Atrial Fibrillation: Clinical Features,

Mechanisms, and Management

38
Fred Morady and Douglas P. Zipes

ELECTROCARDIOGRAPHIC FEATURES, 798 Aspirin and Other Antithrombotic NONPHARMACOLOGIC MANAGEMENT

Agents, 802 OF ATRIAL FIBRILLATION, 808
CLASSIFICATION OF ATRIAL
Warfarin, 803 Pacing to Prevent Atrial Fibrillation, 808
FIBRILLATION, 798
Newer Oral Anticoagulants, 803 Catheter Ablation of Atrial Fibrillation, 808
EPIDEMIOLOGY OF ATRIAL Low-Molecular-Weight Heparin, 804 Ablation of the Atrioventricular Node, 810
FIBRILLATION, 800 Excision or Closure of the Left Atrial Surgical Approaches to Atrial Fibrillation, 811
Appendage, 805
MECHANISMS OF ATRIAL SPECIFIC CLINICAL SYNDROMES, 811
FIBRILLATION, 800 ACUTE MANAGEMENT OF ATRIAL Postoperative Atrial Fibrillation, 811
FIBRILLATION, 805 Wolff-Parkinson-White Syndrome, 811
GENETIC FACTORS, 801
Heart Failure, 811
LONG-TERM MANAGEMENT OF ATRIAL
CAUSES OF ATRIAL FIBRILLATION, 801 Pregnancy, 812
FIBRILLATION, 806
CLINICAL FEATURES, 801 Pharmacologic Rate Control Versus Rhythm FUTURE PERSPECTIVES, 812
Control, 806
DIAGNOSTIC EVALUATION, 801 REFERENCES, 812
Pharmacologic Rate Control, 806
PREVENTION OF THROMBOEMBOLIC Pharmacologic Rhythm Control, 807 GUIDELINES, 813
COMPLICATIONS, 802 Rhythm Control with Agents Other Than
Risk Stratification, 802 Antiarrhythmic Drugs, 807

AF that is persistent for longer than 1 year is termed longstanding,

ELECTROCARDIOGRAPHIC FEATURES
Atrial fibrillation (AF) is a supraventricular arrhythmia characterized
electrocardiographically by low-amplitude baseline oscillations
(fibrillatory or f waves) and an irregularly irregular ventricular rhythm.
The f waves have a rate of 300 to 600 beats/min and are variable in
amplitude, shape, and timing. In contrast, flutter waves have a rate of
250 to 350 beats/min and are constant in timing and morphology
(Fig. 38-1). In lead V1, f waves sometimes appear uniform and can
mimic flutter waves (Fig. 38-2). The distinguishing feature from atrial
flutter is the absence of uniform and regular atrial activity in other
leads of the electrocardiogram. In some patients, f waves are very
small and not perceptible on the electrocardiogram. In such patients
the diagnosis of AF is based on the irregularly irregular ventricular
rhythm (Fig. 38-3).
The ventricular rate during AF in the absence of negative dromo-
tropic agents is typically 100 to 160 beats/min. In patients with Wolff-
Parkinson-White syndrome, the ventricular rate during AF can exceed
250 beats/min because of conduction over the accessory pathway
(see Chapter 37). When the ventricular rate during AF is very rapid
(>170 beats/min), the degree of irregularity is attenuated and the
rhythm can seem regular (Fig. 38-4).
The ventricular rhythm can be regular during AF in patients with
a ventricular pacemaker who are fully paced and when a third-degree
atrioventricular (AV) block with a regular escape rhythm is present
(Fig. 38-5). In these cases the diagnosis of AF is based on the pres-
ence of f waves. When there is a third-degree AV block with a junc-
tional escape, a Wenckebach exit block in the AV junction (as can
occur during digitalis toxicity) results in a regularly irregular ventricu-
lar rate (see Chapters 34 and 37).
CLASSIFICATION OF ATRIAL FIBRILLATION
AF that terminates spontaneously within 7 days is termed paroxysmal,
and AF present continuously for more than 7 days is called persistent.
whereas longstanding AF refractory to cardioversion is termed per-
manent. However, “permanent AF” is not necessarily permanent in
the literal sense because it may be eliminated successfully by surgical
or catheter ablation.
Some patients with paroxysmal AF can occasionally have episodes
that are persistent, and vice versa. The predominant form of AF
determines how it should be categorized.
A confounding factor in the classification of AF is cardioversion
and antiarrhythmic drug therapy. For example, if a patient undergoes
transthoracic cardioversion 24 hours after the onset of AF, it is
unknown whether the AF would have persisted for more than 7 days.
Furthermore, antiarrhythmic drug therapy may change persistent AF
into paroxysmal AF. It is generally thought that the classification of
AF should not be altered on the basis of the effects of electrical car-
dioversion or antiarrhythmic drug therapy.
Lone AF refers to AF that occurs in patients younger than 60 years
who do not have hypertension or any evidence of structural heart
disease. This designation is clinically relevant because patients with
lone AF are at lower risk for thromboembolic complications, thus
eliminating the necessity for anticoagulation with warfarin. In addi-
tion, the absence of structural heart disease allows the safe use of
rhythm-control drugs such as flecainide in patients with lone AF.
Paroxysmal AF can also be classified clinically on the basis of the
autonomic setting in which it most often occurs. Approximately 25%
of patients with paroxysmal AF have vagotonic AF, in which AF is
initiated in the setting of high vagal tone, typically in the evening
when the patient is relaxing or during sleep. Drugs that have a vago-
tonic effect (such as digitalis) can aggravate vagotonic AF, and drugs
that have a vagolytic effect (such as disopyramide) may be particu-
larly appropriate for prophylactic therapy. Adrenergic AF occurs in
approximately 10% to 15% of patients with paroxysmal AF in the
setting of high sympathetic tone, for example, during strenuous exer-
tion. In patients with adrenergic AF, beta blockers not only provide
rate control but can also prevent the onset of AF. Most patients have
a mixed or random form of paroxysmal AF, with no consistent pattern
of onset.

798 Additional content is available online at ExpertConsult.

 799

38
V1

Atrial Fibrillation: Clinical Features, Mechanisms, and Management

II

V5

V1

II

V5

FIGURE 38-1 Comparison of the f waves of AF (top panel) and the flutter waves of atrial flutter (bottom panel). Note that f waves are variable in rate, shape, and amplitude
whereas flutter waves are constant in rate and all aspects of morphology. Shown are leads V1, II, and V5.

V1

II

V5

FIGURE 38-2 Example of AF with prominent f waves in V1 that mimic atrial flutter waves. Note that typical f waves are present in leads II and V5, thereby establishing the
diagnosis of AF.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

FIGURE 38-3 A 12-lead electrocardiogram of AF in which f waves are not discernible. The irregularly irregular ventricular rate indicates that this is AF and not a
junctional rhythm.
 800

V V1
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

II

V5

FIGURE 38-4 Recording of AF with a rapid ventricular rate of 160 beats/min. Shown are leads V1, II, and V5. On quick review there may appear to be a regular rate consistent
with paroxysmal supraventricular tachycardia. On closer inspection, however, it is clear that the rate is irregularly irregular.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

VI

II

V5

FIGURE 38-5 Atrial fibrillation with complete heart block and a regular junctional rhythm at a rate of 45 beats/min.

EPIDEMIOLOGY OF ATRIAL FIBRILLATION
AF is the most common arrhythmia treated in clinical practice and
the most common arrhythmia for which patients are hospitalized;
approximately 33% of arrhythmia-related hospitalizations are for AF.
AF is associated with an approximately fivefold increase in the risk
for stroke and a twofold increase in the risk for all-cause mortality.1
AF is also associated with the development of heart failure.
Estimates of the actual number of individuals with AF in the United
States range between 2.3 and 5 million in most studies. The incidence
of AF is age and sex related and ranges from 0.1% per year before
the age of 40 years to higher than 1.5% per year in women and
higher than 2% per year in men older than 80 years. Heart failure,
aortic and mitral valve disease, left atrial enlargement, hypertension,
and advanced age are independent risk factors for the development
of AF, as are obesity and obstructive sleep apnea2 (see Chapter 75).
Another risk factor is psoriasis, which when severe, triples the risk for
AF in patients younger than 50 years.3
A community-based cohort study in Olmstead County, Minnesota,
reported that the age-adjusted incidence of AF per 1000 person-years
increased significantly between 1980 and 2000 from 4.4 to 5.4 in men
and from 2.4 to 2.8 in women.4 There was a relative increase of 0.6% per
year in the age-adjusted incidence of AF. An increase in obesity
accounted for 60% of the age-adjusted increase in AF incidence. The
number of patients with AF in the United States was estimated to be 3.2
million in 1980 and 5.1 million in 2000 and was projected to be 12.1 to
15.9 million in 2050, all of which are higher than previous estimates.
MECHANISMS OF ATRIAL FIBRILLATION
The mechanisms responsible for AF are complex. Triggering events
may differ from maintenance mechanisms. In addition, the clinical
phenotypes of paroxysmal, persistent, and longstanding persistent
AF have different electrophysiologic characteristics because of
remodeling and different clinical modulators that affect the substrate,
such as heart failure, atrial stretch and ischemia, sympathovagal
influences, inflammation, and fibrosis.
There are probably two electrophysiologic mechanisms of AF:
one or more automatic, triggered, or microreentrant foci, so-called

drivers, which fire at rapid rates and cause fibrillation-like activity,
and multiple reentrant circuits meandering throughout the atria
that annihilate and reform wavelets, thereby perpetuating the fibril-
lation. In many studies the left atrium contains the site of dominant
frequency discharge, with a left-to-right gradient. Both mechanisms
may be present simultaneously. In a recent study, computational
maps were obtained in patients by signal processing of multiple elec-
trograms recorded simultaneously during AF.5 This technique can
reveal electrical rotors and focal sources. A mean of 2.1 sources was
found in 97% of 101 patients, with 70% being rotors and 30% being
focal sources.
Rapid discharges from the pulmonary veins are the most common
triggers of AF and may also play a perpetuating role, more so in
paroxysmal AF than in persistent AF. This is why pulmonary vein
isolation is particularly effective for elimination of paroxysmal AF. In
persistent AF, changes in the atrial substrate, including interstitial
fibrosis, which contributes to slow, discontinuous, and anisotropic
conduction, may give rise to complex fractionated atrial electrograms
(CFAEs) and reentry. Therefore, pulmonary vein isolation is rarely
sufficient to eliminate persistent AF, and additional ablation of the
atrial substrate is usually necessary.
GENETIC FACTORS
Several mutations that are responsible for familial AF and that predis-
pose to AF have been identified.6 These mutations cause a gain of
function of repolarization potassium currents that results in shorten-
ing of atrial refractoriness and facilitation of atrial reentry. Multiple
polymorphisms that are associated with AF that is idiopathic, are
associated with structural heart disease, or occur postoperatively
have also been identified.6 These polymorphisms are in genes that
affect potassium and sodium channels, sarcolipin, the renin-
angiotensin system, connexin 40, endothelial nitric oxide synthase,
and interleukin-10. The end results are changes in calcium handling,
fibrosis, conduction, and inflammation that predispose to AF.
CAUSES OF ATRIAL FIBRILLATION
Most patients with AF have hypertension (usually with left ventricular
hypertrophy; see Chapters 43 and 44) or some other form of struc-
tural heart disease. In addition to hypertensive heart disease, the
most common cardiac abnormalities associated with AF are isch-
emic heart disease, mitral valve disease, hypertrophic cardiomyopa-
thy, and dilated cardiomyopathy. Less common causes of AF are
restrictive cardiomyopathies such as amyloidosis, constrictive peri-
carditis, and cardiac tumors. Severe pulmonary hypertension is often
associated with AF.
Obesity and obstructive sleep apnea (see Chapter 75) are associ-
ated with each other, and both have been found to independently
increase the risk for AF.2 The data available suggest that atrial dilation
and an increase in systemic inflammatory factors are responsible for
the relationship between obesity and AF. Possible mechanisms of AF
in patients with sleep apnea include hypoxia, surges in autonomic
tone, and hypertension.
AF can be due to causes that are temporary or reversible. The most
common temporary causes are excessive alcohol intake (holiday
heart), open heart or thoracic surgery, myocardial infarction, pericar-
ditis (see Chapter 71), myocarditis, and pulmonary embolism (see
Chapter 73). The most common correctable cause is hyperthyroid-
ism (see Chapter 81).
AF is sometimes induced by tachycardia. Patients with tachycardia-
induced AF most often have AV nodal reentrant tachycardia or a
tachycardia related to Wolff-Parkinson-White syndrome that degener-
ates into AF. If a patient with AF has a history of rapid and regular
palpitations before the onset of irregular palpitations or has a Wolff-
Parkinson-White electrocardiographic pattern, this should raise sus-
picion for tachycardia-induced AF. Treatment of the tachycardia that
triggers the AF often but not always prevents recurrences of AF.
801
CLINICAL FEATURES
38
The symptoms of AF vary widely between patients and range from none
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
to severe and functionally disabling. The most common symptoms of
AF are palpitations, fatigue, dyspnea, effort intolerance, and lighthead-
edness. Polyuria can occur because of the release of atrial natriuretic
hormone. Many patients with symptomatic paroxysmal AF also have
asymptomatic episodes, and some patients with persistent AF have
symptoms only intermittently, thus making it difficult to accurately
assess the frequency and duration of AF on the basis of symptoms.
It is estimated that approximately 25% of patients with AF are
asymptomatic, more commonly elderly patients and those with per-
sistent AF. Such patients are sometimes erroneously classified as
having asymptomatic AF despite the presence of fatigue or effort
intolerance. Because fatigue is a nonspecific symptom, it may not be
clearly due to persistent AF. “Diagnostic cardioversion” may be
helpful by maintaining sinus rhythm for at least a few days to deter-
mine whether a patient feels better in sinus rhythm. This can provide
a basis to pursue a rhythm-control versus rate-control strategy.
Syncope is an uncommon symptom of AF. It can be caused by a
long sinus pause on termination of AF in a patient with sick sinus
syndrome. Syncope can also occur during AF with a rapid ventricular
rate either because of neurocardiogenic (vasodepressor) syncope
that is triggered by the tachycardia or because of a severe drop in
blood pressure secondary to a reduction in cardiac output.
Asymptomatic or minimally symptomatic AF patients are not
prompted to seek medical care and can initially be seen with a
thromboembolic complication such as stroke or the insidious onset
of heart failure symptoms that eventually results in florid congestive
heart failure.
The hallmark of AF on physical examination is an irregularly irreg-
ular pulse. Short R-R intervals during AF do not allow adequate time
for left ventricular diastolic filling, which results in a low stroke
volume and the absence of palpable peripheral pulse. This leads to
a “pulse deficit,” during which the peripheral pulse is not as rapid as
the apical rate. Other manifestations of AF on physical examination
are irregular jugular venous pulsations and variable intensity of the
first heart sound.
DIAGNOSTIC EVALUATION
In a patient who describes irregular or rapid palpitations suggestive
of paroxysmal AF, ambulatory monitoring is useful to document
whether AF is responsible for the symptoms. If the symptoms occur
on a daily basis, a 24-hour Holter recording is appropriate. However,
extended monitoring for 2 to 4 weeks with an event monitor or by
mobile cardiac outpatient telemetry is appropriate for patients whose
symptoms are sporadic (see Chapter 34).
The history should be directed at determination of the type and
severity of symptoms, the first onset of AF, whether the AF is parox-
ysmal or persistent, triggers for AF, whether the episodes are random
or occur at particular times (such as during sleep), and the frequency
and duration of episodes. When it is unclear from the history, 2 to 4
weeks of ambulatory monitoring with an autotrigger event monitor
or by mobile cardiac outpatient telemetry is useful to determine
whether the AF is paroxysmal or persistent and to quantitate the AF
burden in patients with paroxysmal AF. The history also should be
directed at identification of potentially correctible causes (e.g., hyper-
thyroidism, excessive alcohol intake), structural heart disease, and
comorbid conditions.
Laboratory testing should include thyroid function tests, liver func-
tion tests, and renal function tests. Echocardiography is always
appropriate to evaluate atrial size and left ventricular function and
to look for left ventricular hypertrophy, congenital heart disease
(see Chapter 62), and valvular heart disease. Chest radiography is
appropriate if the history or findings on physical examination are
suggestive of pulmonary disease (see Chapter 15). A stress test is
appropriate for evaluation of ischemic heart disease in at-risk patients
(see Chapter 13).
 802
PREVENTION OF THROMBOEMBOLIC
V
COMPLICATIONS
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE
Risk Stratification
A major goal of therapy in patients with AF is to prevent thromboem-
bolic complications such as stroke. It is well established that warfarin
is more effective than aspirin for prevention of thromboembolic com-
plications.7 However, because of the risk for hemorrhage during war-
farin therapy, its use should be limited to patients whose risk for
thromboembolic complications is greater than their risk for hemor-
rhage. Therefore, it is useful to risk-stratify patients with AF to identify
appropriate candidates for warfarin therapy.
The strongest predictors of ischemic stroke and systemic thrombo-
embolism are a history of stroke or a transient ischemic episode and
mitral stenosis. When patients with AF and a previous ischemic
stroke are treated with aspirin, the risk for another stroke is very high,
in the range of 10% to 12% per year. At the other end of the risk spec-
trum are patients with lone AF, whose cumulative 15-year risk for
stroke was reported to be in the range of 1% to 2%. Aside from previ-
ous stroke, the best-established risk factors for stroke in patients with
nonvalvular AF are diabetes (relative risk, 1.7), hypertension (relative
risk, 1.6), heart failure (relative risk, 1.4), and age 70 years or older
(relative risk, 1.4 per decade).8
A simple clinical scheme to risk-stratify patients on the basis of
major risk factors is the CHADS2 (cardiac failure, hypertension, age,
diabetes, stroke) score. Each of the first four risk factors is worth 1
point, and a previous stroke or transient ischemic event is worth 2
points. There is a direct relationship between the CHADS2 score and
the annual risk for stroke in the absence of aspirin or warfarin therapy.
The clinical value of the CHADS2 score lies in its simplicity and pre-
dictive value. However, recent studies have demonstrated that the
CHA2DS2-VASc score more accurately discriminates low-risk from
intermediate-risk patients.9
In this risk score system, cardiac failure, hypertension, diabetes,
vascular disease, 65 to 74 years of age, and female sex are worth 1
point each, whereas age 75 years or older and previous stroke or
transient ischemic event are worth 2 points. The annual risk for stroke
is zero or close to zero when the CHA 2DS2-VASc score is 0, as opposed
to approximately 2% when the CHADS2 score is 0.10 A score of 1 is
associated with an annual stroke risk of approximately 3% with the
CHADS2 score versus 0.7% with the CHA 2DS2-VASc score (Fig. 38-6).
A large-scale study demonstrated that renal failure is also an inde-
pendent risk factor for stroke in patients with AF.11 The relative risk
for a thromboembolic event in the absence of anticoagulation was
1.4 in patients with an estimated glomerular filtration rate lower than
45 mL/min/1.73 m2. The predictive strength of this degree of renal
failure for a thromboembolic event appears to be equivalent to that
20
CHADS2
18
CHA2DS2-VASc
ANNUAL STROKE RATE
16
14
12
10
8
6 Except for labile INR, it is likely that the components of the HAS-BLED
4 score also apply to patients in whom a direct thrombin inhibitor or
2 tive value of the HAS-BLED score in patients treated with one of the
0 newer antithrombotic agents has not yet been determined.
0 1 2 3 4 5 6 7 8 9
FIGURE 38-6 Annual risk for stroke (percent risk per year) based on the CHADS2
and CHA2DS2-VASc scores. (Based on data from Lip GY: Implications of the CHA[2]
DS[2]-VASc and HAS-BLED scores for thromboprophylaxis in atrial fibrillation. Am J
Med 124:111, 2011.)
of heart failure and advanced age. Therefore, it may be appropriate
to take renal failure into account in evaluating the risk profile of a
patient with AF.
By definition, the burden of AF is greater in patients with persistent
AF than in those with paroxysmal AF. It may seem reasonable to
assume that the risk for stroke is lower in patients with occasional
episodes of self-limited AF than in those with AF continuously.
However, the data available in fact indicate that the risk for thrombo-
embolic complications is the same in patients with paroxysmal and
persistent AF. Even 15 minutes of AF may be long enough to result in
local cardiac platelet activation and endothelial dysfunction, which
predispose to thrombus formation during an acute episode of AF.12
Therefore, the type of AF should not be taken into account in risk-
stratifying AF patients for thromboembolic risk.
Modern-day dual-chamber pacemakers and implantable
cardioverter-defibrillators (ICDs) are capable of detecting short epi-
sodes of asymptomatic AF that would otherwise not have been
detected clinically. In a recent multicenter prospective study, sub-
clinical atrial tachyarrhythmias (atrial rate >190 beats/min for >6
minutes) were detected by device interrogation in 10.1% of patients
65 years or older with hypertension and no history of AF who received
a pacemaker or ICD.13 Subclinical atrial tachyarrhythmias were inde-
pendently associated with a 2.5-fold increase in the risk for stroke.
An important consideration in patients treated with an oral antico-
agulant is the risk for bleeding. Several risk stratification scoring
systems have been developed to assess a patient’s susceptibility to
hemorrhagic complications. The scoring system with the best balance
of simplicity and accuracy is the HAS-BLED score.14 The components
of this score are hypertension, abnormal renal or liver function,
stroke, bleeding history or predisposition, labile international normal-
ized ratio (INR), older age (>75 years), and concomitant drug (anti-
platelet agent or nonsteroidal anti-inflammatory drug) or alcohol use.
Each of these components is worth 1 point. As the score increases
from 0 to the maximum of 9, there is a stepwise increase in the risk
for bleeding in patients treated with warfarin. For example, in one
study the annual rate of major bleeding was 1.1% in patients with a
HAS-BLED score of 0, 3.7% with a score of 3, and 12.5% with a score
of 5.15
In two large-scale cohort studies totaling 132,372 patients16 and
170,292 patients17 with nonvalvular AF, the CHA 2DS2-VASc and HAS-
BLED scores were calculated for each patient. The net clinical benefit
of warfarin was defined as the number of strokes while not taking
warfarin minus the number of intracranial bleeding episodes while
taking warfarin. In both studies, warfarin was associated with a net
clinical benefit except when the CHA2DS2-VASc score was 0. In
patients with a CHA 2DS2-VASc score of 1 or higher, the risk for stroke
in the absence of warfarin exceeded the number of bleeding compli-
cations during treatment with warfarin.
The results of these large cohort studies notwithstanding, the deci-
sion to institute anticoagulation in a patient in clinical practice should
be individualized. At times it may be appropriate to not initiate anti-
coagulation in a patient with a CHA 2DS2-VASc score of 1 or higher.
For example, the annual risk for stroke in a patient with a CHA 2DS2-
VASc score of 2 is approximately 2%, which usually justifies the use
of warfarin. However, if that patient has a HAS-BLED score of 5 or
higher, which is associated with an annual risk for major bleeding of
12% or higher, it would be imprudent to treat that patient with
warfarin.
It should be noted that the HAS-BLED score was developed and
validated in patients in whom warfarin was used for anticoagulation.
factor Xa inhibitor is used for anticoagulation. However, the predic-
Aspirin and Other Antithrombotic Agents
Aspirin does not prevent thromboembolic complications as effec-
tively as warfarin does in patients with AF. In a meta-analysis of five

