patient developed Wernicke
aphasia. Results of both 1) computed tomography
and magnetic resonance imaging of the head and 2)
neurologic examination were consistent with a left
parietal embolic stroke.
Patient 2
An 83-year-old woman with a history of coronary
artery disease presented with acute palpitations and
angina with new atrial fibrillation (<24 hours' duration), as seen on electrocardiography at admission. At the time of admission, the medications she
was receiving included metoprolol. Therapy with intravenous heparin and oral digoxin were initiated at
presentation. Transthoracic echocardiography done
during admission showed left atrial dimension of 4.3
cm, normal left ventricular systolic function, mild
aortic stenosis, mild aortic regurgitation, mildly
thickened mitral valve leaflets, moderate mitral annular calcification, and moderate mitral regurgitation. After 2 days of atrial fibrillation, spontaneous
conversion to sinus rhythm occurred, and treatment
with heparin was discontinued. The following day,
the patient had paresthesia of the right arm and
hand. Diminished pulses were found on physical
examination, and angiography confirmed the presence of a proximal brachial artery embolus that was
removed by embolectomy.
Patient 3
An 89-year-old woman with a history of hypertension and sinus rhythm (as assessed by electrocardiography the day before admission) presented with
new-onset palpitations of less than 24 hours' duration
in the setting of pneumonia. Electrocardiography
done on admission showed new atrial fibrillation.
The patient was not receiving cardiac medications
before admission; therapy with diltiazem hydrochloride was started for control of ventricular rate.
Echocardiography showed a left atrial dimension of
2.5 cm, normal left ventricular systolic function,
mildly thickened anterior mitral leaflet, mild mitral
annular calcification, and mild mitral regurgitation.
Spontaneous conversion to sinus rhythm occurred
the following day (total duration of atrial fibrillation
<48 hours). Approximately 12 hours after conversion, the patient was noted to be aphasic. Her symptoms resolved gradually within 6 hours. Therapy
with intravenous heparin was initiated, and the
symptoms did not recur.
Effects of Anticoagulation
No significant difference was found in the incidence of thromboembolism after conversion among
patients in whom therapy with heparin or warfarin
had been initiated on presentation (1 of 133 patients; 0.8% [CI, 0.02% to 4.1%]) and among patients in whom therapy was not initiated (2 of 224
patients; 0.9% [CI, 0.1% to 3.1%]) (P > 0.2). No
statistically significant difference was found when
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patients receiving aspirin were included in the anticoagulation group (2 of 153 patients; 1.3% [CI,
0.2% to 4.6%] compared with 1 of 204 patients;
0.5% [CI, 0.01% to 2.7%]; P > 0.2).
Discussion
In this consecutive series, we found that early
cardioversion (without prolonged anticoagulation
therapy or screening by transesophageal echocardiography) in patients who present with atrial fibrillation that had lasted less than 48 hours is associated with a clinical rate of thromboembolism of
0.8% (CI, 0.2% to 2.4%). Early cardioversion without prolonged warfarin therapy has been advocated
for this group for some time (2, 5, 13, 14, 17, 18);
our data provide direct evidence that early cardioversion is associated with a low risk for clinical
thromboembolism in this population. Moreover, all
thromboembolic events in our group occurred in
patients who had converted spontaneously to sinus
rhythm.
The mechanism of atrial thrombus formation and
subsequent embolization is complex. Goldman (26)
first theorized that embolic complications after cardioversion resulted from preexisting atrial thrombi
that became dislodged and were expelled into the
systemic circulation after conversion to sinus
rhythm. More recently, studies in which transesophageal echocardiography was used (11, 27, 28) have
shown that both direct-current cardioversion and
spontaneous conversion result in the development
of new or more pronounced depression of left atrial
and left appendage function; these conditions promote the formation of new thrombi. Evidence of
the formation of new thrombi immediately after
cardioversion (as seen on transesophageal echocardiography) has also been described (11). These data
support the hypothesis that thrombi may develop
after conversion to sinus rhythm. They are particularly intriguing in light of our study, in which no
patient who had clinical thromboembolism received
anticoagulation therapy after conversion.
By using transesophageal echocardiography, Stoddard and colleagues (3) found left atrial thrombi in
14% of patients with atrial fibrillation that had
lasted less than 72 hours. Several explanations for
the disparity between the prevalence of left atrial
thrombi in that series and the very few clinical events
seen in our population are possible. Our population
represents a consecutive series of patients with
atrial fibrillation, whereas the study by Stoddard and
colleagues (3) included patients who were specifically referred for transesophageal echocardiography,
many of whom had transesophageal echocardiography after acute thromboembolism. In our experi618
ence, patients who present with thromboembolism
in the setting of atrial fibrillation have a greater
than 40% likelihood of residual left atrial thrombi
(29). A second explanation involves the use of anticoagulation therapy: In our series, 50% of patients
were receiving heparin or warfarin at the time of
cardioversion, whereas in the study by Stoddard and
colleagues (3), only 24% of patients were receiving
anticoagulation therapy before transesophageal echocardiography was done. Furthermore, in the patients studied by Stoddard and colleagues, thrombi
may have formed during the period between admission and transesophageal study. Data in the literature suggest that it takes several weeks for thrombi
to resolve with anticoagulation (11, 30); thus, thrombi
that exist at the time of presentation would probably also exist at the time of conversion. Finally, it is
possible that thrombi that were present in our patients (and, perhaps, visible on transesophageal
echocardiography) did not embolize or caused subclinical events.
