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to AF is typically irregular, whereas the response to atrial flutter may be
regular. The electrocardiogram is also used to identify comorbid cardiovascular conditions, such as chamber hypertrophy, myocardial ischemia or
infarction, pre-excitation and conduction defects.
Echocardiography
Transthoracic echocardiography (TTE) is useful mainly for evaluating
chamber dimensions and function, excluding valvular disease, and detecting pulmonary hypertension. It is less sensitive than transesophageal
echocardiography (TEE) for detecting thrombi in the left atrium and
left atrial appendage. Hence, TTE cannot substitute for TEE to expedite
cardioversion.
Additional Laboratory Evaluation
Serum electrolytes, renal, thyroid and liver function, and the hemogram
should be measured in all patients with AF or atrial flutter to identify
potential provocative factors and comorbid illness and to aid pharmacological management. Exercise testing, ambulatory rhythm (e.g. Holter)
monitoring, and electrophysiological testing may be useful in selected
cases for guiding therapy.
Management
Optimum management of patients with AF or atrial flutter involves, in
order of priority, adequate control of the ventricular response, selection of
appropriate antithrombotic therapy, and judicious decisions about the
value and approach to rhythm control. Immediate cardioversion to restore
sinus rhythm is indicated only when acute hemodynamic instability
(angina, heart failure, or shock) develops as a consequence of the arrhythmia or in patients with pre-excitation due to an accessory conduction
pathway resulting in extremely rapid ventricular response that threatens to
degenerate into ventricular tachycardia or fibrillation.
234
K. Bhasin and J. L. Halperin
It was long presumed that restoration and maintenance of sinus
rhythm (rhythm control strategy) would be superior to rate control for
prevention of stroke and mortality in patients with AF. However, several
randomized trials have failed to validate this hypothesis, largely because
of the inherent toxicity of most antiarrhythmic drugs, the risk associated
with invasive approaches like catheter-based ablation, and the risk of
thromboembolism associated with asymptomatic recurrence of AF after
withdrawal of anticoagulation.
4,5
Rate Control
The goals of rate control therapy are to alleviate symptoms associated
with AF and prevent the development of tachycardia-mediated cardiomyopathy. In one study, the composite rate of death from cardiovascular
causes and hospitalization for heart failure was not reduced with more
aggressive efforts to control the heart rate compared with more lenient
control.
6
Optimally, however, in managing patients with AF, AV-nodal
blocking medication should be administered as needed to slow the heart
rate to 60–80 beats per minute (bpm) at rest and less than 120 bpm with
moderate exertion.
3
Beta-blockers and the nondihydropyridine calcium channel blockers
diltiazem or verapamil are typically chosen for this purpose. Beta-blockers
may aggravate bronchospasm, however, and, like calcium channel blockers, may aggravate hypotension associated with AF. Calcium channel
blockers should be avoided in patients with impaired LV systolic function,
whereas bisoprolol, extended-release metoprolol, and carvedilol have
each been shown to reduce mortality in patients with LV dysfunction.
3,7
Digoxin is less effective for control of the ventricular response during
exercise, but is indicated in patients with heart failure due to impaired systolic LV function. The antiarrhythmic agent amiodarone, and, to a lesser
extent dronedarone, also slow the ventricular response to AF, but the latter is contraindicated in patients with decompensated heart failure.
8,9
In
general, AV-nodal blocking drugs should be avoided in patients with preexcitation due to the Wolff–Parkinson–White syndrome, because of the
235
Atrial Fibrillation and Flutter
risk that facilitating rapid conduction along an accessory pathway could
lead to ventricular fibrillation.
Stroke Risk Assessment
Certain clinical risk factors are more pertinent than the pattern of AF
(paroxysmal, persistent, or permanent) in stratifying stroke risk. All
patients with AF should be evaluated for risk factors associated with
thromboembolism and candidacy for long-term anticoagulant therapy.
Among several models developed to estimate the risk of thromboembolism in patients with AF or atrial flutter, the most widely used is the
CHADS
2
score, which assigns points as follows:
• History of heart failure or reduced LVEF: 1 point
• Hypertension: 1 point
• Age >75 years: 1 point
• Diabetes: 1 point
• History of stroke, TIA, or systemic embolism 2 points
The CHADS
2
scoring system and other risk prediction tools were
developed at a time when warfarin was the sole oral anticoagulant available. The approximate prevalence and stroke rates without anticoagulation associated with various CHADS
2
risk categories are shown in
Table 1; current recommendations for antithrombotic therapy issued by
several North American professional societies are presented in Table 2. As
new oral anticoagulants are introduced that carry a lower risk of intracerebral hemorrhage, the balance of risk and benefit may shift, such that
many patients who in the past might be treated with aspirin, including
those in the moderate-risk strata, may benefit from anticoagulant therapy.