randomized clinical trials, aspirin reduced the risk for stroke by only
18%.7 In a recent large cohort study of patients with nonvalvular AF,
aspirin had no therapeutic efficacy in preventing strokes.16 Therefore,
if aspirin is used for prophylactic therapy, it should be used only in
patients at lowest risk for thromboembolic complications (CHA 2DS2-
VASc score of 0). The 2011 American College of Cardiology/American
Heart Association/Heart Rhythm Society guidelines still recommend
aspirin for stroke prevention in patients with a CHADS2 score of 0 and
either aspirin or an oral anticoagulant when the CHADS2 score is 1.18
Because of the negligible therapeutic effect of aspirin, a risk for bleed-
ing complications that is close to the risk associated with oral anti-
coagulants, and the ability of the CHA 2DS2-VASc score to accurately
identify low-risk patients, the most recent guidelines of the European
Society of Cardiology recommend no antithrombotic therapy when
the CHA 2DS2-VASc score is 0 and an individualized decision regard-
ing no antithrombotic therapy versus an oral anticoagulant when the
CHA 2DS2-VASc score is 1.19
If aspirin is used for stroke prevention in patients with AF, the
appropriate daily dose is 81 to 325 mg/day. No data are available
to indicate superiority of a particular dose for prevention of
thromboembolism.
In patients with a CHADS2 score higher than 1 who are not able to
tolerate anticoagulation with warfarin, combination therapy with
aspirin and the platelet inhibitor clopidogrel is more efficacious than
aspirin alone for prevention of thromboembolic complications. In a
randomized, double-blind clinical trial (ACTIVE-A), all patients with
AF and one or more risk factors for stroke who were not suitable
candidates for anticoagulation with warfarin were treated with 75 to
100 mg/day of aspirin.20 The patients were randomly assigned to also
receive either 75 mg/day of clopidogrel or a matching placebo. The
primary outcome was a composite of stroke, myocardial infarction,
systemic embolism, and vascular death. When compared with
placebo, clopidogrel reduced the risk for stroke by 28% and risk for
the primary outcome by 11% but increased the risk for major hemor-
rhage. The study demonstrated that for every 1000 patients treated
with the combination of aspirin plus clopidogrel instead of aspirin
alone, 28 strokes (17 fatal or disabling) and 6 myocardial infarctions
would be prevented, at a cost of 20 major bleeding episodes (3 fatal).
Therefore, in high-risk patients who are not suitable candidates for
warfarin, the benefits of combination therapy with aspirin plus clopi-
dogrel outweigh the risk.
Warfarin
A meta-analysis of the major randomized clinical trials in which
warfarin was compared with placebo for prevention of thromboem-
bolism in patients with AF demonstrated that warfarin reduced the
risk for all strokes (ischemic and hemorrhagic) by 61%.7 The target
INR should be 2.0 to 3.0. This range of INRs provides the best balance
between stroke prevention and hemorrhagic complications. In clini-
cal practice, maintenance of the INR in the therapeutic range has
been challenging, and a large proportion of patients often have an
INR lower than 2.0. A large prospective study of community-based
practices demonstrated that the mean time in the therapeutic range
in patients treated with warfarin was just 66% and that the time in the
therapeutic range was less than 60% in 34% of patients.21 Maintaining
the INR at a level of 2.0 or higher is important because even a rela-
tively small decrease in the INR from 2.0 to 1.7 more than doubles the
risk for stroke. Furthermore, the data available indicate that the com-
bination of aspirin and low-intensity anticoagulation with warfarin is
inferior to warfarin in the standard therapeutic range for stroke
prevention.
The annual risk for a major hemorrhagic complication during anti-
coagulation with warfarin is in the range of 1% to 2%, and a strong
predictor of major bleeding events is an INR higher than 3.0. For
example, the risk for intracranial bleeding is approximately twice as
high at an INR of 4.0 than at 3.0. This emphasizes the importance of
maintaining the INR in the range of 2.0 to 3.0.
Some studies have indicated that advanced age can be a risk
factor for intracranial hemorrhage in patients with AF who are treated
803
with warfarin. The fear of hemorrhagic complications may lead
some clinicians to favor the use of aspirin over warfarin in older 38
adults. However, recent data indicate that the risk-to-benefit ratio of
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
warfarin is more favorable than that of aspirin, even in patients older
than 75 years. A randomized clinical trial (the Birmingham Atrial
Fibrillation Treatment of the Aged Study) enrolled 973 patients older
than 75 years (mean age, 82 years) with AF and randomly assigned
them to treatment with 75 mg/day of aspirin or with warfarin adjusted
to maintain an INR of 2.0 to 3.0.22 The primary endpoint was the
composite of stroke (ischemic or hemorrhagic), intracranial hemor-
rhage, and arterial embolism, and the mean duration of follow-up
was 2.7 years. The annual risk for the composite endpoint was signifi-
cantly higher in the aspirin group (3.8%) than in the warfarin group
(1.8%), even when the analysis was limited to patients older than 85
years. These data suggest that age should not be considered a con-
traindication to treatment with warfarin in patients with AF.
It is well established that genetic factors influence the dose of
warfarin required to maintain the INR within the therapeutic range.
Several single nucleotide polymorphisms that affect warfarin metab-
olism have been identified. Algorithms based on pharmacogenetic
(see Chapter 9) and clinical factors improve the accuracy of warfa-
rin dose initiation more than do algorithms based only on clinical
factors, particularly for outliers who require 21 mg/wk or less or
49 mg/wk or more of warfarin to maintain a therapeutic INR.23
However, a randomized study demonstrated that warfarin dosing that
took into account the results of genotyping for CYP2C9 (a cytochrome
P-450 isoform) and VKORC1 (a vitamin K epoxide reductase complex
subunit) did not improve the time in the therapeutic range, which
was approximately 70% in both groups.24 Additional studies are
required to determine whether the clinical benefits of genotyping of
warfarin candidates justify the cost of genetic testing.
Newer Oral Anticoagulants
Direct thrombin inhibitors and factor Xa inhibitors have several
advantages over vitamin K antagonists such as warfarin, the most
notable being a fixed dosing regimen, which eliminates the need for
monitoring of a laboratory test such as the INR. Dabigatran, an oral
direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, were
approved by the Food and Drug Administration for prevention of
stroke/embolism in patients with nonvalvular AF in 2010 and 2011,
respectively. Another factor Xa inhibitor, apixaban, was expected to
gain Food and Drug Administration approval in 2013.
Randomized clinical trials have demonstrated that each of these
three new oral anticoagulants is noninferior or superior to warfarin
in efficacy and safety. These studies included patients with nonval-
vular AF who had risk factors for stroke. In the RE-LY study, dabiga-
tran at a dose of 150 mg twice daily was associated with a lower risk
for stroke and systemic embolism than warfarin was and a similar
rate of major hemorrhage.25 In the ROCKET-AF study, rivaroxaban at
a dose of 20 mg once daily was noninferior to warfarin for prevention
of stroke/systemic embolism and was associated with a risk for major
bleeding that did not differ from that of warfarin.26 However, intracra-
nial hemorrhage and fatal bleeding were less common with rivaroxa-
ban. In the ARISTOTLE study, apixaban at a dose of 5 mg twice daily
was superior to warfarin in prevention of stroke/systemic embolism
and was associated with a lower risk for hemorrhagic complications
and lower mortality (Fig. 38-7).27
The newer oral anticoagulants, in addition to eliminating the need
for laboratory monitoring, have other advantages over warfarin: fewer
drug interactions, no food interactions, and a rapid onset of action
that obviates the need for bridging therapy. However, they also have
some disadvantages in comparison to warfarin: higher cost, more
gastrointestinal side effects in the case of dabigatran, twice-daily
dosing in the case of dabigatran and apixaban, and absence of a
laboratory test to verify compliance. Furthermore, these agents
cannot be used safely in patients with severe renal disease. Another
limitation is that the effects of the newer anticoagulants may be dif-
ficult to reverse in patients with an overdose or hemorrhage. For
example, in a 2011 study, a single bolus of 50 IU/kg of prothrombin
 804
Total mortality used in patients with a creatinine
V clearance lower than 30 mL/min.
NOACs VKAs Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
An issue that has not been
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