The incidence of clinical embolic events in our
patients was too low for us to do meaningful statistical analysis; thus, we could not determine clinical
or echocardiographic indexes that may predispose
patients to clinical thromboembolism. Of note, all
three patients with embolic events were elderly
women (>75 years of age). The Stroke Prevention
and Atrial Fibrillation Study I and II (31) identified
this age group as having increased risk for thromboembolism on the basis of multivariate analysis.
The three patients in our study had normal left
ventricular systolic function and normal or only
minimally enlarged left atria. In addition, none of
the three patients had a history of atrial fibrillation
or thromboembolic events, and all three converted
to sinus rhythm spontaneously.
Our data do not allow us to make any definitive
conclusions about the role of anticoagulation therapy in our study population. We found no statistically significant difference in the incidence of thromboembolism in patients who received heparin and
warfarin or aspirin before cardioversion and patients who did not. The very low incidence of
thromboembolism, however, makes our study underpowered to exclude a benefit of anticoagulation
therapy in this group. At the rate we found (0.8%),
a study sample of more than 2500 patients would be
needed to show a significant difference in risk with
anticoagulation therapy (a = 0.05; power = 0.8).
We recommend that anticoagulation therapy with
intravenous heparin be initiated on admission for all
patients with atrial fibrillation, even if the clinically
estimated duration of atrial fibrillation is less than
48 hours, and that therapy with heparin be continued for at least 24 hours after cardioversion. We
believe this strategy is preferable to delaying initia-
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tion of heparin therapy until the duration of atrial
fibrillation has exceeded 48 hours, although the current data on the benefit of this approach are inconclusive. Data from other studies (32-35) suggest
that long-term anticoagulation therapy with warfarin
or aspirin is also beneficial in preventing thromboembolism. Our study sample included only 23 patients (6.1%) with previous thromboembolism and 7
patients (1.9%) with rheumatic heart disease. This
is probably because patients with these conditions
usually receive long-term therapy with warfarin and
therefore were excluded from our study. Thus, we
cannot draw firm conclusions about the safety of
early cardioversion in these two subgroups that are
considered to be at increased risk for thromboembolism. Until more data are available, we suggest
that these two subgroups be treated conservatively
with heparin and warfarin for 3 to 4 weeks (or with
short-term anticoagulation therapy and transesophageal echocardiography) before cardioversion.
Our study had several limitations. It was not a
randomized, controlled trial comparing early cardioversion with delayed cardioversion, and our conclusions are based on relatively few events. Given the
large percentage of patients who convert spontaneously and the very low frequency of embolic events,
a randomized study would have to enroll many
thousands of patients to see a statistically significant
difference in outcome. We believe that the size and
consecutive design of our study suggest that our
data accurately represent current outcomes for this
group. Although patients were identified prospectively, data collection for adverse events was retrospective and may therefore underestimate events.
We conclude that the likelihood of clinical
thromboembolism is very low among patients with
atrial fibrillation lasting less than 48 hours who convert to sinus rhythm. These data support the current
recommendation for early cardioversion in these
patients.
Acknowledgments: The authors thank Drs. Ary L. Goldberger,
George S. Kurland, Arnold M. Katz, and James P. Morgan for
editorial guidance.
Grant Support: In part by the Edward Mallinckrodt Jr. Foundation, St. Louis, Missouri (Dr. Manning), and a Clinical Associate
Physician Award [M01RR06192] from the National Institutes of
Health General Clinical Research Center, Bethesda, Maryland
(Dr. Silverman).
Requests for Reprints: Warren J. Manning, MD, Cardiovascular
Division, Beth Israel Deaconess Medical Center, 330 Brookline
Avenue, Boston, MA 02215.
Current Author Addresses: Drs. Weigner, Caulfield, and Manning:
Beth Israel Deaconess Medical Center, East Campus, 330 Brookline Avenue, Boston, MA 02215.
Drs. Danias and Silverman: University of Connecticut Health
Center, 263 Farmington Avenue, Cardiology L-3108, Farmington,
CT 06030.
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Lots of things I could tell that boy. I could tell him if a woman gets up to any age
at all she's hard to kill. Once her womb dries up without serious trouble, she's over
the hump; she gets solid. She's got to wear out at the far end of ninety or else
Death's got to come and murder her the hard way. Once a women gets fifty, he's had
his last good, clear chance; now he has to be sneaky. Death has to use all his skill to
get old women.
Fooled Elsie, he did. She slid by pneumonia and childbirth, got over being flushed
and queer by the time she was fifty. Then she turned to iron. Never even got a head
cold. Carried all the furniture around on her back, moving it from place to place,
always moving it.
So Death let her get confident. Let her fall down all the cellar stairs and get nothing
but a bad cut along one arm; and then He waited. Used it to strike her down. Blood
poisoning. A chill, a fever, a breath that toothpaste could not clean, a tongue that
water could not wet, a feeling of gloom, some sudden sweats—all the little symptoms.
Guerrilla warfare she couldn't bring her strength to bear upon. She never even
thought to go to a doctor till she'd lost a war she didn't even know had been
declared. Septicemia, the doctor called it.
Doris Betts
The Astronomer and Other Stories
Baton Rouge, LA: Louisiana State Univ Pr; 1965
Submitted by:
Del J. DeHart MD
Michigan State University
Saginaw, MI 48602
Submissions from readers are welcomed. If the quotation is published, the sender's name will be acknowledged. Please include a complete citation, as done for any reference.—The Editor
620
15 April 1997 • Annals of Internal Medicine • Volume 126 • Number 8
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