This is an area of future research, and new risk stratification models are
likely to arise.
There is less consensus about risk factors for bleeding during antico-
agulation than about stroke risk stratification, but several schemes have
236
K. Bhasin and J. L. Halperin
been developed. For patients at high risk of thromboembolism who are
unable to sustain chronic anticoagulation, left atrial appendage occlusion
devices are under investigation, but the safety, efficacy, and indications
for these devices have not been clearly established.
16
237
Atrial Fibrillation and Flutter
Table 1. The CHADS2 Stroke Risk Score for Patients with
Nonvalvular Atrial Fibrillation
Score Prevalence [%]
Congestive Heart Failure 1 32
Hypertension 1 65
Age greater than 75 years 1 23
Diabetes 1 18
Stroke 2 10
Moderate to High Risk ≥2 50–60
Low Risk 0–1 40–50
[Adapted from: VanWalraven C et al. (2003) Arch Intern Med 163: 936.]
*
Nieuwlaat R et al. (2006) EuroHeart survey, Eur Heart J (e-published).
Table 2. Summary of Recommendations for Antithrombotic
Therapy for Prevention of Stroke and Systemic Embolism in the
Guidelines Published by the American College of Cardiology,
American Heart Association and European Society of Cardiology
Risk Category Recommended Therapy
No risk factors
Aspirin, 81–325 mg qd
CHADS
2
= 0
Aspirin, 81–325 mg/d or
One moderate risk factor Warfarin
CHADS
2
= 1 (INR 2.0–3.0, target 2.5)
Any high risk factor or
>1 moderate risk factor Warfarin
CHADS
2
≥2 (INR 2.0–3.0, target 2.5)
or Mitral stenosis
Prosthetic valve Warfarin
(INR 2.5–3.5, target 3.0)
[Fuster V et al. (2006) J Am Coll Cardiol 48: 854–906.] The European guidelines
were modified in 2010.
Antithrombotic Therapy
Although anticoagulation is more effective than antiplatelet therapy with
aspirin across all risk strata, patients at very low risk of stroke may not
gain sufficient benefit to warrant the inconvenience and risk of bleeding
associated with warfarin. The combination of aspirin and clopidogrel is
less effective than warfarin and is associated with greater risk of bleeding
than aspirin, but was more effective than aspirin alone in a study of
patients who were unwilling or considered ineligible to take a vitamin K
antagonist.
15
The selection of antithrombotic therapy to employ is indi-
vidualized based on age and other risk factors.
The most extensively studied anticoagulant is the vitamin K antagonist warfarin, which in clinical trials yielded, on average, a 68% reduction
in the risk of stroke compared to a placebo or no treatment.
10
Unfortunately, despite this dramatic benefit, approximately 36%–47% of
candidates for anticoagulation do not receive warfarin therapy.
11–13
The
relatively low rate of use is likely multifactorial. Beyond concerns over
hemorrhage, warfarin interacts with multiple foods and drugs, requires
frequent coagulation monitoring, and often results in anticoagulation outside the target range of intensity.
The need for a safe, effective, and convenient oral anticoagulant has
long been recognized and the key targets identified for study have been
coagulation factors IIa (thrombin) and Xa. The first of the novel oral anticoagulants to receive FDA approval was dabigatran etexilate, a prodrug
that is activated after ingestion to directly inhibit thrombin. In the open
label RE-LY trial of patients with nonvalvular AF, dabigatran etexilate,
150 mg twice daily, appeared superior and a lower dose of 110 mg twice
daily was noninferior to warfarin for prevention of stroke and systemic
embolism. The higher dose of dabigatran was not inferior to warfarin in
terms of major bleeding, and the most-feared complication of anticoagulant therapy, intracerebral hemorrhage, occurred less often with dabigatran
than with warfarin.
14
The FDA approved dabigatran etexilate, 150 mg
twice daily, for patients with AF who have one or more stroke risk factors
and adequate renal function (creatinine clearance >30 ml/min); a lower
238
K. Bhasin and J. L. Halperin
dose of 75 mg twice daily was approved for patients with impaired renal
function (15–30 ml/min) based on pharmacokinetic models, but this dose
regimen has not been clinically evaluated; the dose of 110 mg twice daily
has not been approved for use in the U.S. Approximately 10% of patients
receiving dabigatran experienced dyspepsia, and rates of colonic bleeding
were higher with dabigatran than with warfarin in the RE-LY trial.