addressed in a randomized clini-

NCT01136408(D) 0 104 0 62 Not estimable cal trial is whether the newer oral
PETRO 0 166 0 70 Not estimable anticoagulants provide adequate
RE-LY 884 12091 487 6022 41.1% 0.90 (0.81, 1.01)
protection from the thromboem-
WEITZ 11 713 3 250 0.3% 1.29 (0.36, 4.57)
CHUNG 1 159 1 75 0.1% 0.47 (0.03, 7.44) bolic complications of transtho-
YAMASHITA 1 260 1 125 0.1% 0.48 (0.03, 7.62) racic cardioversion. Although
ARISTOTLE-J 0 148 0 74 Not estimable not studied prospectively, the
ARISTOTLE 603 9120 669 9081 42.4% 0.90 (0.81, 1.00) safety of dabigatran in patients
NCT00973245 (R1) 0 75 0 27 Not estimable undergoing cardioversion was
NCT00973323 (R2) 0 50 0 26 Not estimable evaluated in a post hoc analysis
J-ROCKET-AF 7 637 5 637 0.3% 1.40 (0.45, 4.39) of the RE-LY study.30 A subset
ROCKET-AF 208 7061 260 7082 15.8% 0.83 (0.70, 1.00) of 1336 patients underwent
cardioversion after 3 weeks or
Total (95%, Cl) 30584 23531 100.0% 0.89 (0.83, 0.96)
Total events 1715 1416 more of treatment with dabiga-
Heterogeneity: Chi2 = 1.91, df = 6 (P = 0.93); I2 = 0% 0.01 0.1 1 10 100 tran, 150 mg twice daily, or dose-
A Test for overall effect: Z = 3.24 (P = 0.001) Favors NOACs Favors VKAs adjusted warfarin with an INR of
2.0 to 3.0. The stroke/systemic
Cardiovascular mortality embolism rate at 30 days did
NOACs VKAs Risk Ratio Risk Ratio not differ significantly between
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl the dabigatran group (0.3%)
and the warfarin group (0.6%).
NCT01136408 (D) 0 104 0 62 Not estimable
There was also no difference
PETRO 0 166 0 70 Not estimable
RE-LY 563 12091 317 6022 43.8% 0.88 (0.77, 1.01) between the two groups in the
WEITZ 6 713 2 250 0.3% 1.05 (0.21, 5.18) rate of major bleeding (0.6% in
CHUNG 1 159 0 75 0.1% 1.43 (0.06, 34.57) both groups). These data suggest
YAMASHITA 0 260 0 125 Not estimable that dabigatran is a safe and
ARISTOTLE-J 0 148 0 74 Not estimable effective alternative to warfarin
ARISTOTLE 308 9120 344 9081 35.7% 0.89 (0.77, 1.04) in patients requiring cardiover-
NCT00973245 (R1) 0 75 0 27 Not estimable sion. However, because patient
NCT00973323 (R1) 0 50 0 26 Not estimable compliance and a therapeutic
J-ROCKET-AF 6 637 2 637 0.2% 3.00 (0.61, 14.81)
effect of dabigatran cannot be
ROCKET-AF 170 7061 193 7082 19.9% 0.88 (0.72, 1.08)
confirmed by laboratory testing,
Total (95%, Cl) 30584 23531 100.0% 0.89 (0.82, 0.98) a precardioversion transesopha-
Total events 1054 858 geal echocardiogram to rule
Heterogeneity: Chi2 = 2.36, df = 5 (P = 0.80); I2 = 0% 0.01 0.1 1 10 100 out a left atrial thrombus may
B Test for overall effect: Z = 2.50 (P = 0.001) Favors NOACs Favors VKAs be appropriate more often in
patients treated with dabigatran
FIGURE 38-7 Total (A) and cardiovascular (B) mortality during oral anticoagulant treatment. ARISTOTLE = Apixaban for the
Prevention of Stroke in Subjects with Atrial Fibrillation; CI = confidence interval; J-ARISTOTLE = Japanese Apixaban for the Preven- than in those treated with
tion of Stroke in Subjects with Atrial Fibrillation; J-ROCKET-AF = An Efficacy and Safety Study of Rivaroxaban with Warfarin for warfarin.
the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation in The onset of action of dabiga-
Japan; M-H = Mantel-Haenszel; NCT = National Clinical Trials database; NOACs = novel oral anticoagulants; RE-LY = Randomized tran, rivaroxaban, and apixaban
Evaluation of Long-Term Anticoagulant Therapy; ROCKET-AF = An Efficacy and Safety Study of Rivaroxaban with Warfarin for the
Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation; VKAs is approximately 1.5 to 2 hours
= vitamin K antagonists. (From Dentali F, Riva N, Crowther M, et al: Efficacy and safety of the novel oral anticoagulants in atrial after a dose. The half-lives of
fibrillation: A systematic review and meta-analysis of the literature. Circulation 126:2381, 2012.) dabigatran and apixaban range
between 10 and 16 hours, and
the half-life of rivaroxaban is 5 to
complex concentrate was demonstrated to quickly and completely 9 hours. These anticoagulants lose most of their effect by 24 hours
reverse the anticoagulant effect of rivaroxaban, but not dabigatran.28 after discontinuation. The rapid onset of action and washout elimi-
Nonetheless, for many patients with AF, the advantages of the newer nate the need for bridging therapy with heparin when treatment with
anticoagulants outweigh the disadvantages. one of the new anticoagulants is interrupted for a surgical or invasive
The major professional societies have incorporated recommenda- procedure. In a recent study of patients treated with dabigatran who
tions regarding the use of factor Xa and/or direct thrombin inhibitors underwent radiofrequency catheter ablation of AF, dabigatran was
into their most recent updates of guidelines for the management of withheld on the morning of the procedure.31 The study included a
AF. The practice guidelines of the American College of Cardiology/ comparison group of patients who underwent radiofrequency cath-
American Heart Association/Heart Rhythm Society recommend eter ablation of AF during uninterrupted therapy with warfarin at an
dabigatran as a useful alternative to warfarin for prevention of stroke/ INR of 2.0 to 3.0. Major hemorrhagic complications occurred signifi-
systemic embolism in patients with nonvalvular paroxysmal or per- cantly more often in the dabigatran group (6%) than in the warfarin
sistent AF and risk factors for stroke. However, this recommendation group (1%). The results of this study demonstrate that dabigatran
is limited to patients without a prosthetic valve, with creatinine clear- should be withheld for at least 24 hours before an invasive or surgical
ance lower than 15 mL/min, or with impaired clotting function as a procedure.
result of advanced liver disease.29 The European Society of Cardiol-
ogy guidelines recommend dabigatran, rivaroxaban, or apixaban for
patients with AF in whom maintenance of a therapeutic INR during Low-Molecular-Weight Heparin
treatment with warfarin is difficult and state that one of these newer Low-molecular-weight heparin has a longer half-life than unfraction-
anticoagulants should be considered instead of dose-adjusted warfa- ated heparin does and a predictable antithrombotic effect that is
rin for most patients with nonvalvular AF, based on their net clinical attained with a fixed dosage administered subcutaneously twice a
benefits.19 The guidelines also recommend that these agents not be day. Because low-molecular-weight heparin can be self-injected by

patients outside the hospital, it is a practical alternative to unfraction-
ated heparin for initiation of anticoagulation with warfarin in patients
with AF. Bridging therapy with low-molecular heparin should be con-
tinued until the INR is 2.0 or higher.
Because of its high cost, low-molecular-weight heparin is rarely
used in clinical practice as a substitute for long-term conventional
anticoagulation. Low-molecular-weight heparin is typically used as a
temporary bridge to therapeutic anticoagulation when therapy with
warfarin is initiated or in high-risk patients for a few days before and
after a medical or dental procedure when anticoagulation with war-
farin has been suspended.
Excision or Closure of the Left
Atrial Appendage
Approximately 90% of left atrial thrombi form in the appendage,
and therefore successful excision or closure of the left atrial append-
age should markedly reduce the risk for thromboembolic complica-
tions in patients with AF. Surgical techniques consist of either excision
or closure by suturing or stapling. The efficacy of these techniques
is variable and probably dependent on both technique and the
operator. Postoperative transesophageal echocardiography demon-
strated that the appendage was closed successfully in only 40% of
137 patients.32 The rate of successful closure was higher when the
appendage was excised (73%) than when it was closed by suturing
(23%). Of note is that complete closure was never achieved by sta-
pling of the appendage. Left atrial appendage thrombi were never
seen on transesophageal echocardiography after excision of the
appendage but were observed in 41% of patients who underwent
closure of the appendage. Therefore, transesophageal echocardiog-
raphy should be performed after surgical closure of the left atrial
appendage to confirm successful closure before discontinuation of
anticoagulation.
Closure of the left atrial appendage can also be achieved percuta-
neously with an implanted device intended to seal the appendage. A
randomized clinical trial (PROTECT AF) compared the efficacy of a
percutaneous closure device versus warfarin for prevention of throm-
boembolic complications in 707 patients with AF and a CHADS2 score
of 1 or higher.33 The device was found to be noninferior to warfarin
for the primary efficacy composite endpoint of stroke, systemic
emboli, and cardiovascular death and superior to warfarin for hemor-
rhagic stroke (91% reduction). The complication rate was approxi-
mately four times higher in the device arm, with the most common
complication being pericardial effusion. The study demonstrated that
percutaneous closure of the left atrial appendage is an effective
alternative to warfarin in patients with AF. Another recent study
showed that the risk for pericardial effusion declines significantly as
operator experience increases.34 Approval of the left atrial append-
age closure device by the Food and Drug Administration awaits addi-
tional safety data.
It is likely that the left atrial appendage closure device will have its
greatest utility in high-risk patients with AF who cannot tolerate or
refuse to take an oral anticoagulant.
ACUTE MANAGEMENT OF
ATRIAL FIBRILLATION
Patients who go to the emergency department because of AF gener-
ally have a rapid ventricular rate, and control of the ventricular rate
is most rapidly achieved with intravenous diltiazem or esmolol. If the
patient is hemodynamically unstable, immediate transthoracic car-
dioversion may be appropriate. If the AF has been present for more
than 48 hours or if the duration is unclear and the patient is not
already receiving an anticoagulant, cardioversion should be pre-
ceded by transesophageal echocardiography to rule out a left atrial
thrombus.
If the patient is hemodynamically stable, the decision to restore
sinus rhythm by cardioversion is based on several factors, including
805
symptoms, previous AF episodes, age, left atrial size, and current
antiarrhythmic drug therapy. For example, in an elderly patient 38
whose symptoms resolve once the ventricular rate is controlled and
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
who has already had early recurrences of AF despite rhythm-control
drug therapy, further attempts at cardioversion are not usually appro-
priate. On the other hand, cardioversion is generally appropriate for
patients with symptomatic AF who are seen with a first episode of AF
or who have had long intervals of sinus rhythm between previous
episodes.
If cardioversion is decided on for a hemodynamically stable patient
with AF that does not appear to be self-limited, two management
decisions must be made: early versus delayed cardioversion and
pharmacologic versus electrical cardioversion.
The advantages of early cardioversion are rapid relief of symptoms,
avoidance of the need for transesophageal echocardiography or
therapeutic anticoagulation for 3 to 4 weeks before cardioversion if
it is performed within 48 hours of the onset of AF, and possibly a
lower risk for early recurrence of AF because of less atrial remodeling
(see Chapter 33). A reason to defer cardioversion is the unavail-
ability of transesophageal echocardiography in an unanticoagulated
patient with AF of unclear duration or a duration longer than 48
hours. Other reasons include a left atrial thrombus noted on trans-
esophageal echocardiography (see Fig. 15-91), a suspicion (based on
previous AF episodes) that AF will convert spontaneously within a
few days, or a correctable cause of AF (e.g., hyperthyroidism).
When cardioversion is performed early in the course of an episode
of AF, either pharmacologic or electrical cardioversion is an option.
Pharmacologic cardioversion has the advantage of not requiring
general anesthesia or deep sedation. In addition, the probability of
an immediate recurrence of AF may be lower with pharmacologic
cardioversion than with electrical cardioversion. However, pharma-
cologic cardioversion is associated with a risk for adverse drug
effects and is not as effective as electrical cardioversion. Pharmaco-
logic cardioversion is very unlikely to be effective if the duration of
AF is longer than 7 days.
Drugs that can be administered intravenously for cardioversion of
AF consist of ibutilide, procainamide, and amiodarone. For AF epi-
sodes shorter than 2 to 3 days in duration, the efficacy of these drugs
is approximately 60% to 70% for ibutilide, 40% to 50% for amiodarone,
and 30% to 40% for procainamide. To minimize the risk for QT pro-
longation and polymorphic ventricular tachycardia (torsades de
pointes; see Chapter 37), use of ibutilide should be limited to
patients with an ejection fraction higher than 35%. Acute pharmaco-
logic cardioversion of AF can also be attempted with orally adminis-
tered drugs in patients without structural heart disease. The most
commonly used oral agents for acute conversion of AF are propafe-
none (300 to 600 mg) and flecainide (100 to 200 mg). It is prudent to
administer these drugs under surveillance the first time that they are
used. If no adverse drug effects are observed, the patient may then
be an appropriate candidate for episodic, self-administered antiar-
rhythmic drug therapy on an outpatient basis.
The efficacy of transthoracic cardioversion is approximately 95%.
Biphasic waveform shocks convert AF more effectively than do
monophasic waveform shocks and allow the use of lower energy
shocks, which result in a lower risk for skin irritation. An appropriate
first-shock strength using a biphasic waveform is 150 to 200 J followed
by higher output shocks if needed. If a 360-J biphasic shock is unsuc-
cessful, ibutilide should be infused before another shock is delivered
because it lowers the defibrillation energy requirement and improves
the success rate of transthoracic cardioversion.
Two types of failure of transthoracic cardioversion occur in patients
with AF. The first type is complete failure to restore sinus rhythm. In
this situation, an increase in shock strength or infusion of ibutilide
often results in successful cardioversion. The second type of failure
is immediate recurrence of AF within a few seconds of successful
conversion to sinus rhythm. The incidence of immediate recurrence
of AF is approximately 25% for episodes shorter than 24 hours in
duration and approximately 10% for episodes longer than 24 hours
in duration. For this type of failure of cardioversion, an increase in
shock strength is of no value. If the patient has not been receiving an
 806
oral rhythm-control agent, infusion of ibutilide may be helpful for
V prevention of an immediate recurrence of AF.
Regardless of whether cardioversion is performed pharmacologi-
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE
cally or electrically, therapeutic anticoagulation is necessary for 3
weeks or longer before cardioversion to prevent thromboembolic
complications if the AF has been ongoing for more than 48 hours. If
the time of onset of AF is unclear, for the sake of safety, the duration
of AF should be assumed to be greater than 48 hours. These patients
should receive therapeutic anticoagulation for 4 weeks after cardio-
version to prevent the thromboembolic complications that may occur
because of atrial stunning. If the duration of AF is known to be less
than 48 hours, cardioversion can be performed without anticoagula-
tion. To improve the safety margin, it may be appropriate to use a
24-hour cutoff for the AF duration, which allows safe cardioversion
without anticoagulation.
When the duration of AF is longer than 48 hours or unclear, an
alternative to 3 weeks of therapeutic anticoagulation before cardio-
version is anticoagulation with heparin and transesophageal echo-
cardiography to check for a left atrial thrombus. If no thrombi are
seen, the patient can safely be cardioverted but still requires 4 weeks
of therapeutic anticoagulation after cardioversion to prevent throm-
boembolism related to atrial stunning. The major clinical benefit of
the transesophageal echocardiography–guided approach over the
conventional approach is that sinus rhythm is restored several weeks
sooner. When compared with the conventional approach, the trans-
esophageal echocardiography–guided approach has not been found
to reduce the risk for stroke or major bleeding or to affect the propor-
tion of patients still in sinus rhythm at 8 weeks after cardioversion.
LONG-TERM MANAGEMENT
OF ATRIAL FIBRILLATION
Pharmacologic Rate Control Versus
Rhythm Control
Several randomized studies have compared a rate-control strategy
with a rhythm-control strategy in patients with AF. The largest study
by far was the AFFIRM study, which consisted of 4060 patients with
a mean age of 70 years who had AF for 6 hours to 6 months.35 At 5
years of follow-up, the prevalence of sinus rhythm was 35% in the
rate-control arm and 63% in the rhythm-control arm. No significant
difference was noted between the two study arms in total mortality,
stroke rate, or quality of life. The percentage of patients requiring
hospitalization was significantly lower in the rate-control arm (73%)
than in the rhythm-control arm (80%), and the incidence of adverse
drug effects such as torsades de pointes was also significantly lower
in the rate-control arm (0.2% versus 0.8%). The authors of the AFFIRM
study concluded that there is no survival advantage of a rhythm-
control strategy over a rate-control strategy and that a rate-control
strategy has advantages such as a lower probability of hospitalization
and adverse drug effects.
In a post hoc analysis of the AFFIRM study, the relationship between
sinus rhythm, treatment, and survival was determined by an
on-treatment analysis instead of the intention-to-treat analysis used
in the original report.36 Sinus rhythm was found to be independently
associated with lower mortality (hazard ratio, 0.53), and antiarrhyth-
mic drug therapy was independently associated with increased
mortality (hazard ratio, 1.49). Therefore, the potential benefit of main-
taining sinus rhythm with antiarrhythmic drugs was negated by the
adverse effects of the antiarrhythmic drug therapy. This suggested
that therapies that maintain sinus rhythm without major adverse
effects may have a beneficial effect on survival.
The results of the AFFIRM study should not be applied routinely to
all patients with AF. The decision to pursue a rhythm-control strategy
versus a rate-control strategy should be individualized, with several
factors being taken into account, including the nature, frequency, and
severity of symptoms; the length of time that AF has been present
continuously in patients with persistent AF; left atrial size; comorbid
conditions; the response to previous cardioversions; age; the side
effects and efficacy of the antiarrhythmic drugs already used to treat
the patient; and the patient’s preference.
The AFFIRM study convincingly demonstrated that a rate-control
strategy is preferable to a rhythm-control strategy in asymptomatic or
minimally symptomatic patients 65 years or older. In patients with
persistent AF, it is reasonable to attempt to restore sinus rhythm with
antiarrhythmic drug therapy or transthoracic cardioversion at least
once in individuals 65 years or younger and in those 65 years or older
whose AF is symptomatic despite adequate heart rate control. If the
AF has been continuous for longer than 1 year or if the left atrial
diameter is very large (>5.0 cm), there is a high probability of an early
recurrence of AF, and this should be taken into account in deciding
on the best strategy. After cardioversion, the decision to maintain the
patient on antiarrhythmic drug therapy to delay the next episode of
AF is based on the patient’s preference, the perceived risk for early
recurrence of AF, and the duration of sinus rhythm between previous
cardioversions. Treatment by cardioversion without daily antiarrhyth-
mic drug therapy is acceptable if the episodes of AF are separated
by at least 6 months. Treatment with a rhythm-control drug is usually
appropriate when AF recurs within a few months of cardioversion.
The most realistic goal of antiarrhythmic drug therapy in patients
with persistent AF is to delay the onset of the next episode by at least
several months, not for several years. It is often appropriate to con-
tinue therapy with a particular antiarrhythmic drug if recurrences of
AF are limited to approximately one episode per year.
In patients with symptomatic paroxysmal AF, the aggressiveness
with which a rhythm-control strategy is pursued should be dictated
by the frequency and severity of symptoms and how well antiarrhyth-
mic drug therapy is tolerated. Drug therapy is more likely to be judged
successful when patients are reminded that the goal of therapy is not
complete suppression of AF but a clinically meaningful reduction in
the frequency, duration, and severity of episodes.
A pharmacologic rhythm-control strategy need not necessarily
consist of daily drug therapy. Episodic drug therapy (the “pill-in-the-
pocket” approach) is useful for patients whose episodes of AF are
relatively infrequent. Episodic drug therapy is a reasonable option for
patients who are clearly aware of the onset and termination of the
AF episodes and who have lone AF or only minimal structural heart
disease. A typical drug regimen consists of a class IC drug (flecainide
or propafenone) plus a short-acting beta blocker (e.g., propranolol)
or calcium channel blocker (e.g., verapamil) for rate control. Many
patients with infrequent episodes prefer this approach because it
eliminates the inconvenience, cost, and possible side effects of daily
prophylactic therapy. However, patients who are disabled by severe
symptoms during AF may prefer daily prophylactic therapy even if
the episodes are infrequent.
Many patients with symptomatic AF also have asymptomatic epi-
sodes. Therefore, daily antithrombotic therapy to prevent thrombo-
embolic events is appropriate for all patients being treated for
recurrent AF, whether it is persistent or paroxysmal and whether a
rhythm-control or rate-control strategy is used. The choice of no
therapy, an oral anticoagulant, aspirin, or the combination of aspirin
plus clopidogrel should be dictated by an analysis of risk factors and
drug tolerance.
Pharmacologic Rate Control
An excessively rapid ventricular rate during AF often results in
uncomfortable symptoms and decreased effort tolerance and can
cause a tachycardia-induced cardiomyopathy if it is sustained for
several weeks to months. Optimal heart rates during AF vary with age
and should be similar to the heart rates that a patient would have at
a particular degree of exertion during sinus rhythm. Heart rate control
must be assessed both at rest and during exertion. At rest, the ideal
ventricular rate during AF is in the range of 60 to 75 beats/min. During
mild to moderate exertion (e.g., rapid walking), the target rate should
be 90 to 115 beats/min; and during strenuous exercise, the ideal rate
is in the range of 120 to 160 beats/min. Optimal assessment of the
degree of heart rate control is provided by an ambulatory 24-hour
Holter recording or an exercise test.

Oral agents available for long-term heart rate control in patients
with AF are digitalis, beta blockers, calcium channel antagonists, and
amiodarone. The first-line agents for rate control are beta blockers
and the calcium channel antagonists verapamil and diltiazem. A
combination is often used to improve efficacy or to limit side effects
by allowing the use of smaller dosages of the individual drugs. In
patients with sinus node dysfunction and tachy-brady syndrome, use
of a beta blocker with intrinsic sympathomimetic activity (pindolol,
acebutolol) may provide rate control without aggravating the sinus
bradycardia.
Digitalis may adequately control the rate at rest but often does not
provide adequate rate control during exertion. Its use is appropriate
in patients with systolic heart failure, in whom digitalis has been
shown to improve outcomes such as heart failure and all-cause hos-
pitalization. In patients with the vagotonic form of paroxysmal AF,
the vagotonic effect of digitalis may promote AF. Furthermore, in
patients without systolic heart failure, use of a digitalis glycoside may
have a deleterious effect on survival. In a large anticoagulation trial
that compared warfarin with a direct thrombin inhibitor (SPORTIF
III-IV), digitalis was found to be independently associated with a 53%
higher risk for all-cause mortality.37 Although this was demonstrated
by post hoc analysis and not by a randomized comparison of digitalis
versus placebo, the results are of enough concern to limit the use of
digitalis to patients with heart failure.
Amiodarone is much less frequently used for rate control than the
other negative dromotropic agents because of the risk for organ toxic-
ity associated with long-term therapy. Amiodarone may be an appro-
priate choice for rate control if the other agents are not tolerated or
are ineffective. As an example, amiodarone would be an appropriate
choice for a patient with persistent AF, heart failure, and reactive
airway disease who cannot tolerate either a calcium channel antago-
nist or a beta blocker and who has a rapid ventricular rate despite
treatment with digitalis.
Strict heart rate control can be difficult to achieve pharmacologi-
cally. The effects of a lenient rate-control strategy (resting rate <110
beats/min) and a strict rate-control strategy (resting heart rate <80
beats/min, rate during moderate exercise <110 beats/min) on out-
comes were compared in randomized fashion in 614 patients with
persistent AF.38 The primary composite outcome was cardiovascular
death, heart failure hospitalizations, stroke, embolism, major bleed-
ing episodes, and major arrhythmic events. The heart rate target was
achieved in 98% of patients in the lenient rate-control group versus
67% in the strict rate-control group. The incidence of the primary
outcome at 3 years did not differ significantly between the lenient
rate-control group (12.9%) and the strict rate-control group (14.9%).
The results suggest that strict rate control has no advantages over
lenient rate control. However, the study did not present data on the
severity of symptoms, exercise capacity, or left ventricular ejection
fraction, and follow-up was limited to 3 years. Strict rate control is still
often an appropriate goal for relief of symptoms, improvement in
functional capacity, and avoidance of tachycardia-induced cardiomy-
opathy during long-term follow-up.
Pharmacologic Rhythm Control
The results of published studies on the efficacy of antiarrhythmic
drugs for AF suggest that all the drugs available except amiodarone
have similar efficacy and are associated with a 50% to 60% reduction
in the odds of recurrent AF during 1 year of treatment. The one drug
that stands out as having higher efficacy than the others is amioda-
rone. In studies that directly compared amiodarone with sotalol or
class I drugs, amiodarone was 60% to 70% more effective in suppress-
ing AF. However, because of its risk for organ toxicity, amiodarone is
not appropriate first-line drug therapy for many patients with AF.
Because the efficacy of rhythm-control agents other than amioda-
rone is in the same general range, selection of an antiarrhythmic drug
to prevent AF is often dictated by the issues of safety and side effects.
Ventricular proarrhythmia from class IA agents (quinidine, pro-
cainamide, disopyramide) and class III agents (sotalol, dofetilide,
dronedarone, amiodarone) is manifested as QT prolongation and
807
polymorphic ventricular tachycardia (torsades de pointes). Risk
factors for this type of proarrhythmia include female sex, left ventricu- 38
lar dysfunction, and hypokalemia. The risk for torsades de pointes
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
appears to be much lower with dronedarone and amiodarone than
with the other class III drugs. The ventricular proarrhythmia resulting
from class IC agents (flecainide and propafenone) is manifested as
monomorphic ventricular tachycardia, sometimes associated with
widening of the QRS complex during sinus rhythm, but not with QT
prolongation. Published studies indicate that the drugs most likely to
result in ventricular proarrhythmia are quinidine, flecainide, sotalol,
and dofetilide. In controlled studies, these agents increased the risk
for ventricular tachycardia by a factor of 2 to 6.
Adverse drug events resulting in discontinuation of drug therapy
are fairly common with rhythm-control drugs. Withdrawal because
of adverse effects is most frequent with quinidine, disopyramide,
flecainide, sotalol, and amiodarone. A review of studies in which 32
treatment arms received an antiarrhythmic drug for AF found that
10.4% of patients discontinued drug therapy because of an adverse
drug event, most commonly gastrointestinal side effects and
neuropathy.39
The best options for drug therapy to suppress AF depend on the
patient’s comorbid conditions. In patients with lone AF or minimal
heart disease (e.g., mild left ventricular hypertrophy), flecainide,
propafenone, sotalol, and dronedarone are reasonable first-line
drugs, and amiodarone and dofetilide can be considered if the first-
line agents are ineffective or not tolerated. In patients with substantial
left ventricular hypertrophy (left ventricular wall thickness >13 mm),
the hypertrophy heightens the risk for ventricular proarrhythmia, and
the safest choice for drug therapy is amiodarone. In patients with
coronary artery disease, several of the class I drugs have been found
to increase the risk for death, and the safest first-line options are
dofetilide, sotalol, and dronedarone, with amiodarone being reserved
for use as a second-line agent. In patients with heart failure, several
antiarrhythmic drugs have been associated with increased mortality,
and the only two drugs known to have a neutral effect on survival
are amiodarone and dofetilide (see Chapter 35).
At the time of its approval by the Food and Drug Administration,
dronedarone was known to increase mortality in patients with class
IV heart failure or those with a recent episode of decompensated
heart failure. After approval, the categories of patients in whom
dronedarone is contraindicated expanded. A randomized study
(PALLAS) was terminated prematurely when it was found that drone-
darone increased the risk for heart failure, stroke, and cardiovascular
death in the following categories of patients: (1) 65 years or older
with permanent AF and either coronary artery disease, previous
stroke, or symptomatic heart failure and (2) 75 years or older with
hypertension and diabetes.40
Rhythm Control with Agents Other Than
Antiarrhythmic Drugs
Experimental studies indicate that angiotensin-converting enzyme
(ACE) inhibitors and angiotensin receptor blockers (ARBs) have
favorable effects on electrical and structural remodeling (see
Chapter 33). This explains why ACE inhibitors and ARBs have been
shown in some studies to prevent AF. However, other studies have
demonstrated that these agents do not prevent AF. For example, in a
randomized clinical trial of the ARB valsartan versus placebo in 1442
patients with structural heart disease and recurrent AF, the AF recur-
rence rate was approximately 50% in both study arms, and there was
no evidence that valsartan prevented AF.41 Therefore, at present the
evidence is insufficient to support the use of ACE inhibitors and ARBs
for the sole purpose of preventing AF.
Some evidence indicates that statins prevent AF, perhaps because
of their anti-inflammatory effects. A systematic review of 10 observa-
tional studies demonstrated a 23% reduction in the relative risk for
AF in patients treated with statins.42 However, a meta-analysis of six
randomized clinical trials concluded that statins do not prevent AF,
except after open heart surgery.42 Therefore, the data available do not
support the use of statins for the prevention of AF.
 808
Omega-3 polyunsaturated fatty acids (PUFAs) have an anti-
V inflammatory effect and can also have direct ion channel effects.
Several studies in which treatment with omega-3 PUFAs was initiated
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE
at the time of cardioversion of AF demonstrated no prevention of
recurrent AF. However, omega-3 PUFAs did prevent recurrent AF after
cardioversion of persistent AF in two prospective randomized studies
in which patients were pretreated with 2 to 6 g/day of fish oil for 1
month before cardioversion.43,44 Almost all patients in these studies
also received amiodarone or sotalol. The rationale for pretreatment
with the fish oil was to allow enough time for the omega-3 PUFAs
to become incorporated into cell membranes and exert their ion
channel effects. These data suggest that fish oil can be helpful in
preventing recurrent AF when used in combination with an antiar-
rhythmic drug after cardioversion of persistent AF.
NONPHARMACOLOGIC MANAGEMENT
OF ATRIAL FIBRILLATION
Pacing to Prevent Atrial Fibrillation
Randomized clinical trials comparing dual-chamber (DDD) pacing
with right ventricular pacing have concluded that atrial pacing pre-
vents AF. Studies suggest that the higher incidence of AF during
ventricular pacing than during DDD pacing may be at least partially
due to a proarrhythmic effect of ventricular pacing, not only to a
suppressive effect of atrial pacing.
Studies involving small numbers of patients have suggested that
dual-site right atrial pacing or pacing of the interatrial septum near
the Bachmann bundle prevents AF. Although it is possible that these
atrial pacing techniques decrease the propensity for AF, the magni-
tude of the effect appears to be minimal.
Some antibradycardia pacemakers are designed to prevent and
terminate AF. Pacing algorithms to prevent AF consist of atrial pacing
to prevent suppression of postextrasystolic pauses and acceleration
of the atrial pacing rate when repetitive premature atrial complexes
are sensed. When these pacing algorithms have been evaluated in
rigorous fashion, they have been found to be ineffective or at best
minimally effective in reducing the AF burden. Antitachycardia
pacing (ATP) to terminate AF consists of a burst of rapid atrial pacing
at the onset of AF. ATP may be useful for termination of atrial flutter
or atrial tachycardia, but it is rarely if ever effective for AF.
Because of insufficient evidence to support its use, atrial pacing is
not indicated for prevention of AF in patients without bradycardia. In
patients with a bradycardia indication for a pacemaker and paroxys-
mal AF or recurrent episodes of persistent AF, the data available
clearly support the use of atrial-based pacing and programming to
minimize the amount of ventricular pacing.
Catheter Ablation of Atrial Fibrillation
Challenges of Ablating Atrial Fibrillation
Catheter ablation reliably and permanently eliminates several types of
arrhythmia, such as AV nodal reentrant tachycardia and accessory
pathway–mediated tachycardias36 (see Chapters 35 and 37). Success
rates greater than 95% are attainable when the arrhythmia substrate is
well defined, localized, and temporally stable. In contrast, the arrhyth-
mia substrate of AF is not well understood, is usually widespread, is
variable between patients, and may be progressive. Furthermore,
several factors that promote AF cannot be addressed simply by cath-
eter ablation, including comorbid conditions such as hypertension
and obstructive sleep apnea, structural remodeling of the atria, inflam-
matory factors, and genetic factors (see Chapter 8). Therefore, even
though late recurrences of AV nodal reentrant tachycardia or acces-
sory pathway conduction are very rare, AF can recur more than 2 or 3
years after an initially successful ablation procedure.
Selection of Patients
Given the limitations of catheter ablation of AF, it is usually appropri-
ate to treat patients with at least one rhythm-control drug before
catheter ablation is considered, particularly if the AF is persistent,
because the efficacy of catheter ablation is lower for persistent AF
than for paroxysmal AF. The most appropriate candidates for catheter
ablation have symptomatic AF that is affecting their quality of life and
has not responded adequately to drug therapy. The ideal candidate
has lone AF or only minimal structural heart disease. The recom-
mendation for catheter ablation should be influenced by the esti-
mated probability of success, and the procedure is least likely to be
successful if the left atrium is markedly dilated or if the AF has been
persistent for more than 4 years.
Catheter ablation of AF is generally contraindicated in patients who
have a left atrial thrombus or who cannot tolerate anticoagulation for
at least 6 to 8 weeks after ablation. Catheter ablation is also usually
inappropriate in asymptomatic individuals with a CHA 2DS2-VASc
score higher than 1 whose only motivation to undergo the procedure
is to eliminate the need for anticoagulation.
In a recent study, patients with symptomatic paroxysmal AF and
no previous rhythm-control therapy were randomly assigned to
undergo catheter ablation or treatment with an antiarrhythmic drug.45
This study demonstrated that the cumulative AF burden at 2 years of
follow-up did not differ significantly between the two groups. This
result validates the recommendation that catheter ablation be
reserved for patients who have not responded adequately to treat-
ment with an antiarrhythmic drug. However, catheter ablation can
be appropriate first-line therapy in some patients with AF: those
younger than 35 years with symptomatic AF, those with sinus node
dysfunction in whom antiarrhythmic drug therapy is likely to create
the need for a permanent pacemaker, and patients who express an
aversion to drug therapy.
Radiofrequency Catheter Ablation
The most commonly used energy to eliminate paroxysmal AF by
catheter ablation is radiofrequency energy delivered through an
irrigated-tip catheter. Radiofrequency energy is delivered point by
point, typically in association with a three-dimensional electroana-
tomic mapping system as a navigation guide and to create a visual
record of the sites that have already been ablated. To improve ana-
tomic accuracy, the electroanatomic map of the left atrium can be
merged with a computed tomography scan or magnetic resonance
image of the left atrium and pulmonary veins (Fig. 38-8) or with an
ultrasound image generated by intracardiac echocardiography.
Because of their important role in triggering and maintaining epi-
sodes of AF, almost all ablation strategies include electrical isolation
FIGURE 38-8 Electroanatomic map of the left atrium merged with a computed
tomography scan of the left atrium and pulmonary veins. The red and gray tags
indicate the sites at which radiofrequency energy was delivered in the antrum of the
pulmonary veins. LI = left inferior pulmonary vein; LS = left superior pulmonary vein;
RS = right superior pulmonary vein.