Rivaroxaban was the first oral direct factor Xa inhibitor to garner FDA
approval for clinical use. In the ROCKET AF trial, rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism in
patients with non-valvular atrial fibrilllation. While there was no significant difference in overall rates of major bleeding with rivaroxaban as compared with warfarin, the factor Xa inhibitor was associated with less
intracranial and fatal hemorrhage.
17
The FDA approved rivaroxaben in a
dose of 20 mg once daily for patients with creatinine clearance greater than
50 mL/min. For those with moderately impaired renal function (creatinine
clearance between 15 and 49 mL/min), a lower dose of 15 mg once daily
is available. Asubsequent trial evaluating the factor Xa inhibitor, apixaban,
also demonstrated benefit as compared with warfarin and another involving edoxaban is in progress. These agents may also become available as
therapeutic alternatives to warfarin.
Rhythm Control
Given the potential toxicity of antiarrhythmic drugs, efforts to restore and
maintain sinus rhythm are typically reserved for patients with AF of recent
onset (< 1 year), hemodynamic instability, or persistent symptoms despite
adequate rate control. There are two components to the strategy of rhythm
control: cardioversion and maintenance of sinus rhythm.
Cardioversion
Restoration of sinus rhythm can be accomplished by either direct current
cardioversion (DCCV) or administration of pharmacological agents. The
former involves delivery of an R-wave-synchronous biphasic electrical
239
Atrial Fibrillation and Flutter
shock (usually 100–200 J) while the patient is sedated. DCCV is relatively
safe and initial success exceeds 90%; sustained sinus arrest or sinus
bradycardia follows < 1% of procedures.
18
The Vaughan–Williams class IC drugs (flecainide and propafenone)
block sodium channels and are effective in restoring sinus rhythm,
increasing the success of DCCV, and preventing early recurrence of AF.
These agents carry potential proarrhythmic toxicity, leading to torsades de
pointes ventricular tachycardia and ventricular fibrillation in patients with
ischemic heart disease, left ventricular hypertrophy, or heart failure. In
addition, an initial vagolytic effect may accelerate the ventricular
response to AF, requiring concurrent treatment with AV-nodal blocking
agents. The class III antiarrhythmic drugs ibutilide and dofetilide, which
inhibit potassium channels, can be used in patients with ischemic heart
disease or heart failure, but also possess proarrhythmic potential requiring
in-hospital initiation and close monitoring of the QTc interval.
18
Amiodarone is effective and relatively free of proarrhythmic toxicity, but
initiation of treatment is time-consuming and myriad extracardiac side
effects limit its long-term use.
Regardless of the method of cardioversion, antithrombotic therapy is
necessary for reducing the risk of stroke and systemic embolism associated with restoration of organized atrial mechanical activity. When possible, patients with AF for longer than 48 hr should be anticoagulated (INR
>2) for at least 3 weeks prior to cardioversion. When earlier cardioversion
is indicated, TEE should be performed to exclude a thrombus in the LAA.
Since termination of AF may be followed by an uncertain period of “stunning” (atrial mechanical arrest), anticoagulation should be in effect at the
time of cardioversion and continued for at least 3–4 weeks afterward and
longer for patients with risk factors for thromboembolism because of the
possibility of recurrent AF with or without symptoms.
19
Maintenance of sinus rhythm
Long-term antiarrhythmic drug therapy is not indicated after cardioversion for most patients with a first-detected episode of AF. For those
240
K. Bhasin and J. L. Halperin
241
Atrial Fibrillation and Flutter
Fig. 1. Antiarrhythmic therapy for maintenance of sinus rhythm in patients with paroxysmal or persistent atrial fibrillation.
[Adapted from: Fuster V et al. (2006) J Am Coll Cardiol 48: 854–906.]