I
V1
Abl
Ring catheter in LIPV
CS
FIGURE 38-9 Tachycardia with a cycle length of 80 msec arising in a left inferior pulmonary vein. This tachycardia was responsible for generating AF. During radiofrequency
ablation in the antrum of this pulmonary vein, AF terminated (arrow) and converted to sinus rhythm when the pulmonary vein became electrically isolated. The sinus beats are
indicated with asterisks. The pulmonary vein tachycardia was still present inside the vein. Shown are leads I and V1, the electrograms recorded by the ablation catheter (Abl)
outside the left inferior pulmonary vein (LIPV) and by a ring catheter in the LIPV, and the coronary sinus electrograms (CS).
of the pulmonary veins (Fig. 38-9 and Video 38-1). Such isolation can
be accomplished by either ostial ablation or wide-area ablation 1 to
2 cm away from the ostia, in the antral regions of the pulmonary veins.
Most of the data available indicate that wide-area ablation is more
effective than ostial ablation, probably because it also targets drivers
that are in the antrum, outside the pulmonary vein itself.46 Triggers of
AF can also arise from other thoracic veins, such as the superior vena
cava, coronary sinus, and the vein of Marshall. After the pulmonary
veins have been isolated, infusion of isoproterenol is helpful to deter-
mine whether any non–pulmonary vein triggers are present.
Pulmonary vein isolation is often sufficient to eliminate paroxysmal
AF but is usually insufficient for persistent AF. A variety of ablation
strategies have been used for persistent AF after the pulmonary veins
have been isolated: linear ablation across the left atrial roof, mitral
isthmus, or cavotricuspid isthmus; ablation of CFAEs in the left atrium,
coronary sinus, or right atrium; various combinations of linear and
CFAE ablation; and ablation of ganglionated plexuses.46 The endpoint
of catheter ablation of persistent AF is either completion of a prespeci-
fied lesion set (in which case sinus rhythm is restored by cardiover-
sion) or stepwise ablation until the AF converts to sinus rhythm.
A novel approach to ablation of AF is based on the hypothesis that
AF is sustained by localized sources, either rotors and/or focal
impulses.5 Signal processing with proprietary software allowed iden-
tification of focal impulses and rotors, which were then targeted for
radiofrequency ablation during ongoing episodes of AF. A mean of
2.1 localized sources per patient were identified in 97% of 101 patients.
Termination or slowing of AF was successfully achieved by ablation
809
38
* *
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
250 msec
of the localized sources in 86% of cases. At a median of 9 months of
follow-up, 82% of patients were free of AF versus 45% of those in a
control group who underwent conventional ablation. These early
results suggest that focal impulse and rotor modulation can improve
outcomes of catheter ablation of AF.
Based on an extensive review of a large number of published
reports, the overall single-procedure success rate of radiofrequency
catheter ablation of AF without antiarrhythmic drug therapy is 57%,
and the multiple-procedure success rate is 71%.39 Efficacy is strongly
influenced by the type of AF being ablated. For paroxysmal AF, a
single-procedure success rate of 60% to 75% is expected at experi-
enced centers, whereas for persistent AF, the single-procedure
success rate is typically 50% or lower.
The efficacy of radiofrequency catheter ablation of AF compares
favorably with that of antiarrhythmic drug therapy. In a meta-analysis
of four prospective, randomized studies, radiofrequency catheter
ablation was found to result in AF-free survival significantly more
often than antiarrhythmic drug therapy was (76% versus 19%).47 In a
multicenter study of 112 patients with paroxysmal AF resistant to one
or more antiarrhythmic drugs, the patients were randomly assigned
to pulmonary vein isolation plus additional ablation at the operator’s
discretion or antiarrhythmic drug therapy.48 The AF-free survival rate
at 12 months was 89% in the ablation arm after a median of two
procedures per patient versus 23% in the drug arm.
When the efficacy of catheter ablation of AF is evaluated, recur-
rences of AF in the first 3 months after ablation are usually ignored.
A 3-month blanking period excludes early recurrences that are
 809.e1
VIDEO 38-1
Pulmonary vein (PV) isolation using image integration. A semi-trans- 38
lucent computed tomography “cast” of the left atrium appears in

Atrial Fibrillation: Clinical Features, Mechanisms, and Management

orange, viewed first from an anterior perspective. As the movie runs,
black dots appear at sites sampled by a roving mapping catheter in
order to form a “shell” of the inner contours of the left atrium. The
image rotates to be viewed from the right side and then from the left.
Once this acquisition is completed, larger red circles appear at sites at
which radiofrequency energy is delivered to electrically isolate the PVs
by encircling their orifices with ablation lesions, starting with the left
PVs and ending with the right PVs. The image is rotated to allow
viewing of the process from different angles.
 810
caused by a transient inflammatory response or incomplete lesion
V maturation.
Even in patients with symptomatic AF, postablation recurrences
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

can be asymptomatic. Therefore, accurate assessment of efficacy

requires monitoring for at least 7 days and preferably for 1 month with
a device capable of detecting asymptomatic episodes of AF. Ideally,
the monitoring should be performed at 6 and 12 months after the
procedure.
Most recurrences of AF after radiofrequency catheter ablation
occur within the first year of follow-up. However, recurrences con-
tinue to occur at a rate of approximately 5% to 6% per year for several
years after ablation.49 Ongoing comorbid conditions such as valvular
heart disease, obstructive sleep apnea, and hypertension can con-
tribute to late recurrences of AF. Another probable cause of late
recurrences of AF in patients who have undergone pulmonary vein
isolation is delayed recovery from radiofrequency-induced injury
leading to reconnection of the pulmonary veins.50
Atrial tachyarrhythmias that occur after catheter ablation of AF can
take the form of atrial tachycardia/flutter, which can be either focal
or reentrant. When the ablation strategy consists of only pulmonary
vein isolation, postablation focal atrial tachycardias are often attribut-
able to partial recovery of pulmonary vein conduction. The incidence
of reentrant atrial tachycardia/flutter after ablation is related to the
extent of ablation at atrial sites other than the pulmonary vein. When
extensive ablation is performed in the left atrium or in both atria in
an attempt to convert AF to sinus rhythm, atrial tachycardia/flutter
occurs during follow-up in more than 50% of patients. These arrhyth- FIGURE 38-10 Cryoballoon catheter positioned in the antrum of the right supe-
rior pulmonary vein. The balloon is inflated and there is no leakage of contrast mate-
mias do not respond well to antiarrhythmic drug therapy and fre- rial injected through the lumen of the cryoballoon catheter into the vein. A diagnostic
quently require another ablation procedure for elimination. ring catheter is positioned within the vein. Pulmonary vein isolation was achieved
The risk for a major complication after radiofrequency catheter with two 4-minute applications of cryoenergy through the balloon.
ablation of AF is reported to be 5% to 6%.39,51 In a large international
survey, the most common major complications were cardiac tampon-
ade (1.2%), pulmonary vein stenosis (1.3%), and cerebral thrombo-
embolism (0.94%).51 The risk for vascular injury is reported to be 1%
to 2%. The risk for an atrioesophageal fistula is probably less than who underwent endoscopy after cryoballoon ablation. Pulmonary
0.1%. Despite its rarity, this complication is of great concern because vein stenosis causing symptoms or requiring intervention is very infre-
it is often lethal. quent (0.2%), as are thromboembolic complications (0.6%). Cardiac
Large international surveys have reported the risk for a fatal com- tamponade has occurred in 0.6% of patients and vascular access
plication to be in the range of 0.05% to 0.1%.51,52 In a survey of 32,569 complications in approximately 2%.
patients who underwent catheter ablation of AF, the mortality rate
was 0.1%, and the most common causes of death were cardiac tam- Remote Magnetic Navigation
ponade (25% of deaths), stroke (16%), atrioesophageal fistula (16%), Two systems are currently available for remote navigation of a radio-
and pneumonia (16%).52 frequency ablation catheter. In one system, large magnets are posi-
A recently recognized complication of radiofrequency ablation tioned on each side of the patient, and small magnets embedded in
is silent cerebral ischemic lesions. Cerebral magnetic resonance the tip of the ablation catheter allow remote navigation by shifting
imaging demonstrated silent cerebral ischemic lesions in 14% of the magnetic field vectors. With the other system, an ablation cath-
patients in whom an irrigated-tip radiofrequency ablation catheter eter is navigated remotely by a robotic steerable sheath system. The
was used.53 The long-term clinical significance of these lesions is advantages of these systems are improved catheter stability, marked
unclear. reduction in exposure of the operator to radiation, and avoidance of
the technical challenges of manual catheter manipulation. The expe-
Cryoballoon Ablation rience to date with remote magnetic navigation indicates that the
In 2010, a cryoballoon catheter designed to isolate the pulmonary efficacy and safety of radiofrequency catheter ablation of AF
veins became widely available for use in the United States. In contrast are comparable to those of conventional radiofrequency catheter
to point-by-point radiofrequency ablation around pulmonary veins, ablation.55
the cryoballoon is designed to fit into the antrum of a pulmonary vein
and to create a circumferential ablative lesion via cryoenergy (Fig.
38-10). An advantage of cryoenergy over radiofrequency energy is Ablation of the Atrioventricular Node
that it is much less likely to cause pulmonary vein stenosis or esopha- Radiofrequency catheter ablation of the AV node results in complete
geal injury. Experienced operators can achieve complete pulmonary AV nodal blockade and substitutes a regular, paced rhythm for an
vein isolation acutely by using only the cryoballoon catheter in 98% irregular and rapid native rhythm. It is a useful strategy in patients
of patients.54 In patients with paroxysmal AF, 1-year freedom from AF who are symptomatic from AF because of a rapid ventricular rate that
is achieved in approximately 75% of patients.54 Randomized studies cannot be adequately controlled pharmacologically as a result of
have demonstrated no significant difference in freedom from AF at 1 either inefficacy of or intolerance to rate-control drugs and who either
year between cryoballoon ablation and radiofrequency ablation.54 are not good candidates for ablation of the AF or already have under-
The most frequent complication of cryoballoon ablation is phrenic gone an unsuccessful attempt at ablation of the AF.
nerve palsy, which has an incidence of approximately 7%.54 The In patients with AF and an uncontrolled ventricular rate, AV node
phrenic nerve palsy resolves within 1 year in almost all patients. In ablation improves the left ventricular ejection fraction in those with
one study, endoscopy showed esophageal ulcerations in 17% of 35 tachycardia-induced cardiomyopathy. AV node ablation has also
patients after cryoballoon ablation, but two other studies reported been shown to improve symptoms, quality of life, and functional
that there was no evidence of thermal esophageal injury in 81 patients capacity and to reduce the use of health care resources. There is no

evidence that AV node ablation is of benefit in patients whose ven-
tricular rate is well controlled by medications.
Disadvantages of AV node ablation are that it creates a life-long
need for ventricular pacing and does not restore AV synchrony.
Although symptoms and functional capacity typically improve
after AV node ablation in patients with AF and an uncontrolled ven-
tricular rate, some patients may not feel as well as during sinus
rhythm.
AV node ablation is a technically simple procedure with an acute
and long-term success rate of 98% or higher and a very low risk for
complications. In patients with persistent AF, a ventricular pacemaker
is implanted. A dual-chamber pacemaker is appropriate if the AF is
paroxysmal. Most patients have a good clinical outcome with right
ventricular pacing, but in those with borderline or depressed left
ventricular function, biventricular pacing for cardiac resynchroniza-
tion therapy is appropriate. In patients with ischemic or nonischemic
cardiomyopathy and an ejection fraction from 30% or lower to 35%,
an ICD may be appropriate for primary prevention of sudden death.
However, a simple pacemaker without the ICD is often adequate for
patients with a borderline ejection fraction (30% to 35%) and a rapid
ventricular rate because the ejection fraction is likely to improve to
greater than 35% after the ventricular rate has been controlled by AV
node ablation.
Surgical Approaches to Atrial Fibrillation
The most effective surgical procedure for AF is the “cut-and-sew”
maze procedure developed by Cox in 1987.56 This operation involves
12 atrial incisions to isolate the pulmonary veins and create lines of
block in the left atrium and right atrium. In addition, the left and right
atrial appendages are excised. Rates of long-term freedom from AF
after the Cox maze procedure are reported to range from 70% to 95%,
but 10% to 35% of patients still require antiarrhythmic drug therapy.
The efficacy of the Cox maze procedure is lower in patients with a
very large left atrium or with persistent AF for many years. The Cox
maze procedure has not been widely performed because it requires
cardiopulmonary bypass, is technically difficult, and is associated
with a mortality rate of approximately 1% to 2%.
A large variety of surgical ablation tools have been developed to
simplify the classic Cox maze procedure. These tools allow the
surgeon to substitute an ablation line for a surgical incision. Several
different types of energy have been used for surgical ablation: radio-
frequency energy, cryoenergy, microwave, laser, and high-intensity
focused ultrasound. The tool that most consistently produces trans-
mural ablation lines is a clamp device intended to isolate the pulmo-
nary veins with bipolar radiofrequency energy.
Various surgical ablation strategies have been used, including pul-
monary vein isolation, left atrial ablation, and the Cox maze lesion
set. The left atrial appendage is usually excluded and ganglionic
plexuses are often also ablated. In patients who do not require con-
comitant coronary artery bypass grafting or valve repair or replace-
ment, surgical ablation is typically performed via a thorascopic,
minimally invasive epicardial approach. Single-procedure success
rates at 1 year of follow-up have ranged from 65% to 86%.57,58
Radiofrequency catheter ablation of AF was compared with surgi-
cal ablation in a randomized study that selected patients with drug-
refractory AF who had hypertension and left atrial dilation or who
had already undergone unsuccessful catheter ablation.59 Freedom
from AF at 1 year was significantly higher in the surgical group
(65.6%) than in the catheter ablation group (36.5%). However, sub-
stantial procedural adverse events also occurred significantly more
often with surgical ablation (23%) than with catheter ablation (3.2%).
The most common complications of surgical ablation were hemotho-
rax and bradycardia requiring pacemaker implantation.
Surgical therapy for AF is appropriate as a concomitant procedure
in patients undergoing open heart surgery for coronary artery disease
or valvular disease. A stand-alone surgical procedure for AF is an
option for patients who have not had a successful outcome from
catheter ablation, who are not good candidates for catheter ablation,
or who prefer a surgical procedure over catheter ablation.
811
SPECIFIC CLINICAL SYNDROMES 38
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
Postoperative Atrial Fibrillation
AF is common after open heart surgery and is reported to occur in
25% to 40% of patients who undergo coronary artery bypass graft
surgery or valve replacement (see Chapter 80). It is associated with
a twofold increase in the risk for postoperative stroke and is the most
common reason for prolonged hospitalization. The risk for AF peaks
on the second postoperative day. The pathogenesis of postoperative
AF is multifactorial and probably involves adrenergic activation,
inflammation, atrial ischemia, electrolyte disturbances, and genetic
factors. Several risk factors for AF after open heart surgery have been
identified, including age older than 70 years, history of previous AF,
male sex, left ventricular dysfunction, left atrial enlargement, chronic
lung disease, diabetes, and obesity.
The antiarrhythmic drugs that have been shown to decrease the
risk for postoperative AF are beta blockers, sotalol, and amiodarone.
Amiodarone and sotalol decrease the risk for postoperative AF by
50% to 65%, and beta blockers appear to be somewhat less effective,
decreasing the risk by approximately 30%.
Hypomagnesemia is common after open heart surgery and can
heighten the risk for AF. Magnesium administration immediately
preoperatively, perioperatively, or postoperatively is reported to
decreases the risk for postoperative AF by 20% to 40%.
Right atrial or biatrial pacing using temporary electrodes attached
to the right and left atria is reported to reduce the risk for postopera-
tive AF by 40%.
The following agents have also been demonstrated in random-
ized studies to reduce the risk for AF after open heart surgery: atorv-
astatin, which decreases the risk by approximately 60%;
hydrocortisone, which decreases the risk by approximately 35%60;
and colchicine, which decreases the risk by 45%.61 The main mecha-
nism by which these agents prevent AF is probably an anti-
inflammatory effect. Omega-3 PUFAs, which also have an
anti-inflammatory effect, reduced the risk for postoperative AF by
43% in one randomized study62 but did not reduce the risk in another
randomized study.63
Wolff-Parkinson-White Syndrome
Patients with Wolff-Parkinson-White syndrome and an accessory
pathway with a short refractory period can experience a very rapid
ventricular rate during AF (see Chapters 35 and 37). Ventricular
rates higher than 250 to 300 beats/min can result in loss of conscious-
ness or precipitate ventricular fibrillation and cardiac arrest. Patients
with Wolff-Parkinson-White syndrome who have AF with a rapid ven-
tricular rate should undergo transthoracic cardioversion if they are
hemodynamically unstable. If the patient is hemodynamically stable,
intravenous procainamide or ibutilide can be used for pharmaco-
logic cardioversion. Procainamide may be preferable to ibutilide
because it blocks accessory pathway conduction and slows the ven-
tricular rate before AF has converted to sinus rhythm. Digitalis and
calcium channel antagonists are contraindicated in patients with
Wolff-Parkinson-White syndrome and AF. These agents selectively
block conduction in the AV node and can result in acceleration of
conduction through the accessory pathway.
The preferred therapy for patients with Wolff-Parkinson-White syn-
drome and AF with a rapid ventricular rate is catheter ablation of the
accessory pathway. The efficacy of catheter ablation is 95% for most
types of accessory pathways, and the risk for a major complication
is very low. AF typically no longer recurs after successful accessory
pathway ablation, probably because AF in Wolff-Parkinson-White
syndrome is often induced by tachycardia and is a result of AV recip-
rocating tachycardia.
Heart Failure
AF is a common arrhythmia in patients with heart failure, with a
prevalence reported to range from 10% in patients with New York
 812
Heart Association functional class I up to 50% in patients with class
V IV (see Chapter 25). AF may be the cause of heart failure in patients
with nonischemic cardiomyopathy and AF with a rapid ventricular
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE
rate. In patients with structural heart disease and preexisting left
ventricular dysfunction, AF can worsen the heart failure. The deleteri-
ous hemodynamic effects of AF are mediated by a rapid rate or
irregular ventricular rate and loss of AV synchrony.
The most appropriate rate-control drugs in patients with heart
failure are digitalis and beta blockers. If necessary, amiodarone can
also be used for rate control. The only rhythm-control drugs safe to
use in patients with heart failure are amiodarone and dofetilide.
These are the only two rhythm-control drugs that have been demon-
strated to not increase the risk for death in patients with heart failure.
As in other patients with AF, the decision to pursue a rate-control
or rhythm-control strategy in patients with heart failure should be
individualized. In a multicenter study, patients with AF, heart failure,
and a mean left ventricular ejection fraction of 27% were randomly
assigned to a rate-control strategy (most commonly digitalis and beta
blockers) or a rhythm-control strategy (most often amiodarone).64 At
3 years of follow-up, no significant differences were noted in all-cause
mortality, cardiovascular mortality, or worsening heart failure, but the
hospitalization rate was higher in the rhythm-control group. This
study demonstrated no beneficial effect of a rhythm-control strategy
on outcomes in patients with heart failure. However, endpoints such
as ejection fraction and functional capacity were not examined in
the study, and many patients in the rhythm-control arm continued to
have AF. It should be noted that the study compared two treatment
strategies, not sinus rhythm versus AF with a controlled ventricular
rate. The study did not rule out the possibility that sinus rhythm has
advantages over AF with a controlled ventricular rate in patients with
heart failure.
In another randomized study, patients with AF, heart failure, and
an ejection fraction lower than 40% were randomly assigned to
rhythm control by catheter ablation or rate control by AV node
ablation plus a biventricular pacemaker.65 The rate of freedom
from AF at 6 months in the AF ablation arm was 71% in the absence
of antiarrhythmic drug therapy. The mean ejection fraction improved
from approximately 27% to 35% in the AF ablation group and remained
unchanged in the AV node ablation group. Functional capacity
and quality of life also improved significantly in the AF ablation
group, but not in the AV node ablation group. The failure of AV node
ablation to improve these parameters is attributable to the fact
that the patients had already achieved adequate rate control with
drug therapy.
These results suggest that attempts at restoration of sinus rhythm
are worthwhile in patients with heart failure and that catheter abla-
tion of AF should be considered if sinus rhythm is not maintained by
amiodarone or dofetilide. A rate-control strategy is appropriate for
patients who do not respond adequately to amiodarone or dofetilide
and either are not suitable candidates for catheter ablation of AF or
have had an unsuccessful outcome from ablation. AV node ablation
should be reserved for patients whose ventricular rate during AF is
not adequately controlled by drug therapy. Because left ventricular
dysfunction and heart failure can be aggravated by right ventricular
pacing, biventricular pacing should be performed after AV node abla-
tion. The decision to implant a biventricular pacemaker versus a
biventricular ICD is based on clinical judgment. If it seems likely that
the ejection fraction will remain less than 30% to 35% after optimal
heart rate control, a biventricular ICD is appropriate for primary pre-
vention of sudden cardiac death.
Pregnancy
New-onset AF is rare during pregnancy (see Chapter 78), and when
it does occur, it is usually in the setting of underlying congenital or
valvular heart disease, thyrotoxicosis, or electrolyte abnormalities. In
women with paroxysmal AF before pregnancy, the frequency of epi-
sodes may or may not increase during pregnancy. Specific recom-
mendations for the management of AF during pregnancy are provided
in the Guidelines for Atrial Fibrillation.
FUTURE PERSPECTIVES
The ideal antiarrhythmic drug to prevent AF would affect the atrium
only, thereby eliminating the potential for ventricular proarrhythmia.
Such drugs are under development and may improve the safety and
efficacy of pharmacologic therapy for AF. It is likely that drugs that
modify a single channel will not be as effective as those with multiple
actions, and it is possible that targeting of non–channel-related func-
tions such as the development of fibrosis will prove useful.
In the past few years, significant progress has been made in the
field of catheter ablation of AF, but there is still much room for
improvement in efficacy and procedure duration. The failure to
create enduring pulmonary vein isolation often accounts for recur-
rences of AF in patients with paroxysmal AF. The development of new
tools for catheter ablation, such as radiofrequency ablation catheters
that sense tissue contact force, might improve the ability to safely
create transmural lesions, thereby limiting the need for repeated
ablation procedures. In patients with persistent AF, a better under-
standing of AF mechanisms could result in more efficient and suc-
cessful ablation strategies. The recent demonstration of localized
sources of AF (focal impulses and/or atrial rotor) by computed signal
analysis in humans represents an important step in this direction.5
Several studies have shown that a rhythm-control strategy in
patients with AF provides no advantages in outcomes over a rate-
control strategy. The results of these studies were most likely influ-
enced by the suboptimal safety and efficacy of the drugs used for
rhythm control.
To date, no randomized trials have demonstrated that catheter
ablation of AF improves outcomes such as stroke or survival. The
ongoing trial CABANA (Catheter Ablation versus Antiarrhythmic
Drug Therapy for Atrial Fibrillation) has a primary endpoint of mortal-
ity and secondary endpoints of cardiovascular mortality and stroke.
If this study shows improved outcomes with AF ablation, it will
strengthen the case for rhythm control by ablation.
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19. Camm AJ, Lip GY, De Caterina R, et al: 2012 focused update of the ESC guidelines for the
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26. Patel MR, Mahaffey KW, Garg J, et al: Rivaroxaban versus warfarin in nonvalvular atrial fibril-
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27. Granger CB, Alexander JH, McMurray JJ, et al: Apixaban versus warfarin in patients with
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28. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al: Reversal of rivaroxaban and dabigatran
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29. Wann LS, Curtis AB, Ellenbogen KA, et al: 2011 ACCF/AHA/HRS focused update on the man-
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can College Of Cardiology Foundation/American Heart Association Task Force on Practice
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30. Nagarakanti R, Ezekowitz MD, Oldgren J, et al: Dabigatran versus warfarin in patients with
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31. Lakkireddy D, Reddy YM, Di Biase L, et al: Feasibility and safety of dabigatran versus war-
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2012.
32. Kanderian AS, Gillinov AM, Pettersson GB, et al: Success of surgical left atrial appendage
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33. Holmes DR, Reddy VY, Turi ZG, et al: Percutaneous closure of the left atrial appendage versus
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Long-Term Management of Atrial Fibrillation
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study. Circulation 109:1509, 2004.
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the SPORTIF III and V data. Heart 94:191, 2008.
38. Van Gelder IC, Groenveld HF, Crijns HJ, et al: Lenient versus strict rate control in patients with
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39. Calkins H, Reynolds MR, Spector P, et al: Treatment of atrial fibrillation with antiarrhythmic
drugs or radiofrequency ablation: Two systematic literature reviews and meta-analyses. Circ
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40. Connolly SJ, Camm AJ, Halperin JL, et al: Dronedarone in high-risk permanent atrial fibrilla-
tion. N Engl J Med 365:2268, 2011.
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Engl J Med 360:1606, 2009.
GUIDELINES
Atrial Fibrillation
Fred Morady and Douglas P. Zipes
Recent updates have been incorporated into the comprehensive
guidelines for the management of atrial fibrillation (AF) published
in 2006 by the American College of Cardiology/American Heart
Association (ACC/AHA) Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines.1
The following classification system was used for recommendations
and for the level of evidence on which the recommendations are
based:
Class I: conditions for which there is evidence and/or general agree-
ment that the test is useful and effective
813
42. Liu T, Li L, Korantzopoulos P, et al: Statin use and development of atrial fibrillation: A system-
atic review and meta-analysis of randomized clinical trials and observational studies. Int J
Cardiol 126:160, 2008. 38
43. Nodari S, Triggiani M, Campia U, et al: N-3 polyunsaturated fatty acids in the prevention
Atrial Fibrillation: Clinical Features, Mechanisms, and Management
of atrial fibrillation recurrences after electrical cardioversion: A prospective, randomized
study. Circulation 124:1100, 2011.
44. Kumar S, Sutherland F, Morton JB, et al: Long-term omega-3 polyunsaturated fatty acid sup-
plementation reduces the recurrence of persistent atrial fibrillation after electrical cardiover-
sion. Heart Rhythm 9:483, 2012.
Nonpharmacologic Management of Atrial Fibrillation
45. Nielsen JC, Johannsessen A, Raatikainen P, et al: Radiofrequency ablation as initial therapy
in paroxysmal atrial fibrillation. N Engl J Med 367:1587, 2012.
46. Calkins H, Kuck KH, Cappato R, et al: 2012 HRS/EHRA/ECAS expert consensus statement
on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selec-
tion, procedural techniques, patient management and follow-up, definitions, endpoints, and
research trial design. J Interv Card Electrophysiol 33:171, 2012.
47. Noheria A, Kumar A, Wylie JV Jr, Josephson ME: Catheter ablation vs antiarrhythmic drug
therapy for atrial fibrillation: A systematic review. Arch Intern Med 168:581, 2008.
48. Jais P, Cauchemez B, Macle L, et al: Catheter ablation versus antiarrhythmic drugs for atrial
fibrillation: The A4 study. Circulation 118:2498, 2008.
49. Weerasooriya R, Khairy P, Litalien J, et al: Catheter ablation for atrial fibrillation: Are results
maintained at 5 years of follow-up? J Am Coll Cardiol 57:160, 2011.
50. Kowalski M, Grimes MM, Perez FJ, et al: Histopathologic characterization of chronic radiofre-
quency ablation lesions for pulmonary vein isolation. J Am Coll Cardiol 59:930, 2012.
51. Cappato R, Calkins H, Chen SA, et al: Updated worldwide survey on the methods, efficacy,
and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol
3:32, 2010.
52. Cappato R, Calkins H, Chen SA, et al: Prevalence and causes of fatal outcome in catheter
ablation of atrial fibrillation. J Am Coll Cardiol 53:1798, 2009.
53. Gaita F, Caponi D, Pianelli M, et al: Radiofrequency catheter ablation of atrial fibrillation:
A cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral
thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 122:1667,
2010.
54. Andrade JG, Khairy P, Guerra PG, et al: Efficacy and safety of cryoballoon ablation for atrial
fibrillation: A systematic review of published studies. Heart Rhythm 8:1444, 2011.
55. Di Biase L, Wang Y, Horton R, et al: Ablation of atrial fibrillation utilizing robotic catheter
navigation in comparison to manual navigation and ablation: Single-center experience.
J Cardiovasc Electrophysiol 20:1328, 2009.
56. Cox JL, Boineau JP, Schuessler RB, et al: Electrophysiologic basis, surgical development, and
clinical results of the maze procedure for atrial flutter and atrial fibrillation. Adv Card Surg
6:1, 1995.
57. Han FT, Kasirajan V, Kowalski M, et al: Results of a minimally invasive surgical pulmonary
vein isolation and ganglionic plexi ablation for atrial fibrillation: Single-center experience
with 12-month follow-up. Circ Arrhythm Electrophysiol 2:370, 2009.
58. Krul SP, Driessen AH, van Boven WJ, et al: Thoracoscopic video-assisted pulmonary vein
antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation
lesions: First results of a hybrid surgical-electrophysiological approach for atrial fibrillation.
Circ Arrhythm Electrophysiol 4:262, 2011.
59. Boersma LV, Castella M, van Boven W, et al: Atrial fibrillation catheter ablation versus surgi-
cal ablation treatment (FAST): A 2-center randomized clinical trial. Circulation 125:23, 2012.
Specific Clinical Syndromes
60. Halonen J, Halonen P, Jarvinen O, et al: Corticosteroids for the prevention of atrial fibrillation
after cardiac surgery: A randomized controlled trial. JAMA 297:1562, 2007.
61. Imazio M, Brucato A, Ferrazzi P, et al: Colchicine reduces postoperative atrial fibrillation:
Results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS)
atrial fibrillation substudy. Circulation 124:2290, 2011.
62. Heidt MC, Vician M, Stracke SK, et al: Beneficial effects of intravenously administered n-3
fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A
prospective randomized study. Thorac Cardiovasc Surg 57:276, 2009.
63. Saravanan P, Bridgewater B, West AL, et al: Omega-3 fatty acid supplementation does not
reduce risk of atrial fibrillation after coronary artery bypass surgery: A randomized, double-
blind, placebo-controlled clinical trial. Circ Arrhythm Electrophysiol 3:46, 2010.
64. Roy D, Talajic M, Nattel S, et al: Rhythm control versus rate control for atrial fibrillation and
heart failure. N Engl J Med 358:2667, 2008.
65. Khan MN, Jais P, Cummings J, et al: Pulmonary-vein isolation for atrial fibrillation in patients
with heart failure. N Engl J Med 359:1778, 2008.
Class IIa: weight of evidence or opinion in favor of usefulness/efficacy
Class IIb: usefulness or efficacy less well established by evidence or
opinion
Class III: conditions for which there is evidence and/or general agree-
ment that the test is not useful or effective and in some cases may
be harmful
Level A: recommendations derived from data from multiple random-
ized clinical trials
Level B: recommendations derived from a single randomized trial or
nonrandomized studies
Level C: recommendations based on the consensus opinion of
experts
The guidelines do not necessarily define the standard of care.
Management decisions must be individualized on the basis of the
particular circumstances of a patient, and in some situations, devia-
tion from the guidelines may be appropriate.
 814
CLASSIFICATION OF ATRIAL FIBRILLATION Wolff-Parkinson-White syndrome, hyperthyroidism, pregnancy, hyper-
V trophic cardiomyopathy, and pulmonary disease.
The terminology used to classify AF in the guidelines is as follows: An important aspect in the management of patients with AF that
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

paroxysmal AF is defined as episodes of AF that last less than 7 days,
persistent AF is defined as AF that lasts more than 7 days, and long-
standing AF refers to AF that has been persistent for more than 1 year.
These designations are not altered by termination of AF via drug
therapy or electrical cardioversion. AF that is resistant to electrical
cardioversion is referred to as permanent AF. AF is considered recur-
rent after two or more episodes have occurred.
Some patients with paroxysmal AF occasionally have episodes that
are persistent, and vice versa. In this event the AF should be catego-
rized on the basis of the predominant form. Lone AF refers to AF in
patients younger than 60 years who do not have structural heart
disease or hypertension. AF that is secondary to acute myocardial
infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroid-
ism, or an acute pulmonary process is considered separately because
the AF often resolves after treatment of the underlying disorder.
MANAGEMENT OF ATRIAL FIBRILLATION
The guidelines address five aspects of the management of AF: phar-
macologic rate control; prevention of thromboembolic complica-
tions; cardioversion; maintenance of sinus rhythm; and special
considerations, including postoperative AF, myocardial infarction,
is not specifically addressed in the guidelines is how to decide on a
rate-control strategy versus a rhythm-control strategy. Several clinical
trials have demonstrated that pharmacologic rhythm-control and
rate-control strategies result in similar outcomes, even in patients
with AF who have left ventricular dysfunction and heart failure. On
the other hand, a randomized trial of left atrial radiofrequency cath-
eter ablation versus atrioventricular (AV) node ablation and biven-
tricular pacing demonstrated significantly greater improvement in left
ventricular function, exercise capacity, and quality of life in patients
with heart failure who were treated by ablation. It is possible that the
side effects from the drugs used for rhythm control offset the benefits
of sinus rhythm. Specific recommendations regarding rhythm-control
versus rate-control strategies are difficult to provide because the deci-
sion must be individualized on the basis of several factors, including
age, symptom severity, functional limitations, patient preference,
comorbid conditions, sinus node function, and response to drug
therapy.
Pharmacologic Rate Control During Atrial
Fibrillation (Table 38G-1)
In addition to specific recommendations on the use of particular
drugs for control of the ventricular rate, the guidelines recommend