Note: Drugs are listed alphabetically rather than in order of preference or efficacy; catheter
ablation may be an appropriate initial choice for carefully selected, very symptomatic
patients.
with symptomatic recurrent AF, however, selection of antiarrhythmic
medication is based on the pattern of AF and comorbid conditions, as
summarized in Fig. 1. The role of catheter ablation, in which the ostia
of the pulmonary veins are electrically isolated from the left atrium, has
not been fully established. The method appears generally more effective than antiarrhythmic drug therapy, but is associated with a risk of
major complications, including thromboembolism, perforation leading
to hemopericardium or tamponade, and esophageal injury. It is usually
reserved for otherwise healthy patients with little associated structural
heart disease in whom disabling symptoms of AF have not responded
sufficiently to one or more antiarrhythmic drugs, but may be an appropriate initial strategy in carefully selected patients who are very symptomatic of the arrhythmia when drug therapy is considered a less
desirable option (Table 3).
3,20
Ablation of typical atrial flutter is more
Atrial Fibrillation
(Paroxysmal or Persistent)
No (or minimal)
Amiodarone
Dofetilide
heart disease
Dronedarone
Flecainide
Propafenone
Sotalol
Catheter
ablation
Amiodarone
Dofetilide
Substantial LVH
No Yes
Dronedarone
Flecainide
Propafenone
Sotalol
Catheter
ablation
Dronedarone
Amiodarone
Catheter
ablation
Coronary artery
Dronedarone
Amiodarone
disease
Dofetilide
Sotalol
Catheter
ablation
Heart failureHypertension
Amiodarone
Dofetilide
Catheter
ablation
straightforward and is associated with less risk, in part because
transseptal catheterization is not required.
Future Trends
The population with AF is expanding rapidly as patients live longer with
more advanced heart disease and this will continue unless more effective
prophylactic measures are developed. Stroke is the most pressing concern
but new drugs and devices promise to expand treatment more broadly
across the population at risk. More effective drugs, procedures, and
devices are available but their relative safety and efficacy may differ for
defined patient subgroups and comparative cost-effectiveness analyses
are in an early stage of development.
References
1. Go AS, Heyleck EM, Phillips KA, et al. (2001) Prevalence of
diagnosed atrial fibrillation in adults: National implications for
242
K. Bhasin and J. L. Halperin
Table 3. Patient Selection for Catheter-based Ablation of Atrial Fibrillation
(Courtesy of Dr. Hugh Calkins.)
Better Candidate Less Optimal Candidate
Variable
Symptoms Highly symptomatic Minimally symptomatic
Class I and III drugs failed
≥10
AF type Paroxysmal Long-standing persistant
Age Younger (<70 years) Older (
≥70 years)
LA size Smaller (<5.0cm) Larger (
≥5.0 cm)
Ejection fraction Normal Reduced
Congestive heart failure No Yes
Other cardiac disease No Yes
Pulmonary disease No Yes
Sleep apnea No Yes
Obesity No Yes
Prior stroke/TIA No Yes
rhythm management and stroke prevention: The Anticoagulation
and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285:
2370.
2. Miyasaka Y, Barnes ME, Gersh BJ, et al. (2006) Secular trends in
incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to
2000, and implications on the projections for future prevalence.
Circulation 114: 119.
3. Fuster V, Ryden LE, Cannom DS, et al. (2006) ACC/AHA/ESC 2006
guidelines for the management of patients with atrial fibrillation: Areport
of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines and the European Society of Cardiology
Committee for Practice Guidelines (Writing Committee to Revise the
2001 Guidelines for the Management of Patients with Atrial Fibrillation):
Developed in collaboration with the European Heart Rhythm Association
and the Heart Rhythm Society. Circulation 114: 257.
4. De Denus S, Sanoski CA, Carlsson J, et al. (2005) Rate versus rhythm
control in patients with atrial fibrillation: Ameta-analysis. Arch Intern
Med 165: 258.
5. Calkins H, Brugada J, Packer DL, et al. (2007) HRS/EHRA/ECAS
expert consensus statement on catheter and surgical ablation of atrial
fibrillation: Recommendations for personnel, policy, procedure and
follow-up. Areport of the Heart Rhythm Society (HRS) Task Force on
catheter and surgical ablation of atrial fibrillation. Heart Rhythm 4:
816.
6. Van Gelder IC, Hessel F, Groenveld MD, et al. (2010) Lenient versus
strict rate control in patients with atrial fibrillation. N Engl J Med 362:
1363.
7. Torp-Pederson C, Poole-Wilson PA, Swedberg K, et al. (2005) Effects
of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure: COMET. Am Heart J 149:
371.
8. Kober L, Torp-Pederson C, McMurray JJV, et al. (2008) Increased
mortality after dronedarone therapy for severe heart failure. N Engl J
Med 358: 2678.
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Atrial Fibrillation and Flutter