TABLE 38G-1 ACC/AHA Recommendations for Pharmacologic Rate Control of Atrial Fibrillation
LEVEL OF
CLASS INDICATION EVIDENCE
Class I Measurement of the heart rate at rest and control of the rate with pharmacologic agents (in most cases either a B
(indicated) beta blocker or nondihydropyridine calcium channel antagonist) are recommended for patients with persistent or
permanent AF
In the absence of preexcitation, intravenous administration of beta blockers (esmolol, metoprolol, or propranolol) B
or nondihydropyridine calcium channel antagonists (verapamil, diltiazem) is recommended to slow the ventricular
response to AF in the acute setting, with caution being exercised in patients with hypotension or heart failure
Intravenous administration of digoxin or amiodarone is recommended to control the heart rate in patients with AF and B
heart failure who do not have an accessory pathway
In patients who experience symptoms related to AF during activity, the adequacy of heart rate control should be C
assessed during exercise, with pharmacologic treatment being adjusted as necessary to keep the rate in the
physiologic range
Digoxin is effective after oral administration to control the heart rate at rest in patients with AF and is indicated for C
patients with heart failure or left ventricular dysfunction and for sedentary individuals
Class IIa A combination of digoxin and either a beta blocker or nondihydropyridine calcium channel antagonist is reasonable B
(reasonable) to control the heart rate both at rest and during exercise in patients with AF. The choice of medication should be
individualized and the dose modulated to avoid bradycardia
It is reasonable to use ablation of the AV node or accessory pathway to control the heart rate when pharmacologic B
therapy is insufficient or associated with side effects
Intravenous amiodarone can be useful to control heart rate in patients with AF when other measures are unsuccessful C
or contraindicated
When electrical cardioversion is not necessary in patients with AF and an accessory pathway, intravenous procainamide C
or ibutilide is a reasonable alternative
Class IIb When the ventricular rate cannot be adequately controlled both at rest and during exercise in patients with AF by a C
(may be beta blocker, nondihydropyridine calcium channel antagonist, or digoxin, alone or in combination, oral amiodarone
considered) may be administered to control the heart rate
Intravenous procainamide, disopyramide, ibutilide, or amiodarone may be considered for hemodynamically stable B
patients with AF involving conduction over an accessory pathway
When the rate cannot be controlled with pharmacologic agents or tachycardia-mediated cardiomyopathy is suspected, C
catheter-directed ablation of the AV node may be considered in patients with AF to control the heart rate
Class III (not Strict rate control (<80 beats/min at rest or <110 beats/min during a 6-minute walk) is not more beneficial than a B
indicated ) resting rate of <110 beats/min in asymptomatic patients with persistent AF and an ejection fraction >40%, although
uncontrolled tachycardia can lead to reversible left ventricular dysfunction over time
Digitalis should not be used as the sole agent to control the rate of ventricular response in patients with paroxysmal AF B
Catheter ablation of the AV node should not be attempted without a prior trial of medication to control the C
ventricular rate in patients with AF
In patients with decompensated heart failure and AF, intravenous administration of a nondihydropyridine calcium C
channel antagonist may exacerbate the hemodynamic compromise and is not recommended
Intravenous administration of digitalis glycosides or nondihydropyridine calcium channel antagonists to patients with C
AF and a preexcitation syndrome may paradoxically accelerate the ventricular response and is not recommended
 815
that the effects of drug therapy on ventricular rate be measured at AF except those who have lone AF or contraindications. An updated
rest and during exercise to ensure adequate heart rate control. The recommendation as of 2011 is that the direct thrombin inhibitor dabi- 38
criteria used for rate control are rates of 60 to 80 beats/min at rest gatran is a useful alternative to warfarin for prevention of stroke or

Atrial Fibrillation: Clinical Features, Mechanisms, and Management

and 90 to 115 beats/min during moderate exercise.
A new recommendation as of 2011 is that a resting rate of less than
110 beats/min is a reasonable rate-control target in patients with
persistent AF and no arrhythmia-related symptoms who have an ejec-
tion fraction higher than 40%. However, the guidelines caution that
tachycardia can result in a decline in left ventricular function over
time.
Digitalis is much less effective for control of the ventricular rate
during exercise than at rest and is indicated for patients with heart
failure or left ventricular dysfunction and for sedentary patients. A
combination of digitalis and either a beta blocker or a nondihydro-
pyridine calcium channel antagonist is appropriate to control the rate
at rest and during exercise. The guidelines recommend that digitalis
be used as the sole agent for rate control in patients with paroxysmal
AF. Catheter ablation of the AV node should be reserved for patients
whose ventricular rate cannot be adequately controlled by drug
therapy because of either inefficacy or drug intolerance.
Prevention of Thromboembolism
(Table 38G-2)
The 2006 guidelines recommend antithrombotic therapy with either
aspirin or a vitamin K antagonist such as warfarin for all patients with
embolism in patients with AF. The choice between aspirin and an
anticoagulant is based on the patient’s risk profile. Factors associated
with the highest risk for thromboembolism are a previous thrombo-
embolic event and rheumatic mitral stenosis, and warfarin or dabiga-
tran is recommended for patients with one of these risk factors. Risk
factors associated with a moderate risk for thromboembolism are 75
years of age or older, hypertension, heart failure, ejection fraction of
35% or lower, and diabetes. Aspirin is recommended if none of these
risk factors are present, and an anticoagulant is recommended for
patients with one or more of these risk factors. In patients with only
one of the moderate risk factors, either aspirin or an anticoagulant is
reasonable, and the choice should be individualized.
Rivaroxaban was approved by the Food and Drug Administration
in 2011 after publication of the updated guidelines dealing with dabi-
gatran. It seems appropriate to generalize the recommendations
regarding dabigatran to the factor Xa inhibitor rivaroxaban.
Another update to the 2006 guidelines addresses combination
therapy with aspirin and clopidogrel. This combination has been
demonstrated to be less effective than warfarin for preventing strokes
but more effective than aspirin by itself. The guidelines now recom-
mend that aspirin plus clopidogrel be considered for prevention of
stroke in patients who cannot tolerate or refuse to take an oral
anticoagulant.

TABLE 38G-2 ACC/AHA Recommendations for Prevention of Thromboembolism in Atrial Fibrillation

LEVEL OF
CLASS INDICATION EVIDENCE
Class I Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, A
(indicated) except those with lone AF or contraindications
Selection of the antithrombotic agent should be based on the absolute risks for stroke and A
bleeding and the relative risk and benefit in a given patient
For patients without mechanical heart valves at high risk for stroke, chronic oral anticoagulant A
therapy with a vitamin K antagonist is recommended in a dose adjusted to achieve the target
intensity INR of 2.0 to 3.0 unless contraindicated. Factors associated with highest risk for stroke
in patients with AF are previous thromboembolism (stroke, transient ischemic attack, or systemic
embolism) and rheumatic mitral stenosis
Anticoagulation with a vitamin K antagonist is recommended for patients with more than one A
moderate risk factor. Such factors include age 75 years or older, hypertension, heart failure,
impaired left ventricular systolic function (ejection fraction ≤35% or fractional shortening
<25%), and diabetes mellitus
The INR should be determined at least weekly during initiation of therapy and monthly when A
anticoagulation is stable
Dabigatran is a useful alternative to warfarin in patients with AF and risk factors for stroke who do B
not have a prosthetic heart valve or significant valve disease, a creatinine clearance <15 mL/min,
or advanced liver disease
Aspirin, 81 to 325 mg daily, is recommended as an alternative to vitamin K antagonists in low-risk A
patients or in those with contraindications to oral anticoagulation
For patients with AF who have mechanical heart valves, the target intensity of anticoagulation B
should be based on the type of prosthesis while maintaining an INR of at least 2.5
Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF C
Class IIa For primary prevention of thromboembolism in patients with nonvalvular AF who have just one A
(reasonable) of the following validated risk factors, antithrombotic therapy with either aspirin or a vitamin K
antagonist is reasonable based on an assessment of the risk for bleeding complications, ability
to safely sustain adjusted chronic anticoagulation, and the patient’s preferences: age 75 years
or older (especially in women), hypertension, heart failure, impaired left ventricular function, or
diabetes mellitus
For patients with nonvalvular AF who have one or more of the following less well validated risk B
factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable for
prevention of thromboembolism: age 65 to 74 years, female sex, or coronary artery disease.
The choice of agent should be based on the risk for bleeding complications, ability to sustain
adjusted chronic anticoagulation, and the patient’s preferences
It is reasonable to select antithrombotic therapy by the same criteria irrespective of the pattern B
(i.e., paroxysmal, persistent, or permanent) of AF
In patients with AF who do not have mechanical prosthetic heart valves, it is reasonable to C
interrupt anticoagulation for up to 1 week without substituting heparin for surgical or
diagnostic procedures that carry a risk for bleeding
It is reasonable to reevaluate the need for anticoagulation at regular intervals C

Continued
 816

TABLE 38G-2 ACC/AHA Recommendations for Prevention of Thromboembolism in Atrial Fibrillation—cont’d

V
LEVEL OF
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

CLASS INDICATION EVIDENCE

Class IIb In patients 75 years or older at increased risk for bleeding but without frank contraindications C
(may be to oral anticoagulant therapy and in other patients with moderate risk factors for
considered) thromboembolism who are unable to safely tolerate anticoagulation at the standard intensity
of an INR of 2.0 to 3.0, a lower INR target of 2.0 (range, 1.6 to 2.5) may be considered for
prevention of ischemic stroke and systemic embolism
When surgical procedures require interruption of oral anticoagulant therapy for longer than 1 C
week in high-risk patients, unfractionated heparin may be administered or low-molecular-
weight heparin given by subcutaneous injection, although the efficacy of these alternatives in
this situation is uncertain
After percutaneous coronary intervention or revascularization surgery in patients with AF, low- C
dose aspirin (<100 mg/day) and/or clopidogrel (75 mg/day) may be given concurrently with
anticoagulation to prevent myocardial ischemic events, but these strategies have not been
thoroughly evaluated and are associated with an increased risk for bleeding
In patients undergoing percutaneous coronary intervention, anticoagulation may be interrupted to C
prevent bleeding at the site of peripheral arterial puncture, but the vitamin K antagonist should
be resumed as soon as possible after the procedure and the dose adjusted to achieve an INR in
the therapeutic range. Aspirin may be given temporarily during the hiatus, but the maintenance
regimen should then consist of the combination of clopidogrel, 75 mg daily, plus warfarin (INR,
2.0 to 3.0). Clopidogrel should be given for a minimum of 1 month after implantation of a bare-
metal stent, at least 3 months for a sirolimus-eluting stent, at least 6 months for a paclitaxel-
eluting stent, and 12 months or longer in selected patients, following which warfarin may be
continued as monotherapy in the absence of a subsequent coronary event. When warfarin is
given in combination with clopidogrel or low-dose aspirin, the dose intensity must be carefully
regulated
In patients with AF younger than 60 years without heart disease or risk factors for C
thromboembolism (lone AF), the risk for thromboembolism is low without treatment, and the
effectiveness of aspirin for primary prevention of stroke relative to the risk for bleeding has not
been established
In patients with AF who sustain an ischemic stroke or systemic embolism during treatment with C
low-intensity anticoagulation (INR, 2.0 to 3.0), rather than add an antiplatelet agent, it may be
reasonable to raise the intensity of the anticoagulation to a maximum target INR of 3.0 to 3.5
Clopidogrel plus aspirin may be considered in patients who cannot tolerate or who refuse an oral B
anticoagulant
Class III (not Long-term anticoagulation with a vitamin K antagonist is not recommended for primary C
indicated) prevention of stroke in patients younger than 60 years without heart disease (lone AF) or any
risk factors for thromboembolism

INR = international normalized ratio.

patients receiving warfarin, heparin should be continued until the

Cardioversion of Atrial Fibrillation
(Table 38G-3)
The first-line drugs recommended for cardioversion are flecainide,
dofetilide, propafenone, and ibutilide. Amiodarone is considered a
reasonable option. The guidelines state that digoxin and sotalol may
be harmful when they are used for cardioversion and recommend
against use of these agents for that purpose.
Direct-current cardioversion is recommended when the ventricular
rate is rapid and does not respond quickly to drug therapy in patients
with myocardial ischemia, hypotension, or heart failure and in
patients with Wolff-Parkinson-White syndrome and AF with a very
rapid rate or hemodynamic instability. If AF recurs early after direct-
current cardioversion, repeated cardioversion is recommended after
treatment with an antiarrhythmic drug.
If AF has been present for longer than 48 hours or if the duration
is unknown, anticoagulation with warfarin and an international nor-
malized ratio (INR) of 2 to 3 is recommended for 3 or more weeks
before cardioversion, whether pharmacologic or electrical, and for 4
weeks afterward. It is reasonable to presume that dabigatran and
rivaroxaban are suitable alternatives to warfarin.
When cardioversion is performed within 48 hours of the onset of
AF, anticoagulation before and after cardioversion may be based on
the patient’s risk profile.
In patients with AF lasting longer than 48 hours or in whom the
duration is unknown, an alternative to anticoagulation for 3 or more
weeks before cardioversion is to perform transesophageal echocar-
diography, to anticoagulate the patient with heparin, to initiate oral
anticoagulation, and to proceed with immediate cardioversion if no
thrombi are present in the left atrium or left atrial appendage. In
INR is 2, and oral anticoagulation with an INR of 2 to 3 should be
continued for 4 or more weeks. In patients treated with dabigatran or
rivaroxaban, heparin can be discontinued 3 to 4 hours after the first
oral dose. As with warfarin, anticoagulation therapy should be con-
tinued for 4 or more weeks.
Maintenance of Sinus Rhythm (Table 38G-4)
A reasonable outcome of antiarrhythmic drug therapy is infrequent
recurrences of well-tolerated AF. Initiation of a rhythm-control medi-
cation is reasonable on an outpatient basis in patients without heart
disease when the medication is well tolerated. The updated guide-
lines now recommend dronedarone as being a reasonable option in
patients with paroxysmal AF or after conversion of persistent AF. The
guidelines recommend catheter ablation of symptomatic paroxysmal
AF for patients who have failed treatment with an antiarrhythmic
drug and have little or no left atrial enlargement and normal or mildly
reduced left ventricular function.
Special Considerations (Table 38G-5)
Postoperative Atrial Fibrillation
The guidelines recommend prophylactic treatment with an oral beta
blocker to prevent postoperative AF in patients undergoing cardiac
surgery. Preoperative amiodarone is also considered to be appropri-
ate prophylactic therapy to prevent postoperative AF. Use of cardio-
version, rhythm-control medications, and antithrombotic medication
should be based on the same considerations as in nonsurgical
patients.
 817

TABLE 38G-3 ACC/AHA Recommendations for Cardioversion of Atrial Fibrillation

38
CLASS INDICATION LEVEL OF EVIDENCE

Atrial Fibrillation: Clinical Features, Mechanisms, and Management

Pharmacologic Cardioversion
Class I Administration of flecainide, dofetilide, propafenone, or ibutilide is recommended for pharmacologic A
(indicated) cardioversion of AF
Class IIa Administration of amiodarone is a reasonable option for pharmacologic cardioversion of AF A
(reasonable) A single oral bolus dose of propafenone or flecainide (“pill-in-the-pocket” approach) can be administered C
to terminate persistent AF outside the hospital once treatment has proved safe in the hospital for
selected patients without sinus or AV node dysfunction, bundle branch block, prolongation of the QT
interval, Brugada syndrome, or structural heart disease. Before antiarrhythmic medication is initiated,
a beta blocker or nondihydropyridine calcium channel antagonist should be given to prevent rapid AV
conduction in the event that atrial flutter occurs
Administration of amiodarone can be beneficial on an outpatient basis in patients with paroxysmal or C
persistent AF when rapid restoration of sinus rhythm is not deemed necessary
Class IIb (may be Administration of quinidine or procainamide might be considered for pharmacologic cardioversion of AF, C
considered) but the usefulness of these agents is not well established
Class III (not Digoxin and sotalol may be harmful when used for pharmacologic cardioversion of AF and are not A
indicated) recommended
Quinidine, procainamide, disopyramide, and dofetilide should not be started out of the hospital for B
conversion of AF to sinus rhythm
Direct-Current Cardioversion
Class I When a rapid ventricular response to pharmacologic measures does not occur in patients with AF and C
(indicated) ongoing myocardial ischemia, symptomatic hypotension, angina, or heart failure, immediate R wave–
synchronized direct-current cardioversion is recommended
Immediate direct-current cardioversion is recommended for patients with AF involving preexcitation when B
very rapid tachycardia or hemodynamic instability occurs
Cardioversion is recommended in patients without hemodynamic instability when symptoms of AF are C
unacceptable to the patient. In case of early relapse of AF after cardioversion, repeated attempts at
direct-current cardioversion may be made after administration of antiarrhythmic medication
Class IIa Direct-current cardioversion can be useful to restore sinus rhythm as part of a long-term management B
(reasonable) strategy for patients with AF
The patient’s preference is a reasonable consideration in the selection of infrequently repeated C
cardioversions for the management of symptomatic or recurrent AF
Class III (not Frequent repetition of direct-current cardioversion is not recommended for patients who have relatively C
indicated) short periods of sinus rhythm between relapses of AF after multiple cardioversion procedures despite
prophylactic antiarrhythmic drug therapy
Electrical cardioversion is contraindicated in patients with digitalis toxicity or hypokalemia C
Pharmacologic Enhancement of Direct-Current Cardioversion
Class IIa Pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol can be useful to enhance the B
(reasonable) success of direct-current cardioversion and to prevent recurrent AF
In patients in whom AF recurs after successful cardioversion, it can be useful to repeat the procedure C
after prophylactic administration of antiarrhythmic medication
Class IIb (may be For patients with persistent AF, administration of beta blockers, disopyramide, diltiazem, dofetilide, C
considered)) procainamide, or verapamil may be considered, although the efficacy of these agents in enhancing the
success of direct-current cardioversion or in preventing early recurrence of AF is uncertain
Out-of-hospital initiation of antiarrhythmic medications may be considered in patients without heart C
disease to enhance the success of cardioversion of AF
Out-of-hospital administration of antiarrhythmic medications may be considered to enhance the success C
of cardioversion of AF in patients with certain forms of heart disease once the safety of the drug has
been verified for the patient
Prevention of Thromboembolism in Patients with Atrial Fibrillation Undergoing Cardioversion
Class I For patients with AF lasting 48 hours or longer or when the duration of AF is unknown, anticoagulation B
(indicated) (INR of 2.0 to 3.0) is recommended for at least 3 weeks before and 4 weeks after cardioversion,
regardless of the method (electrical or pharmacologic) used to restore sinus rhythm
For patients with AF lasting longer than 48 hours who require immediate cardioversion because of C
hemodynamic instability, heparin should be administered concurrently (unless contraindicated) via an
initial intravenous bolus injection, followed by a continuous infusion in a dose adjusted to prolong the
activated partial thromboplastin time to 1.5 to 2 times the reference control value. Thereafter, oral
anticoagulation (INR of 2.0 to 3.0) should be provided for at least 4 weeks, as for patients undergoing
elective cardioversion. Limited data support subcutaneous administration of low-molecular-weight
heparin for this indication
For patients with AF of less than a 48-hour duration associated with hemodynamic instability (angina C
pectoris, myocardial infarction, shock, or pulmonary edema), cardioversion should be performed
immediately, without delay for initiation of anticoagulation

Continued
 818

TABLE 38G-3 ACC/AHA Recommendations for Cardioversion of Atrial Fibrillation—cont’d

V
CLASS INDICATION LEVEL OF EVIDENCE
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

Class IIa During the 48 hours after the onset of AF, the need for anticoagulation before and after cardioversion C
(reasonable) may be based on the patient’s risk for thromboembolism
As an alternative to anticoagulation before cardioversion of AF, it is reasonable to perform B
transesophageal echocardiography to search for a thrombus in the left atrium or left atrial appendage
a. For patients with no identifiable thrombus, cardioversion is reasonable immediately after B
anticoagulation with unfractionated heparin (e.g., initiated by intravenous bolus injection and an
infusion continued at a dose adjusted to prolong the activated partial thromboplastin time to 1.5
to 2 times the control value until oral anticoagulation has been established with an oral vitamin K
antagonist [e.g., warfarin] as evidenced by an INR ≥2.0)
Thereafter, continuation of oral anticoagulation (INR of 2.0 to 3.0) is reasonable for a total B
anticoagulation period of at least 4 weeks, as for patients undergoing elective cardioversion
Limited data are available to support the subcutaneous administration of a low-molecular-weight C
heparin for this indication
b. For patients in whom a thrombus is identified by transesophageal echocardiography, oral C
anticoagulation (INR of 2.0 to 3.0) is reasonable for at least 3 weeks before and 4 weeks after
restoration of sinus rhythm, and a longer period of anticoagulation may be appropriate even after
apparently successful cardioversion because the risk for thromboembolism often remains elevated in
such cases
For patients with atrial flutter undergoing cardioversion, anticoagulation can be beneficial according C
to the recommendations as for patients with AF

TABLE 38G-4 ACC/AHA Recommendations for Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation
CLASS INDICATION LEVEL OF EVIDENCE
Class I (indicated) Before initiation of antiarrhythmic drug therapy, treatment of precipitating or reversible C
causes of AF is recommended
Catheter ablation by an experienced operator is useful in selected patients with A
symptomatic paroxysmal AF who have failed treatment with an antiarrhythmic drug
and have a normal or mildly dilated left atrium and normal or mildly reduced left
ventricular function
Class IIa (reasonable) Pharmacologic therapy can be useful in patients with AF to maintain sinus rhythm and C
to prevent tachycardia-induced cardiomyopathy
Infrequent, well-tolerated recurrence of AF is reasonable as a successful outcome of C
antiarrhythmic drug therapy
Outpatient initiation of antiarrhythmic drug therapy is reasonable in patients with AF C
who have no associated heart disease when the agent is well tolerated
In patients with lone AF without structural heart disease, initiation of propafenone or B
flecainide can be beneficial on an outpatient basis in patients with paroxysmal AF
who are in sinus rhythm at the time of drug initiation
Sotalol can be beneficial in outpatients in sinus rhythm with little or no heart disease C
who are prone to paroxysmal AF if the baseline uncorrected QT interval is shorter
than 460 msec, serum electrolyte values are normal, and risk factors associated with
class III drug–related proarrhythmia are not present
Catheter ablation is a reasonable option for the treatment of symptomatic persistent AF A
Class IIb (may be Catheter ablation may be reasonable for patients with symptomatic paroxysmal AF and A
considered) significant left atrial dilation or significant left ventricular dysfunction
Class III (not Antiarrhythmic therapy with a particular drug is not recommended for maintenance A
indicated) of sinus rhythm in patients with AF who have well-defined risk factors for
proarrhythmia with that agent
Pharmacologic therapy is not recommended for maintenance of sinus rhythm in C
patients with advanced sinus node disease or AV node dysfunction unless they have
a functioning electronic cardiac pacemaker

Acute Myocardial Infarction Atrial Fibrillation in Wolff-Parkinson-White Syndrome

Electrical cardioversion is recommended for patients with hemody-
namic compromise or ongoing ischemia or when adequate rate
control cannot be achieved with drug therapy. The guidelines recom-
mend intravenous amiodarone or digitalis to slow the ventricular rate
in patients and to improve left ventricular function in those with acute
myocardial infarction. In patients without left ventricular dysfunc-
tion, bronchospasm, or AV block, an intravenous beta blocker or
nondihydropyridine calcium channel antagonist is recommended for
rate control.
Catheter ablation of the accessory pathway is recommended for
patients with symptomatic AF and Wolff-Parkinson-White syndrome.
Immediate electrical cardioversion is recommended for those with
AF and a rapid ventricular rate and hemodynamic instability. If
the patient is hemodynamically stable, intravenous procainamide or
ibutilide is recommended for pharmacologic conversion of AF. Intra-
venous digitalis and nondihydropyridine calcium channel antago-
nists should be avoided in patients with ventricular preexcitation
during AF.
 819

TABLE 38G-5 ACC/AHA Recommendations for Special Considerations in Atrial Fibrillation

38
CLASS INDICATION LEVEL OF EVIDENCE

Atrial Fibrillation: Clinical Features, Mechanisms, and Management

Postoperative Atrial Fibrillation
Class I Unless contraindicated, treatment with an oral beta blocker to prevent postoperative AF is A
(indicated) recommended for patients undergoing cardiac surgery
Administration of AV nodal blocking agents is recommended to achieve rate control in patients in B
whom AF develops postoperatively
Class IIa Preoperative administration of amiodarone reduces the incidence of AF in patients undergoing cardiac A
(reasonable) surgery and represents appropriate prophylactic therapy for patients at high risk for postoperative AF
It is reasonable to restore sinus rhythm by pharmacologic cardioversion with ibutilide or direct-current B
cardioversion in patients in whom AF develops postoperatively, as advised for nonsurgical patients
It is reasonable to administer antiarrhythmic medications in an attempt to maintain sinus rhythm in B
patients with recurrent or refractory postoperative AF, as recommended for other patients in whom
AF develops
It is reasonable to administer antithrombotic medication in patients in whom AF develops B
postoperatively, as recommended for nonsurgical patients
Class IIb (may be Prophylactic administration of sotalol may be considered for patients at risk for the development of AF B
considered) after cardiac surgery
Acute Myocardial Infarction
Class I Direct-current cardioversion is recommended for patients with severe hemodynamic compromise or C
(indicated) intractable ischemia or when adequate rate control cannot be achieved with pharmacologic agents
in patients with acute myocardial infarction and AF
Intravenous administration of amiodarone is recommended to slow a rapid ventricular response to AF C
and to improve left ventricular function in patients with acute myocardial infarction
Intravenous beta blockers and nondihydropyridine calcium channel antagonists are recommended C
to slow a rapid ventricular response to AF in patients with acute myocardial infarction who do not
display clinical left ventricular dysfunction, bronchospasm, or AV block
For patients with AF and acute myocardial infarction, administration of unfractionated heparin by C
either continuous intravenous infusion or intermittent subcutaneous injection is recommended in
a dose sufficient to prolong the activated partial thromboplastin time to 1.5 to 2 times the control
value, unless contraindications to anticoagulation exist
Class IIa Intravenous administration of digitalis is reasonable to slow a rapid ventricular response and to improve C
(reasonable) left ventricular function in patients with acute myocardial infarction and AF associated with severe
left ventricular dysfunction and heart failure
Class III (not Administration of class IC antiarrhythmic drugs is not recommended in patients with AF in the setting C
indicated) of acute myocardial infarction
Management of Atrial Fibrillation Associated with Wolff-Parkinson-White (WPW) Preexcitation Syndrome
Class I Catheter ablation of the accessory pathway is recommended for symptomatic patients with AF who B
(indicated) have WPW syndrome, particularly those with syncope secondary to a rapid heart rate or those with
a short bypass tract refractory period
Immediate direct-current cardioversion is recommended to prevent ventricular fibrillation in patients B
with a short anterograde bypass tract refractory period in whom AF occurs with a rapid ventricular
response associated with hemodynamic instability
Intravenous procainamide or ibutilide is recommended to restore sinus rhythm in patients with WPW C
syndrome in whom AF occurs without hemodynamic instability in association with a wide QRS
complex on the electrocardiogram (≥120-msec duration) or with a rapid preexcited ventricular
response
Class IIa Intravenous flecainide or direct-current cardioversion is reasonable when very rapid ventricular rates B
(reasonable) occur in patients with AF involving conduction over an accessory pathway
Class IIb (may be It may be reasonable to administer intravenous quinidine, procainamide, disopyramide, ibutilide, or B
considered) amiodarone to hemodynamically stable patients with AF involving conduction over an accessory
pathway
Class III (not Intravenous administration of digitalis glycosides or nondihydropyridine calcium channel antagonists B
indicated) is not recommended in patients with WPW syndrome who have preexcited ventricular activation
during AF
Hyperthyroidism
Class I Administration of a beta blocker is recommended to control the rate of ventricular response in patients B
(indicated) with AF complicating thyrotoxicosis, unless contraindicated
In circumstances in which a beta blocker cannot be used, administration of a nondihydropyridine B
calcium channel antagonist (diltiazem or verapamil) is recommended to control the ventricular rate
in patients with AF and thyrotoxicosis
In patients with AF associated with thyrotoxicosis, oral anticoagulation (INR of 2.0 to 3.0) is C
recommended to prevent thromboembolism, as recommended for AF patients with other risk
factors for stroke
Once a euthyroid state is restored, recommendations for antithrombotic prophylaxis are the same as C
for patients without hyperthyroidism

Continued
 820

TABLE 38G-5 ACC/AHA Recommendations for Special Considerations in Atrial Fibrillation—cont’d

V
CLASS INDICATION LEVEL OF EVIDENCE
ARRHYTHMIAS, SUDDEN DEATH, AND SYNCOPE

Management of Atrial Fibrillation During Pregnancy

Class I Digoxin, a beta blocker, or a nondihydropyridine calcium channel antagonist is recommended to C
(indicated) control the rate of ventricular response in pregnant patients with AF
Direct-current cardioversion is recommended in pregnant patients who become hemodynamically C
unstable because of AF
Protection against thromboembolism is recommended throughout pregnancy for all patients with C
AF (except those with lone AF and/or low thromboembolic risk). Therapy (anticoagulant or aspirin)
should be chosen according to the stage of pregnancy
Class IIb (may be Administration of heparin may be considered during the first trimester and last month of pregnancy B
considered) for patients with AF and risk factors for thromboembolism. Unfractionated heparin may be
administered either by continuous intravenous infusion in a dose sufficient to prolong the activated
partial thromboplastin time to 1.5 to 2 times the control value or by intermittent subcutaneous
injection in a dose of 10,000 to 20,000 units every 12 hours, adjusted to prolong the midinterval (6
hours after injection) activated partial thromboplastin time to 1.5 times control
Despite the limited data available, subcutaneous administration of low-molecular-weight heparin may C
be considered during the first trimester and last month of pregnancy for patients with AF and risk
factors for thromboembolism
Administration of an oral anticoagulant may be considered during the second trimester for pregnant C
patients with AF and high thromboembolic risk
Administration of quinidine or procainamide may be considered to achieve pharmacologic C
cardioversion in hemodynamically stable patients in whom AF develops during pregnancy
Management of Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy (HCM)
Class I Oral anticoagulation (INR of 2.0 to 3.0) is recommended in patients with HCM in whom AF develops, B
(indicated) as for other patients at high risk for thromboembolism
Class IIa (may be Antiarrhythmic medications can be useful to prevent recurrent AF in patients with HCM. The C
considered) data available are insufficient to recommend one agent over another in this situation, but (1)
disopyramide combined with a beta blocker or nondihydropyridine calcium channel antagonist or (2)
amiodarone alone is generally preferred
Management of Atrial Fibrillation in Patients with Pulmonary Disease
Class I Correction of hypoxemia and acidosis is the recommended primary therapeutic measure for patients in C
(indicated) whom AF develops during an acute pulmonary illness or exacerbation of chronic pulmonary disease
A nondihydropyridine calcium channel antagonist (diltiazem or verapamil) is recommended to control C
the ventricular rate in patients with obstructive pulmonary disease in whom AF develops
Direct-current cardioversion should be attempted in patients with pulmonary disease who become C
hemodynamically unstable as a consequence of AF
Class III (not Theophylline and beta-adrenergic agonist agents are not recommended for patients with C
indicated) bronchospastic lung disease in whom AF develops
Beta blockers, sotalol, propafenone, and adenosine are not recommended in patients with obstructive C
lung disease in whom AF develops

Hyperthyroidism Hypertrophic Cardiomyopathy

The guidelines recommend a beta blocker as first-line therapy for rate
control in patients with AF and thyrotoxicosis. If a beta blocker cannot
be used, verapamil or diltiazem should be used for rate control.
Recommendations for therapy to prevent thromboembolic complica-
tions are the same as for patients without hyperthyroidism.
The guidelines point out that data are not adequate to determine the
best rhythm-control medication to use for AF in the setting of hyper-
trophic cardiomyopathy. The preferred therapy is either disopyra-
mide plus a beta blocker, verapamil, or diltiazem for rate control or
amiodarone by itself.

Atrial Fibrillation during Pregnancy

The guidelines recommend digoxin, a beta blocker, or a nondihydro-
pyridine calcium channel antagonist for rate control of AF during
pregnancy. Direct-current cardioversion is recommended in hemody-
namically unstable patients.
Except in patients with a low-risk profile, either aspirin or an anti-
coagulant is recommended for prevention of thromboembolic com-
plications, depending on the stage of pregnancy (see Chapter 82).
Unfractionated or low-molecular-weight heparin can be considered
during the first trimester and last month of pregnancy in patients with
risk factors for thromboembolism, and an oral anticoagulant can be
considered during the second trimester in patients at high risk for
thromboembolism.
When AF occurs during pregnancy, quinidine or procainamide can
be considered for pharmacologic cardioversion in hemodynamically
stable patients.
Pulmonary Disease
The primary therapy for AF in the setting of an acute pulmonary
illness or exacerbation of chronic pulmonary disease should be cor-
rection of hypoxemia and acidosis. Verapamil or diltiazem is recom-
mended for rate control in patients with obstructive pulmonary
disease. Theophylline and beta-adrenergic agonists are not recom-
mended in patients with bronchospastic disease, and beta blockers,
sotalol, propafenone, and adenosine are not recommended in
patients with obstructive lung disease.
References
1. Fuster V, Ryden LE, Cannom DS, et al: 2011 ACCF/AHA/HRS focused updates incorporated
into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation:
A report of the American College of Cardiology Foundation/American Heart Association task
force on practice guidelines. Circulation 123:e269, 2011.